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Multiprong strategy makes clinical trials less White
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
AT ASCO 2023
CBSM phone app eases anxiety, depression in cancer patients
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
AT ASCO 2023
T-DXd active in many solid tumors; ‘shift in thinking’
CHICAGO – Trastuzumab deruxtecan (T-DXd) (Enhertu) already has proven efficacy against HER2-expressing metastatic breast, gastroesophageal, and lung cancers.
including malignancies of the cervix, endometrium, ovaries, bladder, and other sites.
The findings come from the ongoing DESTINY-PanTumor02 trial. Among 267 patients with solid tumors at various organ sites, the investigator-assessed objective response rate among all patients was 37.1%, and ranged from as high as 57.5% for patients with endometrial cancers to as low as 4% for patients with pancreatic cancer, reported Funda Meric-Bernstam, MD, from the University of Texas MD Anderson Cancer Center, Houston.
For patients with tumors that had HER2 immunohistochemistry (IHC) scores of 3+, the highest level of HER2 expression, the overall response rate was 61.3%..
The responses were also durable, with a median duration of 11.8 months among all patients and 22.1 months among patients with IHC 3+ scores.
“Our data to date showed that T-DXd had clinically meaningful activity across a variety of tumor types,” she said in a briefing held prior to her presentation of the data at the annual meeting of the American Society of Clinical Oncology.
“HER2 expression has been around a long time. We think about this all the time in breast cancer and drugs are approved there, but HER2 is expressed in other tumors as well, and that really represents an unmet need, because we have limited options in this situation” commented ASCO expert Bradley Alexander McGregor, MD, from the Dana-Farber Cancer Institute, Boston, an invited discussant at the briefing.
“Aside from pancreatic cancer we saw really, really encouraging results with no new safety signals, so while early I think this really exciting and represents a shift in how we think about cancer care,” he added.
After the presentation, invited discussant Kohei Shitara, MD, of National Cancer Center Hospital East, Kashiwa, Japan, said that he agrees with authors that T-DXd is a potential new treatment option for patients with HER2-expressing solid tumors, and that the evidence suggests the potential for further tumor-agnostic development of the agent.
He cautioned, however, that there is a lack of concordance between local and central assessment of HER2 IHC, and that quality assurance will be required to ensure that the HER2 status of solid tumors is accurately characterized.
At a press briefing, Dr. Meric-Bernstam was asked how she envisioned using T-DXd in therapy for various HER2-expressing tumors.
“I think the activity we’ve seen is quite compelling, and one hopes that eventually this will be a drug that’s accessible for patients that are HER2-expressing across tumor types. Clearly, the activity is very compelling in some of the diseases to think about doing studies for earlier lines,” she said.
“The data indicate that there is tumor-agnostic activity across the board,” she said, but noted that tumors with epithelial components such as ovarian and breast cancers appear to have the highest responses to T-DXd therapy.
Briefing moderator Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, asked Dr. McGregor whether, in the light of this new data, oncologists should test more patients for HER2 expression.
“We have some cancers where we know HER2 expression is there. I think the good thing about HER2 testing is that it’s an IHC test, so this is something that can be easily done in local pathology [labs],” he said. As more evidence mounts of potential benefit of T-DXd in HER2 expressing tumors, clinicians will need to consider more routine HER2 testing.
A rendezvous with DESTINY
The DESTINY-PanTumor02 trial is a phase 2, open-label, multicenter study looking at T-DXd in patients with advanced solid tumors who are not eligible for therapy with curative intent.
All patients had disease progression after at least two prior lines of therapy, and had tumors with HER2 expression of IHC 3+ or 2+ either by local or central testing. Patients were allowed to have previously received HER2-targeting therapy. Patients also had to have good performance status (Eastern Cooperative Oncology Group/World Health Organization performance status 0 or 1).
The investigators planned to enroll 40 patients in each cohort, including patients with cervical, endometrial, ovarian, biliary tract, pancreatic, or bladder cancers, as well those with other tumors expressing HER2 who were not included in the other cohorts.
Under the protocol, cohorts in which none of the first 15 patients had objective responses would be closed, as happened with the pancreatic cancer cohort.
At a median follow-up of 9.7 months, an objective response was seen in 99 patients out of the 267 in the entire study population (ORR, 37.1%). This ORR consisted of 15 complete responses and 84 partial responses. An additional 123 patients had stable disease.
An analysis of ORR by HER2 expression showed that IHC 3+ expressing tumors had rates ranging from 84.6% in endometrial cancers, 75% in cervical cancer, 63.6% in ovarian cancers, and 56.3% in bladder cancers, down to zero in IHC 3+ expressing pancreatic cancer.
The T-DXd safety profile was consistent with that seen in other clinical trials, with most common adverse events being nausea, fatigue, neutropenia, anemia, diarrhea, and thrombocytopenia. There were 20 cases of interstitial lung disease, one of which was fatal.
The trial is ongoing, and investigators plan to report overall survival and progression-free survival results with additional follow-up.
DESTINY-PanTumor02 is funded by Daiichi Sankyo. Dr. Meric-Bernstam disclosed a consulting/advisory role with multiple pharmaceutical companies, research funding to her institution from Daiichi Sankyo and others, and travel expenses from ESMO and EORTC. Dr. McGregor disclosed a consulting/advisory role and institutional research funding with multiple companies, not including the study’s funder. Dr. Gralow disclosed a consulting or advisory role with Genentech and Roche.
A version of this article first appeared on Medscape.com.
CHICAGO – Trastuzumab deruxtecan (T-DXd) (Enhertu) already has proven efficacy against HER2-expressing metastatic breast, gastroesophageal, and lung cancers.
including malignancies of the cervix, endometrium, ovaries, bladder, and other sites.
The findings come from the ongoing DESTINY-PanTumor02 trial. Among 267 patients with solid tumors at various organ sites, the investigator-assessed objective response rate among all patients was 37.1%, and ranged from as high as 57.5% for patients with endometrial cancers to as low as 4% for patients with pancreatic cancer, reported Funda Meric-Bernstam, MD, from the University of Texas MD Anderson Cancer Center, Houston.
For patients with tumors that had HER2 immunohistochemistry (IHC) scores of 3+, the highest level of HER2 expression, the overall response rate was 61.3%..
The responses were also durable, with a median duration of 11.8 months among all patients and 22.1 months among patients with IHC 3+ scores.
“Our data to date showed that T-DXd had clinically meaningful activity across a variety of tumor types,” she said in a briefing held prior to her presentation of the data at the annual meeting of the American Society of Clinical Oncology.
“HER2 expression has been around a long time. We think about this all the time in breast cancer and drugs are approved there, but HER2 is expressed in other tumors as well, and that really represents an unmet need, because we have limited options in this situation” commented ASCO expert Bradley Alexander McGregor, MD, from the Dana-Farber Cancer Institute, Boston, an invited discussant at the briefing.
“Aside from pancreatic cancer we saw really, really encouraging results with no new safety signals, so while early I think this really exciting and represents a shift in how we think about cancer care,” he added.
After the presentation, invited discussant Kohei Shitara, MD, of National Cancer Center Hospital East, Kashiwa, Japan, said that he agrees with authors that T-DXd is a potential new treatment option for patients with HER2-expressing solid tumors, and that the evidence suggests the potential for further tumor-agnostic development of the agent.
He cautioned, however, that there is a lack of concordance between local and central assessment of HER2 IHC, and that quality assurance will be required to ensure that the HER2 status of solid tumors is accurately characterized.
At a press briefing, Dr. Meric-Bernstam was asked how she envisioned using T-DXd in therapy for various HER2-expressing tumors.
“I think the activity we’ve seen is quite compelling, and one hopes that eventually this will be a drug that’s accessible for patients that are HER2-expressing across tumor types. Clearly, the activity is very compelling in some of the diseases to think about doing studies for earlier lines,” she said.
“The data indicate that there is tumor-agnostic activity across the board,” she said, but noted that tumors with epithelial components such as ovarian and breast cancers appear to have the highest responses to T-DXd therapy.
Briefing moderator Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, asked Dr. McGregor whether, in the light of this new data, oncologists should test more patients for HER2 expression.
“We have some cancers where we know HER2 expression is there. I think the good thing about HER2 testing is that it’s an IHC test, so this is something that can be easily done in local pathology [labs],” he said. As more evidence mounts of potential benefit of T-DXd in HER2 expressing tumors, clinicians will need to consider more routine HER2 testing.
A rendezvous with DESTINY
The DESTINY-PanTumor02 trial is a phase 2, open-label, multicenter study looking at T-DXd in patients with advanced solid tumors who are not eligible for therapy with curative intent.
All patients had disease progression after at least two prior lines of therapy, and had tumors with HER2 expression of IHC 3+ or 2+ either by local or central testing. Patients were allowed to have previously received HER2-targeting therapy. Patients also had to have good performance status (Eastern Cooperative Oncology Group/World Health Organization performance status 0 or 1).
The investigators planned to enroll 40 patients in each cohort, including patients with cervical, endometrial, ovarian, biliary tract, pancreatic, or bladder cancers, as well those with other tumors expressing HER2 who were not included in the other cohorts.
Under the protocol, cohorts in which none of the first 15 patients had objective responses would be closed, as happened with the pancreatic cancer cohort.
At a median follow-up of 9.7 months, an objective response was seen in 99 patients out of the 267 in the entire study population (ORR, 37.1%). This ORR consisted of 15 complete responses and 84 partial responses. An additional 123 patients had stable disease.
An analysis of ORR by HER2 expression showed that IHC 3+ expressing tumors had rates ranging from 84.6% in endometrial cancers, 75% in cervical cancer, 63.6% in ovarian cancers, and 56.3% in bladder cancers, down to zero in IHC 3+ expressing pancreatic cancer.
The T-DXd safety profile was consistent with that seen in other clinical trials, with most common adverse events being nausea, fatigue, neutropenia, anemia, diarrhea, and thrombocytopenia. There were 20 cases of interstitial lung disease, one of which was fatal.
The trial is ongoing, and investigators plan to report overall survival and progression-free survival results with additional follow-up.
DESTINY-PanTumor02 is funded by Daiichi Sankyo. Dr. Meric-Bernstam disclosed a consulting/advisory role with multiple pharmaceutical companies, research funding to her institution from Daiichi Sankyo and others, and travel expenses from ESMO and EORTC. Dr. McGregor disclosed a consulting/advisory role and institutional research funding with multiple companies, not including the study’s funder. Dr. Gralow disclosed a consulting or advisory role with Genentech and Roche.
A version of this article first appeared on Medscape.com.
CHICAGO – Trastuzumab deruxtecan (T-DXd) (Enhertu) already has proven efficacy against HER2-expressing metastatic breast, gastroesophageal, and lung cancers.
including malignancies of the cervix, endometrium, ovaries, bladder, and other sites.
The findings come from the ongoing DESTINY-PanTumor02 trial. Among 267 patients with solid tumors at various organ sites, the investigator-assessed objective response rate among all patients was 37.1%, and ranged from as high as 57.5% for patients with endometrial cancers to as low as 4% for patients with pancreatic cancer, reported Funda Meric-Bernstam, MD, from the University of Texas MD Anderson Cancer Center, Houston.
For patients with tumors that had HER2 immunohistochemistry (IHC) scores of 3+, the highest level of HER2 expression, the overall response rate was 61.3%..
The responses were also durable, with a median duration of 11.8 months among all patients and 22.1 months among patients with IHC 3+ scores.
“Our data to date showed that T-DXd had clinically meaningful activity across a variety of tumor types,” she said in a briefing held prior to her presentation of the data at the annual meeting of the American Society of Clinical Oncology.
“HER2 expression has been around a long time. We think about this all the time in breast cancer and drugs are approved there, but HER2 is expressed in other tumors as well, and that really represents an unmet need, because we have limited options in this situation” commented ASCO expert Bradley Alexander McGregor, MD, from the Dana-Farber Cancer Institute, Boston, an invited discussant at the briefing.
“Aside from pancreatic cancer we saw really, really encouraging results with no new safety signals, so while early I think this really exciting and represents a shift in how we think about cancer care,” he added.
After the presentation, invited discussant Kohei Shitara, MD, of National Cancer Center Hospital East, Kashiwa, Japan, said that he agrees with authors that T-DXd is a potential new treatment option for patients with HER2-expressing solid tumors, and that the evidence suggests the potential for further tumor-agnostic development of the agent.
He cautioned, however, that there is a lack of concordance between local and central assessment of HER2 IHC, and that quality assurance will be required to ensure that the HER2 status of solid tumors is accurately characterized.
At a press briefing, Dr. Meric-Bernstam was asked how she envisioned using T-DXd in therapy for various HER2-expressing tumors.
“I think the activity we’ve seen is quite compelling, and one hopes that eventually this will be a drug that’s accessible for patients that are HER2-expressing across tumor types. Clearly, the activity is very compelling in some of the diseases to think about doing studies for earlier lines,” she said.
“The data indicate that there is tumor-agnostic activity across the board,” she said, but noted that tumors with epithelial components such as ovarian and breast cancers appear to have the highest responses to T-DXd therapy.
Briefing moderator Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, asked Dr. McGregor whether, in the light of this new data, oncologists should test more patients for HER2 expression.
“We have some cancers where we know HER2 expression is there. I think the good thing about HER2 testing is that it’s an IHC test, so this is something that can be easily done in local pathology [labs],” he said. As more evidence mounts of potential benefit of T-DXd in HER2 expressing tumors, clinicians will need to consider more routine HER2 testing.
A rendezvous with DESTINY
The DESTINY-PanTumor02 trial is a phase 2, open-label, multicenter study looking at T-DXd in patients with advanced solid tumors who are not eligible for therapy with curative intent.
All patients had disease progression after at least two prior lines of therapy, and had tumors with HER2 expression of IHC 3+ or 2+ either by local or central testing. Patients were allowed to have previously received HER2-targeting therapy. Patients also had to have good performance status (Eastern Cooperative Oncology Group/World Health Organization performance status 0 or 1).
The investigators planned to enroll 40 patients in each cohort, including patients with cervical, endometrial, ovarian, biliary tract, pancreatic, or bladder cancers, as well those with other tumors expressing HER2 who were not included in the other cohorts.
Under the protocol, cohorts in which none of the first 15 patients had objective responses would be closed, as happened with the pancreatic cancer cohort.
At a median follow-up of 9.7 months, an objective response was seen in 99 patients out of the 267 in the entire study population (ORR, 37.1%). This ORR consisted of 15 complete responses and 84 partial responses. An additional 123 patients had stable disease.
An analysis of ORR by HER2 expression showed that IHC 3+ expressing tumors had rates ranging from 84.6% in endometrial cancers, 75% in cervical cancer, 63.6% in ovarian cancers, and 56.3% in bladder cancers, down to zero in IHC 3+ expressing pancreatic cancer.
The T-DXd safety profile was consistent with that seen in other clinical trials, with most common adverse events being nausea, fatigue, neutropenia, anemia, diarrhea, and thrombocytopenia. There were 20 cases of interstitial lung disease, one of which was fatal.
The trial is ongoing, and investigators plan to report overall survival and progression-free survival results with additional follow-up.
DESTINY-PanTumor02 is funded by Daiichi Sankyo. Dr. Meric-Bernstam disclosed a consulting/advisory role with multiple pharmaceutical companies, research funding to her institution from Daiichi Sankyo and others, and travel expenses from ESMO and EORTC. Dr. McGregor disclosed a consulting/advisory role and institutional research funding with multiple companies, not including the study’s funder. Dr. Gralow disclosed a consulting or advisory role with Genentech and Roche.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
CAR T-cell benefit in lenalidomide-refractory myeloma
New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).
The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.
Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.
The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.
Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).
Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).
“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.
“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.
Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.
Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
Already approved for refractory myeloma
Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.
Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
CARTITUDE-4 details
For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.
Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.
As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.
Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.
Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.
The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.
The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).
The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.
Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.
The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.
Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).
Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).
“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.
“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.
Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.
Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
Already approved for refractory myeloma
Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.
Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
CARTITUDE-4 details
For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.
Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.
As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.
Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.
Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.
The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.
The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).
The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.
Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.
The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.
Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).
Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).
“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.
“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.
Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.
Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
Already approved for refractory myeloma
Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.
Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
CARTITUDE-4 details
For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.
Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.
As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.
Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.
Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.
The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.
The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
CMML: GM-CSF inhibitor lenzilumab shows early promise
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
FROM EHA 2023
Less therapy may suit older patients with breast cancer
CHICAGO – By definition, all clinical care is – or should be – patient-centered care, and that is especially true for older women with early stage breast cancer.
“Older women need to be informed of the benefits and risks of their treatment options, including the option of omitting a treatment,” said Mara Schonberg, MD, MPH, of the division of general medicine and primary care at Beth Israel Deaconess Medical Center in Boston.
“High quality shared decision-making considers a woman’s risk of recurrence, her tumor characteristics, her overall prognosis based on her general health, the lag-time to benefit from the treatment – how long will it take for this treatment to likely have an effect or a real chance of having any benefit for her – and her values and preferences,” she explained. Dr. Schonberg was speaking at a session on the management of care for older women with breast cancer held during the recent American Society of Clinical Oncology (ASCO) annual meeting.
, Dr. Schonberg said.
For example, patients may need to choose between mastectomy or breast conserving surgery (BCS), whether to have radiotherapy after BCS, what type of radiotherapy (e.g., whole breast, partial breast, accelerated partial breast irradiation, boost dose) to have, whether to undergo a lymph node biopsy, and whether to opt for primary endocrine therapy instead of surgery or radiation.
“It is really important that we think about all these decisions that older women face in their preference-sensitive decisions and that we include them in the decision-making, probably even starting at the time of mammography,” Dr. Schonberg said.
Decision-making partnership
Doctor–patient shared decision making improves patient care by helping the patients understand the best available evidence on the risks and benefits of specific choices and their alternatives, Dr. Schonberg said. Discussing and considering all the available options allows the doctor and patient to arrive together at an informed decision based on the individual patient’s needs and preferences, she emphasized.
“It’s particularly useful when there are multiple treatment options, when there’s uncertainty regarding the evidence or uncertainty regarding which patients may benefit or on the outcome, when there are both treatment advantages and disadvantages that patients must weigh, and when the decision is high impact, like for breast cancer treatment,” she said.
Shared decision-making can be complicated by barriers of time, how care is organized, lack of clinician training in patient-centered communication, and mistaken assumptions on the part of clinicians about a particular patient’s preferences or willingness to participate in the process.
Dr. Schonberg and colleagues created the website ePrognosis to consolidate prognostic indices designed to aid clinical decision-making for older adults who do not have a dominant terminal diagnosis. The site contains links to prognostic calculators, information about time to benefit for various cancer screening programs based on life expectancy, and helpful information about communicating information about prognosis, risks, and benefits to patients.
De-escalating surgery
Also at the session, Jennifer Tseng, MD, medical director of breast surgery at City of Hope Orange County Cancer Center, Irvine, Calif., discussed de-escalation of locoregional therapy. For some patients, this may mean skipping surgery or radiation.
“How do we de-escalate the extent of surgery, the extent of morbidity that we are imparting on our patients with surgery but still maximizing and preserving oncological outcomes?” she asked.
Currently more than 30% of new breast cancer diagnoses are in women age 70 and older, and estrogen receptor positive, HER2-negative disease is the majority biomarker profile.
At present, more than 70% of women with breast cancer in this older population will receive axillary surgery and/or radiation.
But for many patients with early, node-negative breast cancers with favorable tumor characteristics, less extensive surgery may be an appropriate option, especially for patients who have other significant comorbidities, Dr. Tseng said.
“Just at baseline, we know that mastectomy is a harder operation, it’s a harder recovery. You may be incorporating additional surgery such as reconstructive surgery, so breast-conserving surgery is always considered less invasive, less morbid,” she said.
“Do we absolutely have to do a mastectomy for a patient who has a second episode of cancer in the same breast? The answer is no,” she said, adding that omitting axillary surgery in early-stage disease may also be safe for some older patients.
De-escalating radiotherapy
Options for de-escalating radiation therapy include shortening the course of treatment with hypofractionation or ultra hypofractionation, reduction of treatment volumes with partial breast radiation, reducing radiation dose to normal tissues, or even in appropriate cases eliminating radiation entirely, Dr. Tseng said.
“My radiation oncologist turned to me and said, ‘This patient is now eligible for 3 days [or radiation] based on the latest trial we have open at City of Hope.’ I was like, wow, we went from 6 weeks to 3 days of radiation, but that is in the appropriate patient population with those early stage, really more favorable tumor characteristics,” she said.
Moving forward, the debate in radiation oncology is likely to focus on the option of ultra hypofractionation vs no radiation, she added.
Regarding reducing radiation volume, Dr. Tseng noted that most in-breast tumor recurrences happen within 1 cm of the original tumor bed, and partial breast irradiation targets the tumor bed with a 1- to 2-cm margin and provides excellent clinical outcomes with minimal adverse events, allowing for rapid recovery.
Deep inspiration breath holds and prone-positioning of patients with left-side tumors during beam delivery can also significantly decrease the dose to normal tissues, an especially important consideration for patients with cardiopulmonary comorbidities, she said.
Radiation may also be deferred in many older patients who may benefit from endocrine therapy alone and in those who have a very early stage and less aggressive tumor type.
Systemic therapy in the older patient
Etienne GC Brain, PhD, of the department of medical oncology at the Curie Institute in Paris and Saint-Cloud, France, reviewed evidence regarding systemic therapy in older patients with high-risk breast cancers.
For patients with triple-negative breast cancer pathologic stage T1b or greater he usually advises adjuvant chemotherapy with the option of neoadjuvant chemotherapy if breast-conserving surgery is a goal; for patients with HER2-positive disease, he advises 1 year of therapy with an anti-HER2 agent.
Shorter HER2 regimens may be possible for older patients, and frail older adults may have good outcomes with HER2 therapy alone, as shown recently by Japanese investigators, Dr. Brain noted.
“For lumimal disease, endocrine therapy remains the standard of treatment for me, and chemo, of course can be considered in higher risk, but the problem is we don’t know how to define this high risk, given the poor guidance provided by gene expression profiles,” he said.
For older patients, longer follow-up is needed to assess treatment benefit vs. life expectancy, Dr. Brain said, warning that the standard of care established in younger patients cannot be easily extrapolated to the care of older patients.
Dr. Schonberg disclosed authorship of review pages on preventive health for older adults for UpToDate. Dr. Tseng disclosed that she is a breast surgeon and that her discussion of radiation therapy may reflect personal bias. Dr. Brain disclosed honoraria from Lilly, Pfizer, and Seagen, consulting/advising for Daiichi Sankyo, AstraZeneca, Pfizer, and Sandoz-Novartis, and travel expenses from Pfizer.
A version of this article first appeared on Medscape.com.
CHICAGO – By definition, all clinical care is – or should be – patient-centered care, and that is especially true for older women with early stage breast cancer.
“Older women need to be informed of the benefits and risks of their treatment options, including the option of omitting a treatment,” said Mara Schonberg, MD, MPH, of the division of general medicine and primary care at Beth Israel Deaconess Medical Center in Boston.
“High quality shared decision-making considers a woman’s risk of recurrence, her tumor characteristics, her overall prognosis based on her general health, the lag-time to benefit from the treatment – how long will it take for this treatment to likely have an effect or a real chance of having any benefit for her – and her values and preferences,” she explained. Dr. Schonberg was speaking at a session on the management of care for older women with breast cancer held during the recent American Society of Clinical Oncology (ASCO) annual meeting.
, Dr. Schonberg said.
For example, patients may need to choose between mastectomy or breast conserving surgery (BCS), whether to have radiotherapy after BCS, what type of radiotherapy (e.g., whole breast, partial breast, accelerated partial breast irradiation, boost dose) to have, whether to undergo a lymph node biopsy, and whether to opt for primary endocrine therapy instead of surgery or radiation.
“It is really important that we think about all these decisions that older women face in their preference-sensitive decisions and that we include them in the decision-making, probably even starting at the time of mammography,” Dr. Schonberg said.
Decision-making partnership
Doctor–patient shared decision making improves patient care by helping the patients understand the best available evidence on the risks and benefits of specific choices and their alternatives, Dr. Schonberg said. Discussing and considering all the available options allows the doctor and patient to arrive together at an informed decision based on the individual patient’s needs and preferences, she emphasized.
“It’s particularly useful when there are multiple treatment options, when there’s uncertainty regarding the evidence or uncertainty regarding which patients may benefit or on the outcome, when there are both treatment advantages and disadvantages that patients must weigh, and when the decision is high impact, like for breast cancer treatment,” she said.
Shared decision-making can be complicated by barriers of time, how care is organized, lack of clinician training in patient-centered communication, and mistaken assumptions on the part of clinicians about a particular patient’s preferences or willingness to participate in the process.
Dr. Schonberg and colleagues created the website ePrognosis to consolidate prognostic indices designed to aid clinical decision-making for older adults who do not have a dominant terminal diagnosis. The site contains links to prognostic calculators, information about time to benefit for various cancer screening programs based on life expectancy, and helpful information about communicating information about prognosis, risks, and benefits to patients.
De-escalating surgery
Also at the session, Jennifer Tseng, MD, medical director of breast surgery at City of Hope Orange County Cancer Center, Irvine, Calif., discussed de-escalation of locoregional therapy. For some patients, this may mean skipping surgery or radiation.
“How do we de-escalate the extent of surgery, the extent of morbidity that we are imparting on our patients with surgery but still maximizing and preserving oncological outcomes?” she asked.
Currently more than 30% of new breast cancer diagnoses are in women age 70 and older, and estrogen receptor positive, HER2-negative disease is the majority biomarker profile.
At present, more than 70% of women with breast cancer in this older population will receive axillary surgery and/or radiation.
But for many patients with early, node-negative breast cancers with favorable tumor characteristics, less extensive surgery may be an appropriate option, especially for patients who have other significant comorbidities, Dr. Tseng said.
“Just at baseline, we know that mastectomy is a harder operation, it’s a harder recovery. You may be incorporating additional surgery such as reconstructive surgery, so breast-conserving surgery is always considered less invasive, less morbid,” she said.
“Do we absolutely have to do a mastectomy for a patient who has a second episode of cancer in the same breast? The answer is no,” she said, adding that omitting axillary surgery in early-stage disease may also be safe for some older patients.
De-escalating radiotherapy
Options for de-escalating radiation therapy include shortening the course of treatment with hypofractionation or ultra hypofractionation, reduction of treatment volumes with partial breast radiation, reducing radiation dose to normal tissues, or even in appropriate cases eliminating radiation entirely, Dr. Tseng said.
“My radiation oncologist turned to me and said, ‘This patient is now eligible for 3 days [or radiation] based on the latest trial we have open at City of Hope.’ I was like, wow, we went from 6 weeks to 3 days of radiation, but that is in the appropriate patient population with those early stage, really more favorable tumor characteristics,” she said.
Moving forward, the debate in radiation oncology is likely to focus on the option of ultra hypofractionation vs no radiation, she added.
Regarding reducing radiation volume, Dr. Tseng noted that most in-breast tumor recurrences happen within 1 cm of the original tumor bed, and partial breast irradiation targets the tumor bed with a 1- to 2-cm margin and provides excellent clinical outcomes with minimal adverse events, allowing for rapid recovery.
Deep inspiration breath holds and prone-positioning of patients with left-side tumors during beam delivery can also significantly decrease the dose to normal tissues, an especially important consideration for patients with cardiopulmonary comorbidities, she said.
Radiation may also be deferred in many older patients who may benefit from endocrine therapy alone and in those who have a very early stage and less aggressive tumor type.
Systemic therapy in the older patient
Etienne GC Brain, PhD, of the department of medical oncology at the Curie Institute in Paris and Saint-Cloud, France, reviewed evidence regarding systemic therapy in older patients with high-risk breast cancers.
For patients with triple-negative breast cancer pathologic stage T1b or greater he usually advises adjuvant chemotherapy with the option of neoadjuvant chemotherapy if breast-conserving surgery is a goal; for patients with HER2-positive disease, he advises 1 year of therapy with an anti-HER2 agent.
Shorter HER2 regimens may be possible for older patients, and frail older adults may have good outcomes with HER2 therapy alone, as shown recently by Japanese investigators, Dr. Brain noted.
“For lumimal disease, endocrine therapy remains the standard of treatment for me, and chemo, of course can be considered in higher risk, but the problem is we don’t know how to define this high risk, given the poor guidance provided by gene expression profiles,” he said.
For older patients, longer follow-up is needed to assess treatment benefit vs. life expectancy, Dr. Brain said, warning that the standard of care established in younger patients cannot be easily extrapolated to the care of older patients.
Dr. Schonberg disclosed authorship of review pages on preventive health for older adults for UpToDate. Dr. Tseng disclosed that she is a breast surgeon and that her discussion of radiation therapy may reflect personal bias. Dr. Brain disclosed honoraria from Lilly, Pfizer, and Seagen, consulting/advising for Daiichi Sankyo, AstraZeneca, Pfizer, and Sandoz-Novartis, and travel expenses from Pfizer.
A version of this article first appeared on Medscape.com.
CHICAGO – By definition, all clinical care is – or should be – patient-centered care, and that is especially true for older women with early stage breast cancer.
“Older women need to be informed of the benefits and risks of their treatment options, including the option of omitting a treatment,” said Mara Schonberg, MD, MPH, of the division of general medicine and primary care at Beth Israel Deaconess Medical Center in Boston.
“High quality shared decision-making considers a woman’s risk of recurrence, her tumor characteristics, her overall prognosis based on her general health, the lag-time to benefit from the treatment – how long will it take for this treatment to likely have an effect or a real chance of having any benefit for her – and her values and preferences,” she explained. Dr. Schonberg was speaking at a session on the management of care for older women with breast cancer held during the recent American Society of Clinical Oncology (ASCO) annual meeting.
, Dr. Schonberg said.
For example, patients may need to choose between mastectomy or breast conserving surgery (BCS), whether to have radiotherapy after BCS, what type of radiotherapy (e.g., whole breast, partial breast, accelerated partial breast irradiation, boost dose) to have, whether to undergo a lymph node biopsy, and whether to opt for primary endocrine therapy instead of surgery or radiation.
“It is really important that we think about all these decisions that older women face in their preference-sensitive decisions and that we include them in the decision-making, probably even starting at the time of mammography,” Dr. Schonberg said.
Decision-making partnership
Doctor–patient shared decision making improves patient care by helping the patients understand the best available evidence on the risks and benefits of specific choices and their alternatives, Dr. Schonberg said. Discussing and considering all the available options allows the doctor and patient to arrive together at an informed decision based on the individual patient’s needs and preferences, she emphasized.
“It’s particularly useful when there are multiple treatment options, when there’s uncertainty regarding the evidence or uncertainty regarding which patients may benefit or on the outcome, when there are both treatment advantages and disadvantages that patients must weigh, and when the decision is high impact, like for breast cancer treatment,” she said.
Shared decision-making can be complicated by barriers of time, how care is organized, lack of clinician training in patient-centered communication, and mistaken assumptions on the part of clinicians about a particular patient’s preferences or willingness to participate in the process.
Dr. Schonberg and colleagues created the website ePrognosis to consolidate prognostic indices designed to aid clinical decision-making for older adults who do not have a dominant terminal diagnosis. The site contains links to prognostic calculators, information about time to benefit for various cancer screening programs based on life expectancy, and helpful information about communicating information about prognosis, risks, and benefits to patients.
De-escalating surgery
Also at the session, Jennifer Tseng, MD, medical director of breast surgery at City of Hope Orange County Cancer Center, Irvine, Calif., discussed de-escalation of locoregional therapy. For some patients, this may mean skipping surgery or radiation.
“How do we de-escalate the extent of surgery, the extent of morbidity that we are imparting on our patients with surgery but still maximizing and preserving oncological outcomes?” she asked.
Currently more than 30% of new breast cancer diagnoses are in women age 70 and older, and estrogen receptor positive, HER2-negative disease is the majority biomarker profile.
At present, more than 70% of women with breast cancer in this older population will receive axillary surgery and/or radiation.
But for many patients with early, node-negative breast cancers with favorable tumor characteristics, less extensive surgery may be an appropriate option, especially for patients who have other significant comorbidities, Dr. Tseng said.
“Just at baseline, we know that mastectomy is a harder operation, it’s a harder recovery. You may be incorporating additional surgery such as reconstructive surgery, so breast-conserving surgery is always considered less invasive, less morbid,” she said.
“Do we absolutely have to do a mastectomy for a patient who has a second episode of cancer in the same breast? The answer is no,” she said, adding that omitting axillary surgery in early-stage disease may also be safe for some older patients.
De-escalating radiotherapy
Options for de-escalating radiation therapy include shortening the course of treatment with hypofractionation or ultra hypofractionation, reduction of treatment volumes with partial breast radiation, reducing radiation dose to normal tissues, or even in appropriate cases eliminating radiation entirely, Dr. Tseng said.
“My radiation oncologist turned to me and said, ‘This patient is now eligible for 3 days [or radiation] based on the latest trial we have open at City of Hope.’ I was like, wow, we went from 6 weeks to 3 days of radiation, but that is in the appropriate patient population with those early stage, really more favorable tumor characteristics,” she said.
Moving forward, the debate in radiation oncology is likely to focus on the option of ultra hypofractionation vs no radiation, she added.
Regarding reducing radiation volume, Dr. Tseng noted that most in-breast tumor recurrences happen within 1 cm of the original tumor bed, and partial breast irradiation targets the tumor bed with a 1- to 2-cm margin and provides excellent clinical outcomes with minimal adverse events, allowing for rapid recovery.
Deep inspiration breath holds and prone-positioning of patients with left-side tumors during beam delivery can also significantly decrease the dose to normal tissues, an especially important consideration for patients with cardiopulmonary comorbidities, she said.
Radiation may also be deferred in many older patients who may benefit from endocrine therapy alone and in those who have a very early stage and less aggressive tumor type.
Systemic therapy in the older patient
Etienne GC Brain, PhD, of the department of medical oncology at the Curie Institute in Paris and Saint-Cloud, France, reviewed evidence regarding systemic therapy in older patients with high-risk breast cancers.
For patients with triple-negative breast cancer pathologic stage T1b or greater he usually advises adjuvant chemotherapy with the option of neoadjuvant chemotherapy if breast-conserving surgery is a goal; for patients with HER2-positive disease, he advises 1 year of therapy with an anti-HER2 agent.
Shorter HER2 regimens may be possible for older patients, and frail older adults may have good outcomes with HER2 therapy alone, as shown recently by Japanese investigators, Dr. Brain noted.
“For lumimal disease, endocrine therapy remains the standard of treatment for me, and chemo, of course can be considered in higher risk, but the problem is we don’t know how to define this high risk, given the poor guidance provided by gene expression profiles,” he said.
For older patients, longer follow-up is needed to assess treatment benefit vs. life expectancy, Dr. Brain said, warning that the standard of care established in younger patients cannot be easily extrapolated to the care of older patients.
Dr. Schonberg disclosed authorship of review pages on preventive health for older adults for UpToDate. Dr. Tseng disclosed that she is a breast surgeon and that her discussion of radiation therapy may reflect personal bias. Dr. Brain disclosed honoraria from Lilly, Pfizer, and Seagen, consulting/advising for Daiichi Sankyo, AstraZeneca, Pfizer, and Sandoz-Novartis, and travel expenses from Pfizer.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Oral drug for brain tumor could change treatment landscape
say researchers reporting new results that could potentially change the treatment landscape.
The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.
Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.
The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).
Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.
The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.
Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.
The study was published online in the New England Journal of Medicine to coincide with the presentation.
“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.
“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.
“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
Brain-penetrating oral drug
Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.
Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.
Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.
Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
Study details
The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.
Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.
After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.
At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.
The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.
The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).
Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.
Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.
The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.
A version of this article first appeared on Medscape.com.
say researchers reporting new results that could potentially change the treatment landscape.
The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.
Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.
The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).
Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.
The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.
Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.
The study was published online in the New England Journal of Medicine to coincide with the presentation.
“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.
“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.
“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
Brain-penetrating oral drug
Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.
Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.
Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.
Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
Study details
The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.
Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.
After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.
At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.
The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.
The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).
Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.
Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.
The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.
A version of this article first appeared on Medscape.com.
say researchers reporting new results that could potentially change the treatment landscape.
The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.
Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.
The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).
Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.
The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.
Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.
The study was published online in the New England Journal of Medicine to coincide with the presentation.
“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.
“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.
“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
Brain-penetrating oral drug
Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.
Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.
Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.
Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
Study details
The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.
Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.
After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.
At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.
The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.
The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).
Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.
Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.
The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Up-front pembro plus chemo boost survival in cervical cancer
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
Ribociclib forestalls recurrence also in early breast cancer
The new results come from an interim analysis of the phase 3, randomized NATALEE trial, which is comparing maintenance therapy with the (CDK4/6 inhibitor ribociclib plus endocrine therapy with an aromatase inhibitor to endocrine therapy alone.
At a median follow-up of 27.7 months, the 3-year invasive disease–free survival (IDFS) rate was 90.4% for patients who received the combination, compared with 87.1% for patients who received endocrine therapy alone.
This difference translates into a 25% relative reduction in risk for recurrence with the addition of ribociclib, said principal investigator Dennis J. Slamon, MD, PhD, from the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
“The NATALEE results, in summary, do support this as a new treatment of choice available to physicians and patients for this broad population of patients with stage II or stage III hormone receptor–positive, HER2-negative disease in early breast cancer,” he said.
Dr. Slamon was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented
‘Early but impressive’
“Today, Dr. Slamon has shown us early but impressive data demonstrating a significant reduction in the risk of recurrence as defined by an improvement of invasive disease–free survival for patients with high-risk, node-positive and node-negative hormone receptor–positive, HER2-negative early breast cancer,” commented ASCO expert Rita Nanda, MD, director of the breast oncology program at the University of Chicago.
“We know that a substantial proportion of patients with early-stage hormone receptor–positive breast [cancer] can go on to recur,” Dr. Nanda continued. “These recurrences can be quite delayed, and for our patients with node-negative disease, to this point, we haven’t seen any improvements with the addition of a CDK4/6 inhibitor to endocrine therapy for early-stage breast cancer. Dr Slamon has also shown us that ribociclib in the context of the NATALEE trial is effective, it was well tolerated, and I do expect that these trial results will change practice.”
In a comment, Sylvia Adams, MD, a medical oncologist who specializes in breast cancer at the NYU Langone Perlmutter Cancer Center, New York, said she is comfortable with using a CDK4/6 inhibitor such as ribociclib or abemaciclib (Verzenio) in the adjuvant setting for patients with early, localized breast cancer.
She noted, however, that to date the absolute benefit of the combination over endocrine therapy alone has been modest, at 3.3%, but that the difference may be important to many patients who feel that they need to do everything they can to prevent disease recurrence.
“I’m really looking forward to the quality of life data, because it’s certainly known that any of these CDK4/6 inhibitors may add a bit of fatigue, and while there were no unexpected safety signals [in NATALEE], we know that there are some GI [gastrointestinal] effects with this therapy, as well as joint pain,” she said. “Joint pain is a little tricky, because the patients are also getting aromatase inhibitors, which can cause joint pain.”
In addition, premenopausal women in the study also received goserelin, an ovarian suppressor that triggers menopause, which is also associated with arthralgias, Dr. Adams said.
Dr. Adams and Dr. Nanda both noted that the addition of ribociclib to endocrine therapy increases the treatment burden for patients because it requires a commitment of at least 3 years and more frequent monitoring, especially in the first few months of therapy, compared with endocrine therapy alone.
Study details
The combination of ribociclib and standard of care endocrine therapy was the first to show an improvement in overall survival among women with metastatic HR+/HER2– breast cancer.
To see whether the combination could also benefit patients with early breast cancer, the investigators conducted NATALEE. They enrolled premenopausal and postmenopausal women and also men with HR+/HER2– breast cancer. Cases ranged from stage IIA (with either no nodal involvement with additional risk factors or with one to three involved axillary lymph nodes) to stage IIB-III disease, based on American Joint Committee on Cancer staging.
Patients who had previously received neoadjuvant or adjuvant endocrine therapy were accepted into the trial if the therapy had been started within 1 year of randomization.
The patients were stratified by age, menopausal status, disease stage, prior chemotherapy status, and geographic region. They were randomly assigned to receive either ribociclib 400 mg per day for 3 weeks, then were given 1 week off each cycle for 3 years plus endocrine therapy with either letrozole 2.5 mg/day or anastrozole 1 mg/day for at least 5 years, or to endocrine therapy alone. Men and premenopausal women also received goserelin.
Dr. Slamon noted that the 400-mg dose of ribociclib is lower than the recommended starting dose of 600 mg for metastatic disease. They chose the lower dose to allow longer duration of therapy, with a goal of achieving optimal disease suppression by driving tumor cells into irreversible senescence with less side effects.
A total of 2,549 patients were randomly assigned to receive the combination; 2,552 patients received endocrine therapy alone.
At the data cutoff on Jan. 11, 2023, after the prespecified minimum number of IDFS events had occurred, 189 patients in the ribociclib arm experienced recurrence, compared with 237 patients in the endocrine therapy–only arm.
As noted, 3-year IDFS rates were 90.4% with ribociclib and 87.1% with endocrine therapy alone, which translates to a hazard ratio of 0.748 in favor of the combination (P = .0014).
The benefit of ribociclib was generally consistent across subgroups, including node-negative patients, but there were too few patients in this subgroup for the differences to reach statistical significance, Dr. Slamon said.
Safety
The most commonly reported adverse event in the endocrine therapy–alone arm were joint pain and hot flashes
The most common adverse events with ribociclib included neutropenia and joint pain. Rates of gastrointestinal adverse events and fatigue, typical of CDK4/6 inhibitors, were relatively low in this study.
Dr. Slamon compared the rates of neutropenia with ribociclib in this trial to those in pooled data from the MONALEESA series of trials, in which ribociclib was delivered at a 600-mg dose. Grade 3 or 4 neutropenia occurred in 44% of patients in NATALEE, compared with 60% of patients in the MONALEESA trials.
In the ribociclib arm, 5.2% of patients experienced prolongation of the QT interval, compared with 1.2% of patients in the endocrine therapy–alone arm. No cases of torsades des pointes or problematic rhythm disturbances were observed, Dr. Slamon said.
“As frequently happens when we have these lovely, large, phase 3 registration trials but with some restriction in eligibility, when you get out to real-world practice, we don’t know what will happen in women who are on antiarrhythmics and if they’ll have a higher incidence of the QT elongation; they just weren’t included in the study. So it sounds like we’ll have to be paying attention to that,” commented briefing moderator Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO.
The study was funded by Novartis. Dr. Slamon has a leadership position with 1200 Pharma, Biomarin, and Torl Biotherapeutics, a consulting/advisory role for Novartis, and has received honoraria, research funding, and travel expenses from Novartis and others. Multiple coauthors reported financial relationships with Novartis and others. Dr. Nanda has had consulting/advisory roles with and has received institutional research funding from several companies, not including Novartis. Dr. Adams has participated on an advisory board for Cogent Biosciences and her institution has received research funding from various companies.
A version of this article first appeared on Medscape.com.
The new results come from an interim analysis of the phase 3, randomized NATALEE trial, which is comparing maintenance therapy with the (CDK4/6 inhibitor ribociclib plus endocrine therapy with an aromatase inhibitor to endocrine therapy alone.
At a median follow-up of 27.7 months, the 3-year invasive disease–free survival (IDFS) rate was 90.4% for patients who received the combination, compared with 87.1% for patients who received endocrine therapy alone.
This difference translates into a 25% relative reduction in risk for recurrence with the addition of ribociclib, said principal investigator Dennis J. Slamon, MD, PhD, from the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
“The NATALEE results, in summary, do support this as a new treatment of choice available to physicians and patients for this broad population of patients with stage II or stage III hormone receptor–positive, HER2-negative disease in early breast cancer,” he said.
Dr. Slamon was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented
‘Early but impressive’
“Today, Dr. Slamon has shown us early but impressive data demonstrating a significant reduction in the risk of recurrence as defined by an improvement of invasive disease–free survival for patients with high-risk, node-positive and node-negative hormone receptor–positive, HER2-negative early breast cancer,” commented ASCO expert Rita Nanda, MD, director of the breast oncology program at the University of Chicago.
“We know that a substantial proportion of patients with early-stage hormone receptor–positive breast [cancer] can go on to recur,” Dr. Nanda continued. “These recurrences can be quite delayed, and for our patients with node-negative disease, to this point, we haven’t seen any improvements with the addition of a CDK4/6 inhibitor to endocrine therapy for early-stage breast cancer. Dr Slamon has also shown us that ribociclib in the context of the NATALEE trial is effective, it was well tolerated, and I do expect that these trial results will change practice.”
In a comment, Sylvia Adams, MD, a medical oncologist who specializes in breast cancer at the NYU Langone Perlmutter Cancer Center, New York, said she is comfortable with using a CDK4/6 inhibitor such as ribociclib or abemaciclib (Verzenio) in the adjuvant setting for patients with early, localized breast cancer.
She noted, however, that to date the absolute benefit of the combination over endocrine therapy alone has been modest, at 3.3%, but that the difference may be important to many patients who feel that they need to do everything they can to prevent disease recurrence.
“I’m really looking forward to the quality of life data, because it’s certainly known that any of these CDK4/6 inhibitors may add a bit of fatigue, and while there were no unexpected safety signals [in NATALEE], we know that there are some GI [gastrointestinal] effects with this therapy, as well as joint pain,” she said. “Joint pain is a little tricky, because the patients are also getting aromatase inhibitors, which can cause joint pain.”
In addition, premenopausal women in the study also received goserelin, an ovarian suppressor that triggers menopause, which is also associated with arthralgias, Dr. Adams said.
Dr. Adams and Dr. Nanda both noted that the addition of ribociclib to endocrine therapy increases the treatment burden for patients because it requires a commitment of at least 3 years and more frequent monitoring, especially in the first few months of therapy, compared with endocrine therapy alone.
Study details
The combination of ribociclib and standard of care endocrine therapy was the first to show an improvement in overall survival among women with metastatic HR+/HER2– breast cancer.
To see whether the combination could also benefit patients with early breast cancer, the investigators conducted NATALEE. They enrolled premenopausal and postmenopausal women and also men with HR+/HER2– breast cancer. Cases ranged from stage IIA (with either no nodal involvement with additional risk factors or with one to three involved axillary lymph nodes) to stage IIB-III disease, based on American Joint Committee on Cancer staging.
Patients who had previously received neoadjuvant or adjuvant endocrine therapy were accepted into the trial if the therapy had been started within 1 year of randomization.
The patients were stratified by age, menopausal status, disease stage, prior chemotherapy status, and geographic region. They were randomly assigned to receive either ribociclib 400 mg per day for 3 weeks, then were given 1 week off each cycle for 3 years plus endocrine therapy with either letrozole 2.5 mg/day or anastrozole 1 mg/day for at least 5 years, or to endocrine therapy alone. Men and premenopausal women also received goserelin.
Dr. Slamon noted that the 400-mg dose of ribociclib is lower than the recommended starting dose of 600 mg for metastatic disease. They chose the lower dose to allow longer duration of therapy, with a goal of achieving optimal disease suppression by driving tumor cells into irreversible senescence with less side effects.
A total of 2,549 patients were randomly assigned to receive the combination; 2,552 patients received endocrine therapy alone.
At the data cutoff on Jan. 11, 2023, after the prespecified minimum number of IDFS events had occurred, 189 patients in the ribociclib arm experienced recurrence, compared with 237 patients in the endocrine therapy–only arm.
As noted, 3-year IDFS rates were 90.4% with ribociclib and 87.1% with endocrine therapy alone, which translates to a hazard ratio of 0.748 in favor of the combination (P = .0014).
The benefit of ribociclib was generally consistent across subgroups, including node-negative patients, but there were too few patients in this subgroup for the differences to reach statistical significance, Dr. Slamon said.
Safety
The most commonly reported adverse event in the endocrine therapy–alone arm were joint pain and hot flashes
The most common adverse events with ribociclib included neutropenia and joint pain. Rates of gastrointestinal adverse events and fatigue, typical of CDK4/6 inhibitors, were relatively low in this study.
Dr. Slamon compared the rates of neutropenia with ribociclib in this trial to those in pooled data from the MONALEESA series of trials, in which ribociclib was delivered at a 600-mg dose. Grade 3 or 4 neutropenia occurred in 44% of patients in NATALEE, compared with 60% of patients in the MONALEESA trials.
In the ribociclib arm, 5.2% of patients experienced prolongation of the QT interval, compared with 1.2% of patients in the endocrine therapy–alone arm. No cases of torsades des pointes or problematic rhythm disturbances were observed, Dr. Slamon said.
“As frequently happens when we have these lovely, large, phase 3 registration trials but with some restriction in eligibility, when you get out to real-world practice, we don’t know what will happen in women who are on antiarrhythmics and if they’ll have a higher incidence of the QT elongation; they just weren’t included in the study. So it sounds like we’ll have to be paying attention to that,” commented briefing moderator Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO.
The study was funded by Novartis. Dr. Slamon has a leadership position with 1200 Pharma, Biomarin, and Torl Biotherapeutics, a consulting/advisory role for Novartis, and has received honoraria, research funding, and travel expenses from Novartis and others. Multiple coauthors reported financial relationships with Novartis and others. Dr. Nanda has had consulting/advisory roles with and has received institutional research funding from several companies, not including Novartis. Dr. Adams has participated on an advisory board for Cogent Biosciences and her institution has received research funding from various companies.
A version of this article first appeared on Medscape.com.
The new results come from an interim analysis of the phase 3, randomized NATALEE trial, which is comparing maintenance therapy with the (CDK4/6 inhibitor ribociclib plus endocrine therapy with an aromatase inhibitor to endocrine therapy alone.
At a median follow-up of 27.7 months, the 3-year invasive disease–free survival (IDFS) rate was 90.4% for patients who received the combination, compared with 87.1% for patients who received endocrine therapy alone.
This difference translates into a 25% relative reduction in risk for recurrence with the addition of ribociclib, said principal investigator Dennis J. Slamon, MD, PhD, from the UCLA Jonsson Comprehensive Cancer Center, Los Angeles.
“The NATALEE results, in summary, do support this as a new treatment of choice available to physicians and patients for this broad population of patients with stage II or stage III hormone receptor–positive, HER2-negative disease in early breast cancer,” he said.
Dr. Slamon was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented
‘Early but impressive’
“Today, Dr. Slamon has shown us early but impressive data demonstrating a significant reduction in the risk of recurrence as defined by an improvement of invasive disease–free survival for patients with high-risk, node-positive and node-negative hormone receptor–positive, HER2-negative early breast cancer,” commented ASCO expert Rita Nanda, MD, director of the breast oncology program at the University of Chicago.
“We know that a substantial proportion of patients with early-stage hormone receptor–positive breast [cancer] can go on to recur,” Dr. Nanda continued. “These recurrences can be quite delayed, and for our patients with node-negative disease, to this point, we haven’t seen any improvements with the addition of a CDK4/6 inhibitor to endocrine therapy for early-stage breast cancer. Dr Slamon has also shown us that ribociclib in the context of the NATALEE trial is effective, it was well tolerated, and I do expect that these trial results will change practice.”
In a comment, Sylvia Adams, MD, a medical oncologist who specializes in breast cancer at the NYU Langone Perlmutter Cancer Center, New York, said she is comfortable with using a CDK4/6 inhibitor such as ribociclib or abemaciclib (Verzenio) in the adjuvant setting for patients with early, localized breast cancer.
She noted, however, that to date the absolute benefit of the combination over endocrine therapy alone has been modest, at 3.3%, but that the difference may be important to many patients who feel that they need to do everything they can to prevent disease recurrence.
“I’m really looking forward to the quality of life data, because it’s certainly known that any of these CDK4/6 inhibitors may add a bit of fatigue, and while there were no unexpected safety signals [in NATALEE], we know that there are some GI [gastrointestinal] effects with this therapy, as well as joint pain,” she said. “Joint pain is a little tricky, because the patients are also getting aromatase inhibitors, which can cause joint pain.”
In addition, premenopausal women in the study also received goserelin, an ovarian suppressor that triggers menopause, which is also associated with arthralgias, Dr. Adams said.
Dr. Adams and Dr. Nanda both noted that the addition of ribociclib to endocrine therapy increases the treatment burden for patients because it requires a commitment of at least 3 years and more frequent monitoring, especially in the first few months of therapy, compared with endocrine therapy alone.
Study details
The combination of ribociclib and standard of care endocrine therapy was the first to show an improvement in overall survival among women with metastatic HR+/HER2– breast cancer.
To see whether the combination could also benefit patients with early breast cancer, the investigators conducted NATALEE. They enrolled premenopausal and postmenopausal women and also men with HR+/HER2– breast cancer. Cases ranged from stage IIA (with either no nodal involvement with additional risk factors or with one to three involved axillary lymph nodes) to stage IIB-III disease, based on American Joint Committee on Cancer staging.
Patients who had previously received neoadjuvant or adjuvant endocrine therapy were accepted into the trial if the therapy had been started within 1 year of randomization.
The patients were stratified by age, menopausal status, disease stage, prior chemotherapy status, and geographic region. They were randomly assigned to receive either ribociclib 400 mg per day for 3 weeks, then were given 1 week off each cycle for 3 years plus endocrine therapy with either letrozole 2.5 mg/day or anastrozole 1 mg/day for at least 5 years, or to endocrine therapy alone. Men and premenopausal women also received goserelin.
Dr. Slamon noted that the 400-mg dose of ribociclib is lower than the recommended starting dose of 600 mg for metastatic disease. They chose the lower dose to allow longer duration of therapy, with a goal of achieving optimal disease suppression by driving tumor cells into irreversible senescence with less side effects.
A total of 2,549 patients were randomly assigned to receive the combination; 2,552 patients received endocrine therapy alone.
At the data cutoff on Jan. 11, 2023, after the prespecified minimum number of IDFS events had occurred, 189 patients in the ribociclib arm experienced recurrence, compared with 237 patients in the endocrine therapy–only arm.
As noted, 3-year IDFS rates were 90.4% with ribociclib and 87.1% with endocrine therapy alone, which translates to a hazard ratio of 0.748 in favor of the combination (P = .0014).
The benefit of ribociclib was generally consistent across subgroups, including node-negative patients, but there were too few patients in this subgroup for the differences to reach statistical significance, Dr. Slamon said.
Safety
The most commonly reported adverse event in the endocrine therapy–alone arm were joint pain and hot flashes
The most common adverse events with ribociclib included neutropenia and joint pain. Rates of gastrointestinal adverse events and fatigue, typical of CDK4/6 inhibitors, were relatively low in this study.
Dr. Slamon compared the rates of neutropenia with ribociclib in this trial to those in pooled data from the MONALEESA series of trials, in which ribociclib was delivered at a 600-mg dose. Grade 3 or 4 neutropenia occurred in 44% of patients in NATALEE, compared with 60% of patients in the MONALEESA trials.
In the ribociclib arm, 5.2% of patients experienced prolongation of the QT interval, compared with 1.2% of patients in the endocrine therapy–alone arm. No cases of torsades des pointes or problematic rhythm disturbances were observed, Dr. Slamon said.
“As frequently happens when we have these lovely, large, phase 3 registration trials but with some restriction in eligibility, when you get out to real-world practice, we don’t know what will happen in women who are on antiarrhythmics and if they’ll have a higher incidence of the QT elongation; they just weren’t included in the study. So it sounds like we’ll have to be paying attention to that,” commented briefing moderator Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO.
The study was funded by Novartis. Dr. Slamon has a leadership position with 1200 Pharma, Biomarin, and Torl Biotherapeutics, a consulting/advisory role for Novartis, and has received honoraria, research funding, and travel expenses from Novartis and others. Multiple coauthors reported financial relationships with Novartis and others. Dr. Nanda has had consulting/advisory roles with and has received institutional research funding from several companies, not including Novartis. Dr. Adams has participated on an advisory board for Cogent Biosciences and her institution has received research funding from various companies.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
Limit PSA screening to men with symptoms
A new strategy proposed by an international team of experts would limit the use of the prostate-specific antigen (PSA) test for screening tor prostate cancer to men who are younger than 70 years and who are at high risk or symptomatic.
This would reduce potential harms from overdiagnosis and overtreatment, the risk for which is high with the on-demand screening that is the current standard of care in most wealthy nations.
In a paper published online in The BMJ, the panel recommends instead a comprehensive nationwide program that would base PSA testing on individual patient risk and direct those with abnormal results to a managed system of imaging, targeted biopsy only if indicated, and subsequent active monitoring or treatment for those with more aggressive disease features.
Alternatively, government health programs could actively discourage widespread PSA testing and implement policies that would effectively limit PSA-based screening only to men with urologic symptoms warranting further exploration, said the authors, led by Andrew Vickers, PhD, a research epidemiologist at Memorial Sloan Kettering Cancer Center in New York.
“Although we believe that early detection of prostate cancer should involve shared decision making, the current approach of determining testing by shared decision making has resulted in the worst possible practical outcome of high levels of PSA testing and medical harm, with minimal benefit and inequity,” they wrote.
“To make better use of PSA testing, policy makers should choose between a comprehensive, risk adapted approach that is specifically designed to reduce overdiagnosis and overtreatment, or restricting PSA testing to people referred to urologists with symptoms. That choice will need to take into account wider patient and public perspective, as well as health economic concerns,” they continued.
Inappropriate testing
Since the Food and Drug Administration approved the first PSA screen in 1986 as a means for monitoring disease progression in patients being treated for prostate cancer, the test has remained controversial, embraced by some for its presumed ability to spot early prostate cancer but scorned by others for its equivocal results in patients with benign prostate pathology and for its potential to lead to overdiagnosis and overtreatment of low-grade disease in men who would otherwise be likely to die of other causes.
Currently, only Lithuania and Kazakhstan have government-supported population-based screening programs for prostate cancer. In contrast, the United States, United Kingdom, and other high-income countries have opted not to implement nationwide prostate cancer screening but allow so-called “informed choice testing,” in which men can receiving PSA screening after discussion with a primary care physician, urologist, or other specialist.
The U.S. Preventive Services Task Force recommends that for men aged 55-69 years, the decision to undergo PSA testing should be an individual one, based on an understanding of the risks and benefits. For men aged 70 or older, the task force flatly states, “Do not screen for prostate cancer.”
But as Dr. Vickers and colleagues noted, “high income countries that have made PSA testing available to men who request it after shared decision making with their physician now have a high prevalence of PSA testing with an inappropriate age distribution.”
For example, they pointed out that in the United Kingdom, men in their 80s are twice as likely as are men in their 50s to get a PSA test, even though men in the older age group are far less likely to have benefit and far more likely to experience harm from treatment. Similarly, in France, nearly one-third of men over 40 get an annual PSA test, with the highest incidence of PSA testing in men over age 70. There are also high rates of PSA testing in men over 70 in Italy, Germany, and Ireland.
“A key problem is that, in current routine care – and despite guidelines to the contrary – most men with an abnormal PSA result have prostate biopsy, even though only a minority will have aggressive prostate cancer,” Dr. Vickers and colleagues wrote. “Furthermore, most men with biopsy-detected cancers have either surgery or radiotherapy (with or without androgen deprivation therapy) even if they have low-risk tumors that are unlikely to cause cancer related morbidity or mortality.”
In addition, informed-choice PSA testing may lead to health inequities, the team noted, citing data from the United States, Canada, and Switzerland showing an inverse association between income and education and the likelihood of PSA testing. Also, in the United States and Canada, men from ethnic minority groups are less likely to have PSA testing.
Comprehensive risk-based program
Dr. Vickers and colleagues proposed that a “comprehensive, risk-based prostate cancer detection program based on best evidence on how to use PSA testing and manage subsequent diagnostic follow-up and treatment could reduce overdiagnosis and overtreatment.
“Such a program would restrict testing to men (and those not identifying as male but who have a prostate) aged 50-70, define testing intervals by PSA levels, stop testing early for those with lower PSA, offer biopsy only to those identified as at high risk of aggressive disease after a secondary test (such as magnetic resonance imaging [MRI] or blood markers), and limit treatment to those with high Gleason grade tumors,” they wrote.
‘Sound analysis’
Two experts who were not involved with the BMJ paper applaud the suggestions made in comments posted on the U.K. Science Media Centre.
Benjamin W. Lamb, MBBS, MA, PhD, a consultant urologist and surgeon at Barts Health NHS Trust in London, said the analysis conducted by the panel “is sound as there are known benefits from risk-adapted comprehensive screening trials in men aged 50-70, but discordance with current practice, meaning benefits and harms are not those seen in trials.”
However, he also said that the strategies proposed by the authors would be unlikely to prevent older, well-informed men from requesting and getting a PSA test.
“In my view, the emphasis should be on engaging younger and at-risk men rather than restricting access for older men,” he said, noting that the alternative proposal of restricting PSA testing “in my view, is not feasible.”
Nick James, MBBS, PhD, professor of prostate and bladder cancer research at the Institute of Cancer Research, London, and consultant oncologist at the Royal Marsden NHS Foundation Trust, said, “I agree with the authors and strongly support the implementation of a risk-based approach to PSA testing at a national level.
“There is an urgent need for a more equitable and targeted screening strategy, which could help address existing health disparities,” Dr. James said. “Currently, individuals from economically disadvantaged backgrounds are less likely to undergo PSA testing. Men in their 50s or younger, who may stand to benefit more from these tests, are also less likely to receive PSA tests compared to older men who benefit less. Linked to better diagnostic pathways with MRI, already standard in the UK, potential harms from overdiagnosis and overtreatment can be mitigated.”
The analysis was supported in part by the U.S. National Institutes of Health/National Cancer Institute with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center, and NIH grants to coauthors. Dr. Vickers is a coinventor of the 4Kscore, a commercial test for predicting prostate biopsy outcome. He receives royalties from sales of the test and owns stock options in OPKO, which offers the test. Coauthor James W.F. Catto, PhD, disclosed ties to Astellas, AstraZeneca, BMS, Ferring, Gilead, Janssen, MSD, Nucleix, Photocure, QED Therapeutics, and Roche.
A version of this article first appeared on Medscape.com.
A new strategy proposed by an international team of experts would limit the use of the prostate-specific antigen (PSA) test for screening tor prostate cancer to men who are younger than 70 years and who are at high risk or symptomatic.
This would reduce potential harms from overdiagnosis and overtreatment, the risk for which is high with the on-demand screening that is the current standard of care in most wealthy nations.
In a paper published online in The BMJ, the panel recommends instead a comprehensive nationwide program that would base PSA testing on individual patient risk and direct those with abnormal results to a managed system of imaging, targeted biopsy only if indicated, and subsequent active monitoring or treatment for those with more aggressive disease features.
Alternatively, government health programs could actively discourage widespread PSA testing and implement policies that would effectively limit PSA-based screening only to men with urologic symptoms warranting further exploration, said the authors, led by Andrew Vickers, PhD, a research epidemiologist at Memorial Sloan Kettering Cancer Center in New York.
“Although we believe that early detection of prostate cancer should involve shared decision making, the current approach of determining testing by shared decision making has resulted in the worst possible practical outcome of high levels of PSA testing and medical harm, with minimal benefit and inequity,” they wrote.
“To make better use of PSA testing, policy makers should choose between a comprehensive, risk adapted approach that is specifically designed to reduce overdiagnosis and overtreatment, or restricting PSA testing to people referred to urologists with symptoms. That choice will need to take into account wider patient and public perspective, as well as health economic concerns,” they continued.
Inappropriate testing
Since the Food and Drug Administration approved the first PSA screen in 1986 as a means for monitoring disease progression in patients being treated for prostate cancer, the test has remained controversial, embraced by some for its presumed ability to spot early prostate cancer but scorned by others for its equivocal results in patients with benign prostate pathology and for its potential to lead to overdiagnosis and overtreatment of low-grade disease in men who would otherwise be likely to die of other causes.
Currently, only Lithuania and Kazakhstan have government-supported population-based screening programs for prostate cancer. In contrast, the United States, United Kingdom, and other high-income countries have opted not to implement nationwide prostate cancer screening but allow so-called “informed choice testing,” in which men can receiving PSA screening after discussion with a primary care physician, urologist, or other specialist.
The U.S. Preventive Services Task Force recommends that for men aged 55-69 years, the decision to undergo PSA testing should be an individual one, based on an understanding of the risks and benefits. For men aged 70 or older, the task force flatly states, “Do not screen for prostate cancer.”
But as Dr. Vickers and colleagues noted, “high income countries that have made PSA testing available to men who request it after shared decision making with their physician now have a high prevalence of PSA testing with an inappropriate age distribution.”
For example, they pointed out that in the United Kingdom, men in their 80s are twice as likely as are men in their 50s to get a PSA test, even though men in the older age group are far less likely to have benefit and far more likely to experience harm from treatment. Similarly, in France, nearly one-third of men over 40 get an annual PSA test, with the highest incidence of PSA testing in men over age 70. There are also high rates of PSA testing in men over 70 in Italy, Germany, and Ireland.
“A key problem is that, in current routine care – and despite guidelines to the contrary – most men with an abnormal PSA result have prostate biopsy, even though only a minority will have aggressive prostate cancer,” Dr. Vickers and colleagues wrote. “Furthermore, most men with biopsy-detected cancers have either surgery or radiotherapy (with or without androgen deprivation therapy) even if they have low-risk tumors that are unlikely to cause cancer related morbidity or mortality.”
In addition, informed-choice PSA testing may lead to health inequities, the team noted, citing data from the United States, Canada, and Switzerland showing an inverse association between income and education and the likelihood of PSA testing. Also, in the United States and Canada, men from ethnic minority groups are less likely to have PSA testing.
Comprehensive risk-based program
Dr. Vickers and colleagues proposed that a “comprehensive, risk-based prostate cancer detection program based on best evidence on how to use PSA testing and manage subsequent diagnostic follow-up and treatment could reduce overdiagnosis and overtreatment.
“Such a program would restrict testing to men (and those not identifying as male but who have a prostate) aged 50-70, define testing intervals by PSA levels, stop testing early for those with lower PSA, offer biopsy only to those identified as at high risk of aggressive disease after a secondary test (such as magnetic resonance imaging [MRI] or blood markers), and limit treatment to those with high Gleason grade tumors,” they wrote.
‘Sound analysis’
Two experts who were not involved with the BMJ paper applaud the suggestions made in comments posted on the U.K. Science Media Centre.
Benjamin W. Lamb, MBBS, MA, PhD, a consultant urologist and surgeon at Barts Health NHS Trust in London, said the analysis conducted by the panel “is sound as there are known benefits from risk-adapted comprehensive screening trials in men aged 50-70, but discordance with current practice, meaning benefits and harms are not those seen in trials.”
However, he also said that the strategies proposed by the authors would be unlikely to prevent older, well-informed men from requesting and getting a PSA test.
“In my view, the emphasis should be on engaging younger and at-risk men rather than restricting access for older men,” he said, noting that the alternative proposal of restricting PSA testing “in my view, is not feasible.”
Nick James, MBBS, PhD, professor of prostate and bladder cancer research at the Institute of Cancer Research, London, and consultant oncologist at the Royal Marsden NHS Foundation Trust, said, “I agree with the authors and strongly support the implementation of a risk-based approach to PSA testing at a national level.
“There is an urgent need for a more equitable and targeted screening strategy, which could help address existing health disparities,” Dr. James said. “Currently, individuals from economically disadvantaged backgrounds are less likely to undergo PSA testing. Men in their 50s or younger, who may stand to benefit more from these tests, are also less likely to receive PSA tests compared to older men who benefit less. Linked to better diagnostic pathways with MRI, already standard in the UK, potential harms from overdiagnosis and overtreatment can be mitigated.”
The analysis was supported in part by the U.S. National Institutes of Health/National Cancer Institute with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center, and NIH grants to coauthors. Dr. Vickers is a coinventor of the 4Kscore, a commercial test for predicting prostate biopsy outcome. He receives royalties from sales of the test and owns stock options in OPKO, which offers the test. Coauthor James W.F. Catto, PhD, disclosed ties to Astellas, AstraZeneca, BMS, Ferring, Gilead, Janssen, MSD, Nucleix, Photocure, QED Therapeutics, and Roche.
A version of this article first appeared on Medscape.com.
A new strategy proposed by an international team of experts would limit the use of the prostate-specific antigen (PSA) test for screening tor prostate cancer to men who are younger than 70 years and who are at high risk or symptomatic.
This would reduce potential harms from overdiagnosis and overtreatment, the risk for which is high with the on-demand screening that is the current standard of care in most wealthy nations.
In a paper published online in The BMJ, the panel recommends instead a comprehensive nationwide program that would base PSA testing on individual patient risk and direct those with abnormal results to a managed system of imaging, targeted biopsy only if indicated, and subsequent active monitoring or treatment for those with more aggressive disease features.
Alternatively, government health programs could actively discourage widespread PSA testing and implement policies that would effectively limit PSA-based screening only to men with urologic symptoms warranting further exploration, said the authors, led by Andrew Vickers, PhD, a research epidemiologist at Memorial Sloan Kettering Cancer Center in New York.
“Although we believe that early detection of prostate cancer should involve shared decision making, the current approach of determining testing by shared decision making has resulted in the worst possible practical outcome of high levels of PSA testing and medical harm, with minimal benefit and inequity,” they wrote.
“To make better use of PSA testing, policy makers should choose between a comprehensive, risk adapted approach that is specifically designed to reduce overdiagnosis and overtreatment, or restricting PSA testing to people referred to urologists with symptoms. That choice will need to take into account wider patient and public perspective, as well as health economic concerns,” they continued.
Inappropriate testing
Since the Food and Drug Administration approved the first PSA screen in 1986 as a means for monitoring disease progression in patients being treated for prostate cancer, the test has remained controversial, embraced by some for its presumed ability to spot early prostate cancer but scorned by others for its equivocal results in patients with benign prostate pathology and for its potential to lead to overdiagnosis and overtreatment of low-grade disease in men who would otherwise be likely to die of other causes.
Currently, only Lithuania and Kazakhstan have government-supported population-based screening programs for prostate cancer. In contrast, the United States, United Kingdom, and other high-income countries have opted not to implement nationwide prostate cancer screening but allow so-called “informed choice testing,” in which men can receiving PSA screening after discussion with a primary care physician, urologist, or other specialist.
The U.S. Preventive Services Task Force recommends that for men aged 55-69 years, the decision to undergo PSA testing should be an individual one, based on an understanding of the risks and benefits. For men aged 70 or older, the task force flatly states, “Do not screen for prostate cancer.”
But as Dr. Vickers and colleagues noted, “high income countries that have made PSA testing available to men who request it after shared decision making with their physician now have a high prevalence of PSA testing with an inappropriate age distribution.”
For example, they pointed out that in the United Kingdom, men in their 80s are twice as likely as are men in their 50s to get a PSA test, even though men in the older age group are far less likely to have benefit and far more likely to experience harm from treatment. Similarly, in France, nearly one-third of men over 40 get an annual PSA test, with the highest incidence of PSA testing in men over age 70. There are also high rates of PSA testing in men over 70 in Italy, Germany, and Ireland.
“A key problem is that, in current routine care – and despite guidelines to the contrary – most men with an abnormal PSA result have prostate biopsy, even though only a minority will have aggressive prostate cancer,” Dr. Vickers and colleagues wrote. “Furthermore, most men with biopsy-detected cancers have either surgery or radiotherapy (with or without androgen deprivation therapy) even if they have low-risk tumors that are unlikely to cause cancer related morbidity or mortality.”
In addition, informed-choice PSA testing may lead to health inequities, the team noted, citing data from the United States, Canada, and Switzerland showing an inverse association between income and education and the likelihood of PSA testing. Also, in the United States and Canada, men from ethnic minority groups are less likely to have PSA testing.
Comprehensive risk-based program
Dr. Vickers and colleagues proposed that a “comprehensive, risk-based prostate cancer detection program based on best evidence on how to use PSA testing and manage subsequent diagnostic follow-up and treatment could reduce overdiagnosis and overtreatment.
“Such a program would restrict testing to men (and those not identifying as male but who have a prostate) aged 50-70, define testing intervals by PSA levels, stop testing early for those with lower PSA, offer biopsy only to those identified as at high risk of aggressive disease after a secondary test (such as magnetic resonance imaging [MRI] or blood markers), and limit treatment to those with high Gleason grade tumors,” they wrote.
‘Sound analysis’
Two experts who were not involved with the BMJ paper applaud the suggestions made in comments posted on the U.K. Science Media Centre.
Benjamin W. Lamb, MBBS, MA, PhD, a consultant urologist and surgeon at Barts Health NHS Trust in London, said the analysis conducted by the panel “is sound as there are known benefits from risk-adapted comprehensive screening trials in men aged 50-70, but discordance with current practice, meaning benefits and harms are not those seen in trials.”
However, he also said that the strategies proposed by the authors would be unlikely to prevent older, well-informed men from requesting and getting a PSA test.
“In my view, the emphasis should be on engaging younger and at-risk men rather than restricting access for older men,” he said, noting that the alternative proposal of restricting PSA testing “in my view, is not feasible.”
Nick James, MBBS, PhD, professor of prostate and bladder cancer research at the Institute of Cancer Research, London, and consultant oncologist at the Royal Marsden NHS Foundation Trust, said, “I agree with the authors and strongly support the implementation of a risk-based approach to PSA testing at a national level.
“There is an urgent need for a more equitable and targeted screening strategy, which could help address existing health disparities,” Dr. James said. “Currently, individuals from economically disadvantaged backgrounds are less likely to undergo PSA testing. Men in their 50s or younger, who may stand to benefit more from these tests, are also less likely to receive PSA tests compared to older men who benefit less. Linked to better diagnostic pathways with MRI, already standard in the UK, potential harms from overdiagnosis and overtreatment can be mitigated.”
The analysis was supported in part by the U.S. National Institutes of Health/National Cancer Institute with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center, and NIH grants to coauthors. Dr. Vickers is a coinventor of the 4Kscore, a commercial test for predicting prostate biopsy outcome. He receives royalties from sales of the test and owns stock options in OPKO, which offers the test. Coauthor James W.F. Catto, PhD, disclosed ties to Astellas, AstraZeneca, BMS, Ferring, Gilead, Janssen, MSD, Nucleix, Photocure, QED Therapeutics, and Roche.
A version of this article first appeared on Medscape.com.