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The ASCO Annual Meeting Starts This Week
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
Liposomal Irinotecan for Pancreatic Cancer: Is It Worth It?
In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.
The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.
Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.
The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m2, while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.
While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.
“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
No Head-to-Head Comparison
Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.
Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.
Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.
The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.
Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.
With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.
When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.
However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.
NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).
The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m2 instead of 85 mg/m2.
Is It Worth It?
During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.
The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”
However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.
In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.
The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.
Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.
On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.
Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.
In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.
The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.
Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”
The higher cost of NALIRIFOX, in particular, remains a major drawback.
“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.
Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.
Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.
NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.
A version of this article appeared on Medscape.com.
In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.
The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.
Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.
The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m2, while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.
While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.
“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
No Head-to-Head Comparison
Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.
Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.
Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.
The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.
Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.
With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.
When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.
However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.
NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).
The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m2 instead of 85 mg/m2.
Is It Worth It?
During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.
The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”
However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.
In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.
The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.
Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.
On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.
Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.
In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.
The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.
Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”
The higher cost of NALIRIFOX, in particular, remains a major drawback.
“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.
Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.
Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.
NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.
A version of this article appeared on Medscape.com.
In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.
The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.
Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.
The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m2, while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.
While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.
“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
No Head-to-Head Comparison
Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.
Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.
Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.
The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.
Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.
With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.
When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.
However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.
NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).
The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m2 instead of 85 mg/m2.
Is It Worth It?
During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.
The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”
However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.
In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.
The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.
Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.
On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.
Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.
In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.
The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.
Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”
The higher cost of NALIRIFOX, in particular, remains a major drawback.
“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.
Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.
Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.
NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.
A version of this article appeared on Medscape.com.
FDA Approves Tarlatamab for Extensive-Stage Small Cell Lung Cancer
Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling.
Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded.
The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease.
Continued approval may depend on verification of clinical benefit in a confirmatory trial.
Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome.
The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea.
The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.
The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com
A version of this article appeared on Medscape.com.
Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling.
Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded.
The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease.
Continued approval may depend on verification of clinical benefit in a confirmatory trial.
Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome.
The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea.
The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.
The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com
A version of this article appeared on Medscape.com.
Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling.
Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded.
The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease.
Continued approval may depend on verification of clinical benefit in a confirmatory trial.
Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome.
The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea.
The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.
The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com
A version of this article appeared on Medscape.com.
FDA Broadens Breyanzi’s Follicular Lymphoma Indication
The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.
The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.
Adequate bone marrow function and a performance score of 0-1 were required.
Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.
The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.
The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.
Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.
A single treatment is almost a half million dollars, according to drugs.com.
A version of this article appeared on Medscape.com.
The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.
The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.
Adequate bone marrow function and a performance score of 0-1 were required.
Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.
The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.
The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.
Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.
A single treatment is almost a half million dollars, according to drugs.com.
A version of this article appeared on Medscape.com.
The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.
The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.
Adequate bone marrow function and a performance score of 0-1 were required.
Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.
The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.
The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.
Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.
A single treatment is almost a half million dollars, according to drugs.com.
A version of this article appeared on Medscape.com.
Potential Cure for Early BRCA-Mutated Breast Cancer?
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
FROM AACR 2024
FDA Approves Second Gene Therapy for Hemophilia B
Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes.
Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022.
Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector.
Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.
Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector.
The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.
Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred.
Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.
A version of this article appeared on Medscape.com.
Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes.
Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022.
Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector.
Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.
Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector.
The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.
Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred.
Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.
A version of this article appeared on Medscape.com.
Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes.
Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022.
Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector.
Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.
Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector.
The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.
Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred.
Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.
A version of this article appeared on Medscape.com.
Is Osimertinib Better Alone or With Chemotherapy in Non–Small Cell Lung Cancer?
SAN DIEGO —
That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.
An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.
An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.
Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.
“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.
The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.
Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.
In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).
In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).
The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.
“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.
Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.
Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.
The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.
It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.
The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
A version of this article appeared on Medscape.com.
SAN DIEGO —
That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.
An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.
An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.
Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.
“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.
The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.
Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.
In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).
In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).
The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.
“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.
Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.
Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.
The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.
It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.
The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
A version of this article appeared on Medscape.com.
SAN DIEGO —
That is a question brewing among some oncologists now that the US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso, AstraZeneca) for both indications in patients with epidermal growth factor receptor (EGFR) mutations.
An answer began to emerge in research presented at the American Association for Cancer Research annual meeting.
An exploratory analysis of the FLAURA2 trial found that, when patients have EGFR mutations on baseline circulating tumor DNA (ctDNA) testing, the combination treatment can extend progression-free survival (PFS). In this patient group, those receiving osimertinib alongside pemetrexed plus cisplatin or carboplatin had a 9-month PFS advantage compared with those who received osimertinib alone.
Conversely, when patients do not have EGFR mutations following baseline ctDNA testing, osimertinib alone appears to offer similar PFS outcomes to the combination therapy, but with less toxicity.
“Baseline detection of plasma EGFR mutations may identify a subgroup of patients who derive most benefit from the addition of platinum-pemetrexed to osimertinib as first-line treatment of EGFR-mutated advance non–small cell lung cancer,” investigator Pasi A. Jänne, MD, PhD, a lung cancer oncologist at the Dana-Farber Cancer Institute, Boston, said during his presentation.
The FLAURA2 trial randomized 557 patients equally to daily osimertinib either alone or with pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by pemetrexed every 3 weeks until disease progression or unacceptable toxicity.
Patients were tested for Ex19del or L858R EGFR mutations at baseline and at 3 and 6 weeks; baseline mutations were found in 73% of evaluable patients.
In patients with baseline mutations, the median PFS was 24.8 months with the combination therapy vs 13.9 months with osimertinib alone (hazard ratio [HR], 0.60).
In patients without baseline mutations, the median PFS was similar in both groups — 33.3 months with the combination vs 30.3 months with monotherapy (HR, 0.93; 95% CI, 0.51-1.72).
The investigators also found that having baseline mutations was associated with worse outcomes regardless of study arm, and mutation clearance was associated with improved outcomes. Clearance occurred more quickly among patients receiving the combination treatment, but almost 90% of patients in both arms cleared their mutations by week 6.
“As we move forward and think about which of our patients we would treat with the combination ... the presence of baseline EGFR mutations in ctDNA may be one of the features that goes into the conversation,” Dr. Jänne said.
Study discussant Marina Chiara Garassino, MD, a thoracic oncologist at the University of Chicago, agreed that this trial can help oncologists make this kind of treatment decision.
Patients with baseline EGFR mutations also tended to have larger tumors, more brain metastases, and worse performance scores; the combination therapy makes sense when such factors are present in patients with baseline EGFR mutations, Dr. Garassino said.
The wrinkle in the findings is that the study used digital droplet polymerase chain reaction (Biodesix) to test for EGFR mutations, which is not commonly used. Clinicians often use next-generation sequencing, which is less sensitive and can lead to false negatives.
It makes it difficult to know how to apply the findings to everyday practice, but Janne hopes a study will be done to correlate next-generation sequencing detection with outcomes.
The study was funded by AstraZeneca, maker of osimertinib, and researchers included AstraZeneca employees. Dr. Jänne is a consultant for and reported research funding from the company. He is a co-inventor on an EGFR mutations patent. Dr. Garassino is also an AstraZeneca consultant and reported institutional financial interests in the company.
A version of this article appeared on Medscape.com.
FROM AACR
Has Immunotherapy Found Its Place in Pancreatic Cancer?
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AACR 2024
Ovarian Cancer: Another Promising Target for Liquid Biopsy
according to an initial analysis.
The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore.
The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors.
While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.
The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.
The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.
The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%.
“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.
Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.
If validated, the test “could enable population-wide ovarian cancer screening,” he added.
Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty.
With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.”
This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages.
“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut.
He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure.
However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors.
What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.
The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics.
A version of this article appeared on Medscape.com .
according to an initial analysis.
The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore.
The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors.
While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.
The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.
The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.
The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%.
“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.
Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.
If validated, the test “could enable population-wide ovarian cancer screening,” he added.
Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty.
With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.”
This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages.
“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut.
He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure.
However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors.
What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.
The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics.
A version of this article appeared on Medscape.com .
according to an initial analysis.
The test, under development by Delfi Diagnostics, “looks very sensitive for detecting ovarian cancer early,” said company founder and board member Victor E. Velculescu, MD, PhD, codirector of Cancer Genetics and Epigenetics at Johns Hopkins University, Baltimore.
The assay uses machine learning to integrate cell-free DNA fragment patterns with concentrations of two ovarian cancer biomarkers — CA125 and HE4 — to detect tumors.
While fragmentation patterns are organized in healthy people, they are chaotic in cancer and reveal both its presence and location, said Velculescu who presented the findings at the American Association for Cancer Research annual meeting.
The researchers tested the assay in 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. The approach identified 69% of stage 1 cancers, 76% of stage 2, 85% of stage 3, and 100% of stage 4 at a specificity of over 99% and an area under the curve (AUC) of 0.97.
The test identified 91% of high-grade serous ovarian cancers — the most common type of ovarian cancer.
The AUC for distinguishing benign masses from cancer was 0.87, with 60% of ovarian cancers detected at a specificity of 95%.
“In the preoperative setting where lower specificity is acceptable, this approach may improve management of adnexal masses,” the investigators said in their abstract.
Dr. Velculescu cautioned that the report “is an initial analysis” and that his team is working on validating the finding on a larger scale in both average and high-risk women.
If validated, the test “could enable population-wide ovarian cancer screening,” he added.
Delfi recently launched a lung cancer screening blood test — FirstLook Lung— that also uses a “fragmentomics” approach to detect tumors. The company is hopeful it will reach the market with a similar test for ovarian cancer, but it’s not a certainty.
With lung cancer, we know screening helps. For ovarian cancer, however, it’s unclear whether this will help or not, said Dr. Velculescu. But based on the study findings, but “we are now optimistic that this could make an impact. We have more work to do.”
This presentation was one of many at the meeting about liquid biopsies using DNA, RNA, and proteins to detect cancer, including a new assay for pancreatic cancer, another cancer that like ovarian cancer is difficult to detect in the early stages.
“This is the future,” said study moderator Roy S. Herbst, MD, PhD, chief of medical oncology at Yale University in New Haven, Connecticut.
He called liquid biopsy “a great advance” in many oncology settings, including cancer screening because finding tumors early offers the best chance at cure.
However, one of the main concerns about rolling out liquid biopsies for wide-scale cancer screening is the possibility that a test will come back positive, but no tumor will be seen on diagnostic imaging, said Herbst. It won’t be clear if the test was a false positive or if the patient has a brewing tumor that can’t be located and treated, a difficult situation for both patients and doctors.
What to do in that situation is “a policy question that the entire country is asking now as liquid biopsies are moving forward,” he said. We are going to have to come together to figure it out and learn how to use these tests.
The work was funded by Delfi Diagnostics, the National Institutes of Health, and others. Dr. Velculescu, in addition to founding Delfi, holds patents on the technology. Dr. Herbst is a consultant, researcher, and/or holds stock in many companies, including AstraZeneca, Pfizer, and Checkpoint Therapeutics.
A version of this article appeared on Medscape.com .
FROM AACR 2024
What to Know About the Next-Gen FIT for CRC Screening
These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.
Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.
But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.
In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.
Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes.
Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that.
Cologuard 2.0: Multitarget Stool DNA-Based Test
An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.
In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces.
The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.
Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.
Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%.
However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.
Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.
Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
Multitarget Stool RNA-Based Test
ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC.
The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays.
Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.
The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations.
ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.
However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.
Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
Multitarget Protein-Based Test
The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer.
A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias.
In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.
Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants.
In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT.
But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).
Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.
As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions.
Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.
In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.
Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.
The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.
Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy.
Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.
A version of this article appeared on Medscape.com.
These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.
Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.
But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.
In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.
Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes.
Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that.
Cologuard 2.0: Multitarget Stool DNA-Based Test
An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.
In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces.
The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.
Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.
Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%.
However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.
Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.
Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
Multitarget Stool RNA-Based Test
ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC.
The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays.
Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.
The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations.
ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.
However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.
Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
Multitarget Protein-Based Test
The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer.
A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias.
In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.
Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants.
In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT.
But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).
Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.
As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions.
Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.
In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.
Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.
The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.
Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy.
Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.
A version of this article appeared on Medscape.com.
These new tests aren’t radical departures from the standard FIT. Like the standard test, the multitarget FIT uses antibodies to test for hemoglobin in stool samples. But these multitarget approaches take the standard FIT a step further by testing for additional DNA, RNA, or protein biomarkers associated with CRC to help improve early detection.
Currently, the US Preventive Services Task Force (USPSTF) recommends two FIT tests — standard FIT and stool FIT-DNA — as well as a third noninvasive CRC screening test, guaiac fecal occult blood test (gFOBT). gFOBT detects heme, a component of hemoglobin, through a chemical reaction.
But both standard FIT and stool FIT-DNA come with caveats. Compared to the standard test, FIT-DNA tends to be better at detecting traces of blood in the stool, and thus can uncover more instances of CRC or other advanced lesions. The flipside is that the DNA test also often leads to more false-positive findings.
In fact, the American College of Physicians does not recommend stool FIT-DNA for screening, citing issues such as cost — more than $600 per test vs about $30 for standard FIT — and the greater likelihood of false-positives compared with both standard FIT and gFOBT.
Given these trade-offs with current noninvasive screening options, developing a FIT option that can improve early detection of CRC and advanced precancerous lesions without increasing false-positives could make a big difference in outcomes.
Three new noninvasive multitarget tests under investigation — an updated DNA-based test, Cologuard 2.0 (Exact Sciences; Madison, WI); an RNA-based test, ColoSense (Geneoscopy; St Louis, MO); and a protein-based test from CRCbioscreen (Amsterdam, the Netherlands) — may be able to do just that.
Cologuard 2.0: Multitarget Stool DNA-Based Test
An updated version of the stool FIT-DNA is currently under development. Dubbed Next Generation Cologuard, or Cologuard 2.0, this multitarget test detects three novel methylated DNA markers along with fecal hemoglobin.
In a recent trial comparing Cologuard 2.0 vs standard FIT, 20,176 participants aged 40 years or older were screened with Cologuard 2.0 as well as standard FIT before they all also received a colonoscopy. The researchers compared findings with Cologuard 2.0 and standard FIT, which used a positivity cutoff ≥ 20 mcg hemoglobin/g feces.
The researchers then assessed Cologuard 2.0’s sensitivity (a gauge of how well it detects disease that is truly present) and specificity (a measure of how well a test indicates the absence of disease when no disease is present) compared with standard FIT and the original Cologuard test.
Overall, Cologuard 2.0 demonstrated better sensitivity for CRC than did standard FIT (93.9% vs 67.3%, respectively) and for advanced precancerous lesions (43.4% vs 23.3%). The next-generation test, for instance, identified 92 of 98 participants with colonoscopy-confirmed CRC diagnoses vs 66 cases using standard FIT.
Compared with the original Cologuard, Cologuard 2.0’s sensitivity improved slightly for CRC, from 92% to 93.9%,; for advanced precancerous lesions, from 42% to 43.4%; and for high-grade dysplasia, from 69% to 75%. Specificity also improved with the latest version, from 87% to 90.6%.
However, Cologuard 2.0’s specificity for advanced neoplasia was worse than that of standard FIT (90.6% vs 94.8%, respectively), which would increase the likelihood of false-positive findings.
Despite its lower specificity compared with standard FIT, Cologuard 2.0 has several advantages. The test can identify more people with CRC and advanced precancerous lesions than the standard test and can lead to fewer false-positives than the original Cologuard test.
Cologuard maker Exact Sciences has submitted trial data to the US Food and Drug Administration (FDA) for approval.
Multitarget Stool RNA-Based Test
ColoSense, an RNA-based stool test, looks for eight RNA biomarkers associated with CRC.
The company says that RNA-based testing has an advantage over DNA biomarker assays, such as the currently marketed Cologuard test, because it isn›t subject to the age-related changes in DNA methylation that can throw off the results from DNA assays.
Like Cologuard 2.0, Geneoscopy’s Colosense test is under review by the FDA.
The data Geneoscopy submitted to the FDA came from the CRC-PREVENT trial, which included 8920 participants who were screened with both ColoSense and standard FIT before all had a colonoscopy. The participants ranged in age from 45 to 90 years, with 22% between 45 and 50 years old, a population recently added to the USPSTF screening recommendations.
ColoSense showed higher sensitivity than standard FIT for the presence of CRC (94% vs 78%, respectively) and advanced adenomas (46% vs 29%). In the group aged 45-50 years, the RNA-based test had a sensitivity of 100% for CRC, correctly identifying all five people with colonoscopy-confirmed CRC, and 45% for advanced adenomas.
However, ColoSense was less specific than standard FIT compared with negative colonoscopy findings (88% vs 96%, respectively) and negative findings for advanced lesions or CRC (85.5% vs 94.9%); thus, it was more likely to lead to false-positive results.
Overall, the investigators said ColoSense is comparable to Cologuard — its chief market rival — in terms of sensitivity for CRC and advanced adenomas but has higher sensitivity for colorectal neoplasia in people aged 50 years or younger.
Multitarget Protein-Based Test
The multitarget protein-based FIT uses antibodies to test for two additional proteins: calprotectin, an inflammatory marker associated with CRC, and serpin family F member 2, a protease inhibitor thought to be upregulated in colon cancer.
A 2021 study of 1284 patients found that the sensitivity of the multitarget protein-based test was 42.9% for advanced neoplasias compared with 37.3% with standard FIT. Its specificity was similar to that of standard FIT, at 96.6% for advanced neoplasias.
In a more recent report published in The Lancet Oncology, the team modeled three scenarios comparing the two FIT tests. These scenarios used different cutoff values for a test to be positive for CRC or an advanced lesion.
Overall, the analysis included stool samples from 13,187 patients aged 55-75 years who were in the Netherlands’ national CRC screening program. Stool samples were evaluated with both the multitarget test and the standard FIT, using a positivity cutoff ≥ 47 mcg hemoglobin/g feces. Colonoscopy data were available for only 1270 participants.
In scenario 1, the multitarget test had a lower threshold for a positive test and consequently identified more precancerous lesions than the standard FIT (828 vs 354, respectively). The multitarget FIT identified a few more CRC cases: Of 29 colonoscopy-confirmed CRC cases, the multitarget FIT identified 26 vs 23 with standard FIT.
But the multitarget FIT also had more than double the number of false-positives than the standard FIT (347 vs 161, respectively).
Perhaps the most telling comparison occurred in scenario 2, with both tests set at the same low positivity threshold to minimize false-positives.
As expected, the two tests had similar positivity rates for advanced lesions, with the multitarget test correctly identifying 22 of 29 people with CRC, one fewer than the standard test. The protein-based test identified slightly more people with advanced lesions (156 vs 136 with the standard test), leading to a higher sensitivity for advanced lesions.
Most notably, the protein-based test resulted in fewer false-positives than did the standard test (295 vs 311, respectively) , resulting in a slightly higher specificity.
In this scenario, “a single screening round might not have the biggest impact on cancer incidence and mortality,” the authors said, but the higher detection rate would still accumulate over 20 years of testing. The authors estimated that, under this scenario, substituting the multitarget FIT for the standard test in the Netherlands’ CRC screening program could reduce CRC incidence by 5% and CRC mortality by 4%.
Gerrit Meijer, MD, PhD, a pathologist at the Netherlands Cancer Institute, and colleagues recently launched a company called CRCbioscreen to commercialize this multitarget FIT for large-scale programs. The company›s priority is to develop and validate a clinical-grade test to sell to federal governments with national screening programs, such as those throughout Europe, Australia, and Asia, Dr. Meijer told this news organization. Dr. Meijer expects this process will take about 4 years.
The test will be developed for the US market, but with no nationwide screening program in the United States, future availability will depend on interest from providers and institutions, noted Dr. Meijer, who is also chief scientific officer at CRCbioscreen.
Overall, these three new multitarget stool-based CRC screening tests could help catch more cancers and advanced precancerous lesions. And, if the tests have a high enough specificity, a negative test result could also allow people to forgo screening colonoscopy.
Still, people with a positive FIT finding would require follow-up colonoscopy, but about 10% of patients decline colonoscopy following an abnormal FIT, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health in Murray, Utah, told this news organization last year. That means that even if precancerous lesions and CRC are being caught earlier, treatment can’t be started unless people follow through with colonoscopy.
A version of this article appeared on Medscape.com.