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Quality of life preserved with ribociclib + letrozole for advanced breast cancer
CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.
Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).
The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.
Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).
“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.
Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.
“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.
Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.
Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.
In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.
It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.
Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.
Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).
The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.
Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).
“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.
Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.
“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.
Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.
Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.
In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.
It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.
Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.
Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).
The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.
Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).
“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.
Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.
“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.
Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.
Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.
In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.
It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.
Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT ASCO 2017
Key clinical point:
Major finding: Quality of life was sustained and pain scores decreased when ribociclib was added to letrozole for patients with advanced breast cancer.
Data source: Double-blind, placebo-controlled phase III trial of letrozole plus ribociclib compared to letrozole plus placebo in 668 patients with advanced hormone receptor-positive, HER-2 negative breast cancer.
Disclosures: Dr. Verma reported financial relationships with multiple companies, including Novartis, which markets ribociclib.
Dacomitinib boosts PFS in advanced NSCLC
CHICAGO – The clear advantage goes to the second-generation tyrosine kinase inhibitor in a new trial comparing dacomitinib to gefitinib for advanced non–small cell lung cancer.
In a randomized, open-label phase III trial designed as a head-to-head comparison of the two drugs for the first-line treatment of advanced non–small cell lung cancer (NSCLC), “the blinded, independent review showed that we have a median progression-free survival (PFS) of 14.7 months versus 9.2 months,” said first author Tony Mok, MD, professor and chair of the department of clinical oncology at the Chinese University of Hong Kong. This PFS rate, he said, “is among the highest of randomized phase III trials in the first-line setting.”
Two years into the study, those taking dacomitinib had triple the PFS rate of those on gefitinib (30.6% versus 9.6%). The overall hazard ratio (HR) for PFS with dacomitinib compared to gefitinib was 0.59 (95% confidence interval [CI], 0.47-0.74, P less than .0001).
A previous single-arm phase II trial of the drug, ARCHER 2017, showed a response rate of 75.6% and a median PFS of 18.2 months for patients with NSCLC and an EGFR-activating mutation.
“Based on these data, we thought it was likely that we could have a hypothesis for dacomitinib to be superior to gefitinib, a first-generation TKI [tyrosine kinase inhibitor], in terms of progression-free survival,” Dr. Mok said in a press conference at the annual meeting of the American Society of Clinical Oncology. Dacomitinib is a second-generation TKI.
Patients in the new study, ARCHER 1050, had advanced NSCLC with EGFR-activating mutations and no prior systemic treatment for their advanced disease. In addition, patients had good performance status, could not have had prior TKI exposure, and could not have CNS metastases. This last exclusion, explained Dr. Mok, was because investigators were uncertain about dacomitinib’s CNS penetration at the time of study design, and because gefitinib may also not be the best therapeutic choice for CNS metastases.
Patients were randomized 1:1 to receive either dacomitinib 45 mg orally daily (n = 227), or gefitinib 250 mg orally daily (n = 225). Patients were stratified by whether or not they were ethnically Asian, and by whether they had EGFR mutation of exon 19 or exon 21. Patients were balanced in terms of age, gender, ethnicity, smoking, and performance status between arms. About 75% of the patients were Asian, and 65% were nonsmokers.
The international study enrolled patients from 71 centers in Asia and Europe. At the time of the data cutoff, investigators saw PFS events totaling 59.9% in the dacomitinib arm and 79.6% in the gefitinib arm. Patients were followed for PFS for a median of 22.1 months. “We have relatively mature data,” said Dr. Mok, except for overall survival, with only 36.9% of events occurring at the time of the data cutoff.
The primary endpoint in the open-label trial was PFS in the intention-to-treat population, as assessed by an independent, blinded reviewer. Dr. Mok said that the study was powered to see at least 256 PFS events, and to see an improvement in PFS for dacomitinib that equated to an HR of no more than 0.667. This would translate to median PFS for dacomitinib of 14.3 months versus 9.5 months for gefitinib, values Dr. Mok said were “reasonable.” And, he pointed out, the study results fell almost exactly in line with these predictions, though the actual HR was a bit lower than predicted.
An analysis of PFS by subgroup, also conducted by independent review, found that dacomitinib was favored for all subgroups except for non-Asian patients, for whom the HR was 0.89 but did not reach statistical significance. Since these patients made up about one-fourth of the study population, said Dr. Mok, small sample size was a potential issue. “But we have to ask ourselves the question, do they really perform worse than the Asians, if they have a response?”
To attempt to answer this question, the investigators performed an exploratory analysis of the 72 non-Asian patients who had responded to therapy. Among this group, they saw data similar to that of the overall group, with an HR of 0.547 (95% CI, 0.321-0.933, P less than .0123).
Secondary endpoints included investigator-assessed PFS, overall survival, objective response rate, duration of response, quality of life, and safety assessments.
Objective response rates were similar between arms, at 74.9% for dacomitinib and 71.6% for gefitinib (P = .3883). However, the median duration of response was significantly longer for those on dacomitinib (14.8 versus 8.3 months, P less than .0001).
“This may be best explained by looking into the depth of the response,” said Dr. Mok. Patient-level data showed that dacomitinib patients had a larger reduction in target lesion size; “this may reflect a more potent inhibition of EGFR,” he said.
With the more potent inhibition, however, came more frequent grade 3 adverse events involving diarrhea, dermatitis, stomatitis, and paronychia for those on dacomitinib; however, noted Dr. Mok, serious transaminase elevations were more common in the gefitinib group. “There is no new signal” for concerning toxicity, he said. Dose reductions were more common in dacomitinib than in gefitinib (66.1% versus 18%), but there are two tiers of dose reductions permissible with dacomitinib, giving some flexibility.
Dr. Mok reported financial relationships with multiple pharmaceutical companies, including Pfizer and SFJ Pharmaceuticals, which sponsored the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO – The clear advantage goes to the second-generation tyrosine kinase inhibitor in a new trial comparing dacomitinib to gefitinib for advanced non–small cell lung cancer.
In a randomized, open-label phase III trial designed as a head-to-head comparison of the two drugs for the first-line treatment of advanced non–small cell lung cancer (NSCLC), “the blinded, independent review showed that we have a median progression-free survival (PFS) of 14.7 months versus 9.2 months,” said first author Tony Mok, MD, professor and chair of the department of clinical oncology at the Chinese University of Hong Kong. This PFS rate, he said, “is among the highest of randomized phase III trials in the first-line setting.”
Two years into the study, those taking dacomitinib had triple the PFS rate of those on gefitinib (30.6% versus 9.6%). The overall hazard ratio (HR) for PFS with dacomitinib compared to gefitinib was 0.59 (95% confidence interval [CI], 0.47-0.74, P less than .0001).
A previous single-arm phase II trial of the drug, ARCHER 2017, showed a response rate of 75.6% and a median PFS of 18.2 months for patients with NSCLC and an EGFR-activating mutation.
“Based on these data, we thought it was likely that we could have a hypothesis for dacomitinib to be superior to gefitinib, a first-generation TKI [tyrosine kinase inhibitor], in terms of progression-free survival,” Dr. Mok said in a press conference at the annual meeting of the American Society of Clinical Oncology. Dacomitinib is a second-generation TKI.
Patients in the new study, ARCHER 1050, had advanced NSCLC with EGFR-activating mutations and no prior systemic treatment for their advanced disease. In addition, patients had good performance status, could not have had prior TKI exposure, and could not have CNS metastases. This last exclusion, explained Dr. Mok, was because investigators were uncertain about dacomitinib’s CNS penetration at the time of study design, and because gefitinib may also not be the best therapeutic choice for CNS metastases.
Patients were randomized 1:1 to receive either dacomitinib 45 mg orally daily (n = 227), or gefitinib 250 mg orally daily (n = 225). Patients were stratified by whether or not they were ethnically Asian, and by whether they had EGFR mutation of exon 19 or exon 21. Patients were balanced in terms of age, gender, ethnicity, smoking, and performance status between arms. About 75% of the patients were Asian, and 65% were nonsmokers.
The international study enrolled patients from 71 centers in Asia and Europe. At the time of the data cutoff, investigators saw PFS events totaling 59.9% in the dacomitinib arm and 79.6% in the gefitinib arm. Patients were followed for PFS for a median of 22.1 months. “We have relatively mature data,” said Dr. Mok, except for overall survival, with only 36.9% of events occurring at the time of the data cutoff.
The primary endpoint in the open-label trial was PFS in the intention-to-treat population, as assessed by an independent, blinded reviewer. Dr. Mok said that the study was powered to see at least 256 PFS events, and to see an improvement in PFS for dacomitinib that equated to an HR of no more than 0.667. This would translate to median PFS for dacomitinib of 14.3 months versus 9.5 months for gefitinib, values Dr. Mok said were “reasonable.” And, he pointed out, the study results fell almost exactly in line with these predictions, though the actual HR was a bit lower than predicted.
An analysis of PFS by subgroup, also conducted by independent review, found that dacomitinib was favored for all subgroups except for non-Asian patients, for whom the HR was 0.89 but did not reach statistical significance. Since these patients made up about one-fourth of the study population, said Dr. Mok, small sample size was a potential issue. “But we have to ask ourselves the question, do they really perform worse than the Asians, if they have a response?”
To attempt to answer this question, the investigators performed an exploratory analysis of the 72 non-Asian patients who had responded to therapy. Among this group, they saw data similar to that of the overall group, with an HR of 0.547 (95% CI, 0.321-0.933, P less than .0123).
Secondary endpoints included investigator-assessed PFS, overall survival, objective response rate, duration of response, quality of life, and safety assessments.
Objective response rates were similar between arms, at 74.9% for dacomitinib and 71.6% for gefitinib (P = .3883). However, the median duration of response was significantly longer for those on dacomitinib (14.8 versus 8.3 months, P less than .0001).
“This may be best explained by looking into the depth of the response,” said Dr. Mok. Patient-level data showed that dacomitinib patients had a larger reduction in target lesion size; “this may reflect a more potent inhibition of EGFR,” he said.
With the more potent inhibition, however, came more frequent grade 3 adverse events involving diarrhea, dermatitis, stomatitis, and paronychia for those on dacomitinib; however, noted Dr. Mok, serious transaminase elevations were more common in the gefitinib group. “There is no new signal” for concerning toxicity, he said. Dose reductions were more common in dacomitinib than in gefitinib (66.1% versus 18%), but there are two tiers of dose reductions permissible with dacomitinib, giving some flexibility.
Dr. Mok reported financial relationships with multiple pharmaceutical companies, including Pfizer and SFJ Pharmaceuticals, which sponsored the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO – The clear advantage goes to the second-generation tyrosine kinase inhibitor in a new trial comparing dacomitinib to gefitinib for advanced non–small cell lung cancer.
In a randomized, open-label phase III trial designed as a head-to-head comparison of the two drugs for the first-line treatment of advanced non–small cell lung cancer (NSCLC), “the blinded, independent review showed that we have a median progression-free survival (PFS) of 14.7 months versus 9.2 months,” said first author Tony Mok, MD, professor and chair of the department of clinical oncology at the Chinese University of Hong Kong. This PFS rate, he said, “is among the highest of randomized phase III trials in the first-line setting.”
Two years into the study, those taking dacomitinib had triple the PFS rate of those on gefitinib (30.6% versus 9.6%). The overall hazard ratio (HR) for PFS with dacomitinib compared to gefitinib was 0.59 (95% confidence interval [CI], 0.47-0.74, P less than .0001).
A previous single-arm phase II trial of the drug, ARCHER 2017, showed a response rate of 75.6% and a median PFS of 18.2 months for patients with NSCLC and an EGFR-activating mutation.
“Based on these data, we thought it was likely that we could have a hypothesis for dacomitinib to be superior to gefitinib, a first-generation TKI [tyrosine kinase inhibitor], in terms of progression-free survival,” Dr. Mok said in a press conference at the annual meeting of the American Society of Clinical Oncology. Dacomitinib is a second-generation TKI.
Patients in the new study, ARCHER 1050, had advanced NSCLC with EGFR-activating mutations and no prior systemic treatment for their advanced disease. In addition, patients had good performance status, could not have had prior TKI exposure, and could not have CNS metastases. This last exclusion, explained Dr. Mok, was because investigators were uncertain about dacomitinib’s CNS penetration at the time of study design, and because gefitinib may also not be the best therapeutic choice for CNS metastases.
Patients were randomized 1:1 to receive either dacomitinib 45 mg orally daily (n = 227), or gefitinib 250 mg orally daily (n = 225). Patients were stratified by whether or not they were ethnically Asian, and by whether they had EGFR mutation of exon 19 or exon 21. Patients were balanced in terms of age, gender, ethnicity, smoking, and performance status between arms. About 75% of the patients were Asian, and 65% were nonsmokers.
The international study enrolled patients from 71 centers in Asia and Europe. At the time of the data cutoff, investigators saw PFS events totaling 59.9% in the dacomitinib arm and 79.6% in the gefitinib arm. Patients were followed for PFS for a median of 22.1 months. “We have relatively mature data,” said Dr. Mok, except for overall survival, with only 36.9% of events occurring at the time of the data cutoff.
The primary endpoint in the open-label trial was PFS in the intention-to-treat population, as assessed by an independent, blinded reviewer. Dr. Mok said that the study was powered to see at least 256 PFS events, and to see an improvement in PFS for dacomitinib that equated to an HR of no more than 0.667. This would translate to median PFS for dacomitinib of 14.3 months versus 9.5 months for gefitinib, values Dr. Mok said were “reasonable.” And, he pointed out, the study results fell almost exactly in line with these predictions, though the actual HR was a bit lower than predicted.
An analysis of PFS by subgroup, also conducted by independent review, found that dacomitinib was favored for all subgroups except for non-Asian patients, for whom the HR was 0.89 but did not reach statistical significance. Since these patients made up about one-fourth of the study population, said Dr. Mok, small sample size was a potential issue. “But we have to ask ourselves the question, do they really perform worse than the Asians, if they have a response?”
To attempt to answer this question, the investigators performed an exploratory analysis of the 72 non-Asian patients who had responded to therapy. Among this group, they saw data similar to that of the overall group, with an HR of 0.547 (95% CI, 0.321-0.933, P less than .0123).
Secondary endpoints included investigator-assessed PFS, overall survival, objective response rate, duration of response, quality of life, and safety assessments.
Objective response rates were similar between arms, at 74.9% for dacomitinib and 71.6% for gefitinib (P = .3883). However, the median duration of response was significantly longer for those on dacomitinib (14.8 versus 8.3 months, P less than .0001).
“This may be best explained by looking into the depth of the response,” said Dr. Mok. Patient-level data showed that dacomitinib patients had a larger reduction in target lesion size; “this may reflect a more potent inhibition of EGFR,” he said.
With the more potent inhibition, however, came more frequent grade 3 adverse events involving diarrhea, dermatitis, stomatitis, and paronychia for those on dacomitinib; however, noted Dr. Mok, serious transaminase elevations were more common in the gefitinib group. “There is no new signal” for concerning toxicity, he said. Dose reductions were more common in dacomitinib than in gefitinib (66.1% versus 18%), but there are two tiers of dose reductions permissible with dacomitinib, giving some flexibility.
Dr. Mok reported financial relationships with multiple pharmaceutical companies, including Pfizer and SFJ Pharmaceuticals, which sponsored the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT ASCO 2017
Key clinical point:
Major finding: At 2 years, the dacomitinib arm had triple the PFS rate of the gefitinib arm (30.6% versus 9.6%).
Data source: Randomized, open-label phase III clinical trial of 452 patients who received dacomitinib or gefitinib for first-line therapy for advanced non–small cell lung cancer.
Disclosures: Dr. Mok reported financial relationships with multiple pharmaceutical companies, including Pfizer and SFJ Pharmaceuticals, which funded the study.
SOLE trial: Intermittent letrozole may provide benefit for some breast cancer patients
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
AT ASCO 2017
Key clinical point:
Major finding: Disease-free survival was 85.8% and 87.5% with intermittent and continuous letrozole, respectively (hazard ratio, 1.08).
Data source: The phase III SOLE study of 4,851 women.
Disclosures: The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
SUNSHINE: High-dose vitamin D boosts PFS in metastatic CRC
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
CHICAGO – High-dose vitamin D supplementation is a simple, safe approach for improving on the efficacy of first-line chemotherapy for metastatic colorectal cancer, suggest findings of the SUNSHINE trial reported at the annual meeting of the American Society of Clinical Oncology.
“Vitamin D has shown anti-neoplastic properties in the laboratory, including inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, as well as anti-inflammatory and immunomodulatory effects,” said lead author Kimmie Ng, MD, director of clinical research and a Gastrointestinal Cancer Center physician at the Dana-Farber Cancer Institute in Boston.
“The vitamin D hypothesis is also supported by a large body of epidemiologic evidence, both from our group as well as from others, that have shown that higher plasma 25-hydroxyvitamin D levels are associated with improved survival in patients with colorectal cancer,” she added.
Notably, in the CALGB/SWOG 80405 trial of first-line therapy for colorectal cancer, patients’ median 25-hydroxy vitamin D level at baseline fell below the cutoff for deficiency (ASCO 2015 meeting, Abstract 3503). Moreover, those having higher levels ultimately had better overall survival even after other factors were taken into account.
In the SUNSHINE trial, the investigators studied 139 patients with untreated metastatic colorectal cancer. Results showed that those given FOLFOX chemotherapy and the antiangiogenic agent bevacizumab (Avastin) plus high-dose vitamin D had a one-third lower risk of progression or death compared with counterparts given the same regimen plus low-dose vitamin D.
High-dose supplementation was not associated with greater toxicity. In fact, patients in that group had a much lower incidence of grade 3 or 4 diarrhea.
“After a decade of observational data linking higher vitamin D status with improved outcomes in colorectal cancer patients, SUNSHINE is the first completed randomized double-blind controlled clinical trial of vitamin D supplementation for treatment of colorectal cancer,” Dr. Ng said. “The trial met its primary endpoint. Given this data, a larger, confirmatory phase III trial is warranted.”
The investigators are performing subgroup analyses and analyzing overall survival, and will measure patients’ 25-hydroxyvitamin D levels in plasma samples collected serially throughout the study to determine whether they correlate with outcomes.
In addition, “to help understand and elucidate underlying mechanisms and biology, we have planned several correlative studies looking at tumoral and plasma biomarkers related to the vitamin D pathway, inflammation, and tumor immunity, among other pathways,” she further noted. “We will also be conducting next-generation sequencing and gene expression analyses.”
Expert perspective
“It will be interesting to know [patients’ vitamin D levels] as the majority of patients were enrolled in New England, where I think there is a little less sunshine than in other parts of the United States, so perhaps the vitamin D levels will reflect that,” said invited discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York.
Data on vitamin D pertaining to chemoprevention and to outcomes in other malignancies have been mixed, she cautioned. For example, supplementation did not reduce the risk of recurrent colorectal adenomas in one study (N Engl J Med. 2015;373:1519-30), and benefit or harm in terms of developing advanced colorectal adenomas in another study hinged on vitamin D receptor genotype (JAMA Oncol. 2017;3:628-35). Among patients with prostate cancer, addition of vitamin D to chemotherapy was actually associated with poorer overall survival (J Clin Oncol. 2011;29:2191-8).
“SUNSHINE was a positive study. It was a very well carried out phase II trial with a significant progression-free survival benefit. Correlative analyses are ongoing, and these will be critical, looking at biomarkers, perhaps helping us identify those patients who will benefit,” Dr. Cercek summarized. “I agree 100% with the investigators that a phase III study is warranted, and I look forward to it.”
Study details
Patients in SUNSHINE were randomized to receive first-line modified FOLFOX chemotherapy and bevacizumab plus either high-dose vitamin D (oral vitamin D3 8,000 IU/day for 2 weeks as a loading dose, followed by 4,000 IU/day) or low-dose vitamin D (oral vitamin D3 400 IU/day) on a double-blind basis. The latter “is an amount you would find in a multivitamin and only increases plasma levels by about 3 ng/mL, thus serving as a useful active control” Dr. Ng noted.
Receipt of chemotherapy and bevacizumab was generally similar between groups. “It is interesting to note that more patients receiving high-dose vitamin D discontinued treatment to undergo potentially curative surgery compared to those in the control arm, though this was not statistically different,” she noted.
In intent-to-treat analysis conducted at a median follow-up of 17-18 months, progression-free survival, the trial’s primary endpoint, was a median of 13.1 months in the high-dose group and 11.2 months in the low-dose group (P = .04). The difference in favor of high-dose vitamin D remained significant in multivariate analysis (hazard ratio, 0.67; P = .02).
The groups were statistically indistinguishable with respect to overall response rate, but the disease control rate was marginally better with high-dose versus low-dose vitamin D (96% vs. 84%, P = .05).
Rates of most grade 3 or 4 adverse events did not differ significantly between groups. However, diarrhea of these grades was less common in the high-dose vitamin D group (1% vs. 12%; P = .02). With respect to grade 3 or 4 events possibly related to the vitamin therapy, there was one case of hyperphosphatemia in the high-dose group and one case of kidney stones in the low-dose group.
Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
AT ASCO 2017
Key clinical point:
Major finding: Compared with chemotherapy plus low-dose vitamin D, chemotherapy plus high-dose vitamin D was associated with a reduced risk of progression or death (hazard ratio, 0.67).
Data source: A phase II randomized trial (SUNSHINE) among 139 patients with untreated metastatic colorectal cancer.
Disclosures: Dr. Ng disclosed that she receives honoraria from Prime Oncology and Sage Publications; has a consulting or advisory role with Defined Health and Genentech/Roche; and receives research funding from Celgene, Genentech/Roche (institutional), Gilead Sciences, Pharmavite (institutional), and Trovagene.
ALTTO follow-up: Dual HER2 blockade may benefit HER2+/HR- tumors
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
AT ASCO 2017
Key clinical point:
Major finding: DFS differed slightly between lapatinib plus trastuzumab and trastuzumab alone (84% vs. 80%; HR, 0.80) among those with HER2+/HR-negative tumors but not among those with HER2+/HR+ tumors.
Data source: The phase III ALTTO trial of 8,381 patients.
Disclosures: The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
Optimizing therapy in relapsed CLL: ibrutinib and beyond
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.
Ibrutinib monotherapy
In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.
Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.
Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.
The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.
The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).
The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.
The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.
“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”
Taken together, experience to date with ibrutinib highlights some issues and unmet needs, she said: greater treatment discontinuation in the real-world setting, early relapse in patients having higher-risk genetics or complex karyotypes, and an overall low rate of remission or minimal residual disease negativity.
These are important for several reasons, Dr. Brown maintained. “Persistent disease will lead to relapse eventually. If we have up to 40% discontinuation for adverse events, then, if people are in deeper remission at the time of discontinuation, they are likely to have a longer remission off drug. And, ultimately, of course, cure would require absence of disease,” she elaborated. “Then enhancing tolerability to keep patients on drug is an ongoing unmet need.”
Ibrutinib plus ublituximab and umbralisib
In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.
A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.
The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).
The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.
“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”
“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
Ibrutinib plus CAR-T cells
In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.
Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.
At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.
Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.
Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.
“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.
“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”
AT ASCO 2017
Key clinical point:
Major finding: Long-term progression-free survival was better with ibrutinib than with ofatumumab (hazard ratio, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. Fully 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib.
Data source: An update of a phase III randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL.
Disclosures: Dr. Byrd disclosed that he receives research funding from Genentech, Acerta, and Pharmacyclics. The RESONATE trial was funded by Pharmacyclics. Dr. Nastoupil disclosed that she receives honoraria from Abbvie, Celgene, Genentech/Roche, Gilead Sciences, Pharmacyclics, and TG Therapeutics; receives research funding from Abbvie, Celgene, Janssen Biotech, and TG Therapeutics; and receives travel, accommodations, and/or expenses from Janssen Biotech. The trial was funded by TG Therapeutics. Dr. Gill disclosed that he receives honoraria from Alexion Pharmaceuticals, receives research funding from Novartis (institutional), and has patents for CAR-T cells for acute myeloid leukemia. The trial was funded by Novartis.
Patch is early indicator of temperature rise after HSCT
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
A fever-monitoring patch was well tolerated in hospitalized patients undergoing stem cell transplant or intensive chemotherapy for leukemia, and alerted physicians to the presence of a fever much earlier than did standard temperature-taking procedures, according to findings from a study abstract that was published in conjunction with the annual meeting of the American Society of Clinical Oncology.
The patch can transmit data via Bluetooth to an iPad or smartphone, and it attempts to bring temperature recording in line with other vital signs. “It’s the only vital sign that’s not continuously monitored outside of the ICU,” said John Gannon, CEO of Blue Spark, which markets the TempTraq underarm patch used in the study.
The units are constructed with thin batteries that can be “printed” on to any surface. “Being disposable makes it a very usable work flow device,” said Mr. Gannon.
The researchers tested the TempTraq in 10 patients who had been admitted for stem cell transplant or high dose chemotherapy for leukemia.
In addition to wearing the patch, patients had their temperature measured in standard fashion every 4 hours. The researchers defined a temperature rise as a spike above 100.4° F. The device measured body temperature every 10 minutes (14,342 temperature measurements).
Standard of care measurement identified 23 temperature rise episodes, 21 of which were recorded by the TempTraq patch. The device caught temperature spikes much sooner than did standard of care measures – a median of 140.1 minutes earlier (range, 30-180 minutes).
All 10 patients continued to wear the patch throughout the hospital stay, with 9 of 10 reporting that the patch was comfortable and didn’t produce any skin irritation. Eight patients indicated interest in using the patch again, and 8 said they were completely satisfied with the patch.
The next step is to determine if the patch could be used successfully in an outpatient stem cell transplant setting.
The device could also be integrated directly with hospital central monitoring systems using Blue Spark’s TempTraq Connect, which is a HIPAA-compliant service supported by the Google Healthcare Cloud Platform, though this was not tested in the current study.
The TempTraq could be used to monitor patients for the onset of sepsis and allow faster interventions, according to Mr. Gannon. Also, patients who are susceptible to infections could be sent home with a TempTraq monitor, which would send signals to a central monitoring station.
FROM ASCO 2017
Key clinical point: The device has the potential to detect infections as well as sepsis.
Major finding: The device detected fevers a median of 140 minutes sooner than did standard hospital testing.
Data source: Prospective study of 10 patients.
Disclosures: Mr. Gannon is an employee of Blue Spark Technologies, which sponsored the study.
Antibody from AML survivor may prove therapeutic
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – A therapeutic target and possibly a treatment for acute myeloid leukemia and myelodysplastic syndrome may lie in the immortalized B cells of a patient whose acute myeloid leukemia was cured after allogeneic stem cell transplantation.
A B cell clone isolated from this patient makes a hypermutated immunoglobulin G1 antibody that binds leukemic blasts of all World Health Organization 2008 AML and myelodysplastic syndrome (MDS) types, based on cells obtained from 60 AML or MDS patients, but does not target healthy cells and lymphoid tissue, Mette D. Hazenberg, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“CD43 is broadly expressed on AML and MDS and, therefore, is a highly interesting target for immunotherapy,” said Dr. Hazenberg of AIMM Therapeutics and Academic Medical Center, Amsterdam.
The growth of luciferase-labeled AML cells expressing CD43s was inhibited in highly immunodeficient NOD scid-gamma mice that were reconstituted with human hematopoietic stem cells injected with AT1413. Healthy human hematopoietic cells, which express low levels of the target, were not affected by the treatment.
Next steps include further in vivo preclinical studies, according to Dr. Hazenberg.
AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: The growth of luciferase-labeled SH2 cells was inhibited in highly immunodeficient NSG (NOD scid-gamma) mice that were reconstituted with human hematopoietic stem cells injected with AT1413.
Data source: Cellular studies and studies in severely immunodeficient mice.
Disclosures: Dr. Hazenberg is with AIMM Therapeutics and Academic Medical Center, Amsterdam. AIMM Therapeutics is a biotech company comprising a joint venture between Immpact and the Academic Medical Center (AMC) at the University of Amsterdam. The study was supported by an AMC PhD scholarship and the KWF Dutch Cancer Society.
Lenalidomide consolidation linked to extended overall survival in non-del(11q) CLL
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Data source: Results from 342 patients in the phase 2 CALGB 10404 trial.
Disclosures: Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
Bendamustine plus rituximab may have edge for treating indolent NHL, MCL
CHICAGO – Overall survival was comparable at 5 years of follow up for three regimens in treatment-naive patients with indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL), based on long-term results from the BRIGHT study.
While progression-free survival, event-free survival, and duration of response were significantly better with bendamustine plus rituximab (BR), overall survival at 5 years did not significantly differ in patients given this regimen and compared to patients given rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP), Ian Flinn, MD, of Tennessee Oncology, Nashville, reported at the annual meeting of the American Society of Clinical Oncology.
Quality of life was somewhat better for the patients given BR, but those patients were also at higher risk for secondary malignancies (42 vs. 24), most of which were squamous cell carcinomas, observed Dr. Kahl, professor of medicine at Washington University, St. Louis.
In BRIGHT, 224 treatment-naive patients with indolent NHL or MCL were randomized to receive BR and were compared to 223 similar patients who received either R-CHOP (104 patients) or R-CVP (119 patients). At least six cycles of therapy were completed by 203 patients in the BR group and by 196 in the R-CHOP/R-CVP group. Rituximab maintenance therapy was given to 43% of the BR group and to 45% of the R-CHOP/R-CVP group.
For BR and R-CHOP/R-CVP, the 5-year progression-free survival rate was 65.5% (95% CI, 58.5-71.6) and 55.8% (95% CI, 48.4-62.5), respectively. The overall survival rate for the entire patient group was 81.7% (75.7-86.3) and 85% (79.3-89.3) respectively. Comparing BR and R-CHOP/R-CVP, the hazard ratio (95% CI) for progression-free survival was 0.61 (0.45-0.85; P = .0025), the HR for event-free survival was 0.63 (0.46-0.84; P = .0020), the HR for duration of response was 0.66 (0.47-0.92; P = .0134), and the HR for overall survival was 1.15 (0.72-1.84; P = .5461).
Similar results were found in indolent NHL (progression-free survival 0.70 [0.49-1.01; P = .0582]) and MCL (progression-free survival 0.40 [0.21-0.75; P = .0035]), with the strongest effect in MCL, Dr. Flinn said.
Dr. Kahl noted that the advantages for the BR regimen include that it is not associated with alopecia, neuropathy, or steroid issues, and that it may extend progression-free survival and time to next treatment. On the other hand, R-CHOP is associated with less GI toxicity, rash, opportunistic infections, and prolonged cytopenia. Also, the BR regimen was associated with a higher risk of secondary cancers, primarily squamous cell carcinomas.
There were 42 secondary malignancies in the BR group and 24 in the R-CHOP/R-CVP group, Dr. Flinn reported.
It is theoretically possible that BR equals R-CHOP plus maintenance therapy from an efficacy perspective, Dr. Kahl said.
As virtually all excess adverse event fatalities occurred during maintenance therapy, it is possible that maintenance therapy after BR “does more harm than good.” This high priority issue “should be evaluated in the BRIGHT data set,” Dr. Kahl recommended.
Teva Branded Pharmaceutical Products R&D sponsored the study. Dr. Flinn had no relationships to disclose; two of his fellow researchers are Teva employees. Dr. Kahl disclosed serving as an adviser or consultant to Abbvie, Acerta Pharma, Celgene, Cell Therapeutics, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Juno Therapeutics, Millennium, Pharmacyclics, Sandoz, and Seattle Genetics.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – Overall survival was comparable at 5 years of follow up for three regimens in treatment-naive patients with indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL), based on long-term results from the BRIGHT study.
While progression-free survival, event-free survival, and duration of response were significantly better with bendamustine plus rituximab (BR), overall survival at 5 years did not significantly differ in patients given this regimen and compared to patients given rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP), Ian Flinn, MD, of Tennessee Oncology, Nashville, reported at the annual meeting of the American Society of Clinical Oncology.
Quality of life was somewhat better for the patients given BR, but those patients were also at higher risk for secondary malignancies (42 vs. 24), most of which were squamous cell carcinomas, observed Dr. Kahl, professor of medicine at Washington University, St. Louis.
In BRIGHT, 224 treatment-naive patients with indolent NHL or MCL were randomized to receive BR and were compared to 223 similar patients who received either R-CHOP (104 patients) or R-CVP (119 patients). At least six cycles of therapy were completed by 203 patients in the BR group and by 196 in the R-CHOP/R-CVP group. Rituximab maintenance therapy was given to 43% of the BR group and to 45% of the R-CHOP/R-CVP group.
For BR and R-CHOP/R-CVP, the 5-year progression-free survival rate was 65.5% (95% CI, 58.5-71.6) and 55.8% (95% CI, 48.4-62.5), respectively. The overall survival rate for the entire patient group was 81.7% (75.7-86.3) and 85% (79.3-89.3) respectively. Comparing BR and R-CHOP/R-CVP, the hazard ratio (95% CI) for progression-free survival was 0.61 (0.45-0.85; P = .0025), the HR for event-free survival was 0.63 (0.46-0.84; P = .0020), the HR for duration of response was 0.66 (0.47-0.92; P = .0134), and the HR for overall survival was 1.15 (0.72-1.84; P = .5461).
Similar results were found in indolent NHL (progression-free survival 0.70 [0.49-1.01; P = .0582]) and MCL (progression-free survival 0.40 [0.21-0.75; P = .0035]), with the strongest effect in MCL, Dr. Flinn said.
Dr. Kahl noted that the advantages for the BR regimen include that it is not associated with alopecia, neuropathy, or steroid issues, and that it may extend progression-free survival and time to next treatment. On the other hand, R-CHOP is associated with less GI toxicity, rash, opportunistic infections, and prolonged cytopenia. Also, the BR regimen was associated with a higher risk of secondary cancers, primarily squamous cell carcinomas.
There were 42 secondary malignancies in the BR group and 24 in the R-CHOP/R-CVP group, Dr. Flinn reported.
It is theoretically possible that BR equals R-CHOP plus maintenance therapy from an efficacy perspective, Dr. Kahl said.
As virtually all excess adverse event fatalities occurred during maintenance therapy, it is possible that maintenance therapy after BR “does more harm than good.” This high priority issue “should be evaluated in the BRIGHT data set,” Dr. Kahl recommended.
Teva Branded Pharmaceutical Products R&D sponsored the study. Dr. Flinn had no relationships to disclose; two of his fellow researchers are Teva employees. Dr. Kahl disclosed serving as an adviser or consultant to Abbvie, Acerta Pharma, Celgene, Cell Therapeutics, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Juno Therapeutics, Millennium, Pharmacyclics, Sandoz, and Seattle Genetics.
mdales@frontlinemedcom.com
On Twitter @maryjodales
CHICAGO – Overall survival was comparable at 5 years of follow up for three regimens in treatment-naive patients with indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL), based on long-term results from the BRIGHT study.
While progression-free survival, event-free survival, and duration of response were significantly better with bendamustine plus rituximab (BR), overall survival at 5 years did not significantly differ in patients given this regimen and compared to patients given rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP), Ian Flinn, MD, of Tennessee Oncology, Nashville, reported at the annual meeting of the American Society of Clinical Oncology.
Quality of life was somewhat better for the patients given BR, but those patients were also at higher risk for secondary malignancies (42 vs. 24), most of which were squamous cell carcinomas, observed Dr. Kahl, professor of medicine at Washington University, St. Louis.
In BRIGHT, 224 treatment-naive patients with indolent NHL or MCL were randomized to receive BR and were compared to 223 similar patients who received either R-CHOP (104 patients) or R-CVP (119 patients). At least six cycles of therapy were completed by 203 patients in the BR group and by 196 in the R-CHOP/R-CVP group. Rituximab maintenance therapy was given to 43% of the BR group and to 45% of the R-CHOP/R-CVP group.
For BR and R-CHOP/R-CVP, the 5-year progression-free survival rate was 65.5% (95% CI, 58.5-71.6) and 55.8% (95% CI, 48.4-62.5), respectively. The overall survival rate for the entire patient group was 81.7% (75.7-86.3) and 85% (79.3-89.3) respectively. Comparing BR and R-CHOP/R-CVP, the hazard ratio (95% CI) for progression-free survival was 0.61 (0.45-0.85; P = .0025), the HR for event-free survival was 0.63 (0.46-0.84; P = .0020), the HR for duration of response was 0.66 (0.47-0.92; P = .0134), and the HR for overall survival was 1.15 (0.72-1.84; P = .5461).
Similar results were found in indolent NHL (progression-free survival 0.70 [0.49-1.01; P = .0582]) and MCL (progression-free survival 0.40 [0.21-0.75; P = .0035]), with the strongest effect in MCL, Dr. Flinn said.
Dr. Kahl noted that the advantages for the BR regimen include that it is not associated with alopecia, neuropathy, or steroid issues, and that it may extend progression-free survival and time to next treatment. On the other hand, R-CHOP is associated with less GI toxicity, rash, opportunistic infections, and prolonged cytopenia. Also, the BR regimen was associated with a higher risk of secondary cancers, primarily squamous cell carcinomas.
There were 42 secondary malignancies in the BR group and 24 in the R-CHOP/R-CVP group, Dr. Flinn reported.
It is theoretically possible that BR equals R-CHOP plus maintenance therapy from an efficacy perspective, Dr. Kahl said.
As virtually all excess adverse event fatalities occurred during maintenance therapy, it is possible that maintenance therapy after BR “does more harm than good.” This high priority issue “should be evaluated in the BRIGHT data set,” Dr. Kahl recommended.
Teva Branded Pharmaceutical Products R&D sponsored the study. Dr. Flinn had no relationships to disclose; two of his fellow researchers are Teva employees. Dr. Kahl disclosed serving as an adviser or consultant to Abbvie, Acerta Pharma, Celgene, Cell Therapeutics, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Juno Therapeutics, Millennium, Pharmacyclics, Sandoz, and Seattle Genetics.
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: For BR and R-CHOP/R-CVP, the 5-year progression-free survival rate was 65.5% (95% CI, 58.5-71.6) and 55.8% (95% CI, 48.4-62.5), respectively.
Data source: In BRIGHT, 224 treatment-naive patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma were randomized to receive BR and were compared to 223 similar patients who received either R-CHOP (104 patients) or R-CVP (119 patients).
Disclosures: Teva Branded Pharmaceutical Products R&D sponsored the study. Dr. Flinn had no relationships to disclose; two of his fellow researchers are Teva employees. Dr. Kahl disclosed serving as an adviser or consultant to Abbvie, Acerta Pharma, Celgene, Cell Therapeutics, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Juno Therapeutics, Millennium, Pharmacyclics, Sandoz, and Seattle Genetics.