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Survival of patients with mCRPC on hormone therapy differs by race
SAN FRANCISCO – When given the same hormonal therapy for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), African American men live about 4 months longer than do white men, finds a retrospective cohort study being reported at the 2019 Genitourinary Cancers Symposium.
“We know that African American men have a higher risk of mCRPC and worse survival than white men,” said lead study author Megan McNamara, MD, of Duke University, Durham, N.C. “However, despite this, there is also evidence to suggest that African Americans with advanced prostate cancer actually have better outcomes in response to several prostate cancer treatments compared to Caucasians.”
She and her colleagues analyzed data from the Veterans Health Administration database for a 5-year period (2013-2018), focusing on 2,123 white and 787 African American male veterans with chemotherapy-naive mCRPC who were treated with the anti-androgen abiraterone (Zytiga) or the androgen receptor inhibitor enzalutamide (Xtandi). Overall survival was measured from the first prescription claim for either drug following medical or surgical castration.
Main results reported in a presscast leading up to the symposium showed that with a median follow-up of about 1.6 years, median overall survival was 30 months for African American men, compared with 26 months for white men. The difference corresponded to a significantly lower risk of death for African American men in both univariate analysis (hazard ratio, 0.887; P = .0435) and multivariate analysis adjusted for age and comorbidities (HR, 0.826; P = .0020).
“When controlling for access to care through a single-payer system – in this case, the VA Health System – in chemotherapy-naive mCRPC patients, African Americans may have better overall survival than Caucasians when treated with abiraterone or enzalutamide,” Dr. McNamara summarized. “These results are consistent with what we have seen in prior studies in this population involving docetaxel (Taxotere), sipuleucel-T (Provenge), and abiraterone.”
Importantly, the data expand on previous findings for abiraterone in the Abi Race study, she noted. That study established that African American men had a better prostate-specific antigen (PSA) response to the drug (J Clin Oncol. 2018 Jun 7. doi: 10.1200/JCO.2018.36.18_suppl.LBA5009).
The new findings do not alter but rather reinforce current clinical practice, according to Dr. McNamara. “These are standard-of-care treatments, and it’s important that we have real-world studies that show that the standard-of-care treatments really work,” she elaborated. “So I don’t think that they necessarily change what we are doing. But they reinforce what we are already doing, and that it’s important that we make sure that every African American who is eligible for these medicines gets them.
“Our study is retrospective,” she acknowledged. “But it emphasizes the need for prospective trials in order to validate these findings and in order to try to understand the mechanism that underlies these differences in survival outcomes between African Americans and Caucasians with mCRPC when treated with these novel hormone therapies.”
The data are “very provocative, and it adds to an emerging database that if confirmed prospectively, really changes the way we think about racial differences,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Full results of the study will be reported at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Dr. McNamara disclosed that she receives travel, accommodations, and/or expenses from Clovis Oncology; honoraria from Bayer and Exelixis; and research funding (institutional) from Bayer, Seattle Genetics/Astellas, Agensys, Clovis Oncology, and Janssen. The study was funded by Pfizer.
SOURCE: McNamara MA et al. Abstract 212.
SAN FRANCISCO – When given the same hormonal therapy for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), African American men live about 4 months longer than do white men, finds a retrospective cohort study being reported at the 2019 Genitourinary Cancers Symposium.
“We know that African American men have a higher risk of mCRPC and worse survival than white men,” said lead study author Megan McNamara, MD, of Duke University, Durham, N.C. “However, despite this, there is also evidence to suggest that African Americans with advanced prostate cancer actually have better outcomes in response to several prostate cancer treatments compared to Caucasians.”
She and her colleagues analyzed data from the Veterans Health Administration database for a 5-year period (2013-2018), focusing on 2,123 white and 787 African American male veterans with chemotherapy-naive mCRPC who were treated with the anti-androgen abiraterone (Zytiga) or the androgen receptor inhibitor enzalutamide (Xtandi). Overall survival was measured from the first prescription claim for either drug following medical or surgical castration.
Main results reported in a presscast leading up to the symposium showed that with a median follow-up of about 1.6 years, median overall survival was 30 months for African American men, compared with 26 months for white men. The difference corresponded to a significantly lower risk of death for African American men in both univariate analysis (hazard ratio, 0.887; P = .0435) and multivariate analysis adjusted for age and comorbidities (HR, 0.826; P = .0020).
“When controlling for access to care through a single-payer system – in this case, the VA Health System – in chemotherapy-naive mCRPC patients, African Americans may have better overall survival than Caucasians when treated with abiraterone or enzalutamide,” Dr. McNamara summarized. “These results are consistent with what we have seen in prior studies in this population involving docetaxel (Taxotere), sipuleucel-T (Provenge), and abiraterone.”
Importantly, the data expand on previous findings for abiraterone in the Abi Race study, she noted. That study established that African American men had a better prostate-specific antigen (PSA) response to the drug (J Clin Oncol. 2018 Jun 7. doi: 10.1200/JCO.2018.36.18_suppl.LBA5009).
The new findings do not alter but rather reinforce current clinical practice, according to Dr. McNamara. “These are standard-of-care treatments, and it’s important that we have real-world studies that show that the standard-of-care treatments really work,” she elaborated. “So I don’t think that they necessarily change what we are doing. But they reinforce what we are already doing, and that it’s important that we make sure that every African American who is eligible for these medicines gets them.
“Our study is retrospective,” she acknowledged. “But it emphasizes the need for prospective trials in order to validate these findings and in order to try to understand the mechanism that underlies these differences in survival outcomes between African Americans and Caucasians with mCRPC when treated with these novel hormone therapies.”
The data are “very provocative, and it adds to an emerging database that if confirmed prospectively, really changes the way we think about racial differences,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Full results of the study will be reported at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Dr. McNamara disclosed that she receives travel, accommodations, and/or expenses from Clovis Oncology; honoraria from Bayer and Exelixis; and research funding (institutional) from Bayer, Seattle Genetics/Astellas, Agensys, Clovis Oncology, and Janssen. The study was funded by Pfizer.
SOURCE: McNamara MA et al. Abstract 212.
SAN FRANCISCO – When given the same hormonal therapy for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), African American men live about 4 months longer than do white men, finds a retrospective cohort study being reported at the 2019 Genitourinary Cancers Symposium.
“We know that African American men have a higher risk of mCRPC and worse survival than white men,” said lead study author Megan McNamara, MD, of Duke University, Durham, N.C. “However, despite this, there is also evidence to suggest that African Americans with advanced prostate cancer actually have better outcomes in response to several prostate cancer treatments compared to Caucasians.”
She and her colleagues analyzed data from the Veterans Health Administration database for a 5-year period (2013-2018), focusing on 2,123 white and 787 African American male veterans with chemotherapy-naive mCRPC who were treated with the anti-androgen abiraterone (Zytiga) or the androgen receptor inhibitor enzalutamide (Xtandi). Overall survival was measured from the first prescription claim for either drug following medical or surgical castration.
Main results reported in a presscast leading up to the symposium showed that with a median follow-up of about 1.6 years, median overall survival was 30 months for African American men, compared with 26 months for white men. The difference corresponded to a significantly lower risk of death for African American men in both univariate analysis (hazard ratio, 0.887; P = .0435) and multivariate analysis adjusted for age and comorbidities (HR, 0.826; P = .0020).
“When controlling for access to care through a single-payer system – in this case, the VA Health System – in chemotherapy-naive mCRPC patients, African Americans may have better overall survival than Caucasians when treated with abiraterone or enzalutamide,” Dr. McNamara summarized. “These results are consistent with what we have seen in prior studies in this population involving docetaxel (Taxotere), sipuleucel-T (Provenge), and abiraterone.”
Importantly, the data expand on previous findings for abiraterone in the Abi Race study, she noted. That study established that African American men had a better prostate-specific antigen (PSA) response to the drug (J Clin Oncol. 2018 Jun 7. doi: 10.1200/JCO.2018.36.18_suppl.LBA5009).
The new findings do not alter but rather reinforce current clinical practice, according to Dr. McNamara. “These are standard-of-care treatments, and it’s important that we have real-world studies that show that the standard-of-care treatments really work,” she elaborated. “So I don’t think that they necessarily change what we are doing. But they reinforce what we are already doing, and that it’s important that we make sure that every African American who is eligible for these medicines gets them.
“Our study is retrospective,” she acknowledged. “But it emphasizes the need for prospective trials in order to validate these findings and in order to try to understand the mechanism that underlies these differences in survival outcomes between African Americans and Caucasians with mCRPC when treated with these novel hormone therapies.”
The data are “very provocative, and it adds to an emerging database that if confirmed prospectively, really changes the way we think about racial differences,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Full results of the study will be reported at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Dr. McNamara disclosed that she receives travel, accommodations, and/or expenses from Clovis Oncology; honoraria from Bayer and Exelixis; and research funding (institutional) from Bayer, Seattle Genetics/Astellas, Agensys, Clovis Oncology, and Janssen. The study was funded by Pfizer.
SOURCE: McNamara MA et al. Abstract 212.
REPORTING FROM GUCS 2019
Key clinical point: Benefit of contemporary hormone therapy for mCRPC may vary by race.
Major finding: Median overall survival on hormone therapy was 30 months for African American men versus 26 months for white men (adjusted hazard ratio, 0.826; P = .0020).
Study details: A retrospective cohort study of 2,123 white and 787 African American male veterans with chemotherapy-naive mCRPC treated with abiraterone or enzalutamide.
Disclosures: Dr. McNamara disclosed that she receives travel, accommodations, and/or expenses from Clovis Oncology; honoraria from Bayer and Exelixis; and research funding (institutional) from Bayer, Seattle Genetics/Astellas, Agensys, Clovis Oncology, and Janssen. The study was funded by Pfizer.
Source: McNamara MA et al. GUCS 2019, Abstract 212.
Pembrolizumab-axitinib nearly halves risk of death in RCC
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
REPORTING FROM GUCS 2019
Key clinical point: The combination of pembrolizumab and axitinib may become a new first-line standard of care in advanced renal cell carcinoma.
Major finding: Compared with sunitinib monotherapy, pembrolizumab and axitinib combination therapy prolonged progression-free survival (hazard ratio, 0.69; P = .0001) and overall survival (HR, 0.53; P less than .0001).
Study details: A phase 3, randomized, controlled trial among 861 patients with untreated locally advanced or metastatic renal cell carcinoma (KEYNOTE-426).
Disclosures: Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from AstraZeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
Source: Powles T et al. GUCS 2019, Abstract 543.
Radioligand is highly active in metastatic castrate-resistant prostate cancer
SAN FRANCISCO – (LuPSMA), finds a single-center phase 2 trial to be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“Whilst there have been major advances in the last few years with several drugs that prolong survival in these men, the disease remains fatal in a relatively short period of time, and there is an urgent need for new effective therapies,” said lead study author Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne.
LuPSMA is a radiolabeled small molecule that binds with high affinity to PSMA (prostate-specific membrane antigen), enabling targeted delivery of beta radiation to lesions throughout the body. To be eligible for the trial, patients had to have PSMA-positive disease. Results among the first 30 patients treated showed good activity and acceptable toxicity (Lancet Oncol. 2018;19:825-33), leading to enrollment of an expansion cohort of 20 patients.
With a median follow-up of 23.5 months among all 50 patients, nearly two-thirds achieved a 50% or greater reduction in their PSA level, Dr. Hofman reported in a presscast held before the symposium. Median overall survival exceeded 12 months for the whole cohort and was especially good for the subset achieving that level of PSA reduction, at 18 months.
“This is a single-arm study with no control arm. So whilst my impression is that this is a life-prolonging therapy, this is not a claim that we can make yet because there is no comparator arm with an existing treatment or therapy,” he acknowledged. However, data from the literature suggest that in the absence of this novel radioligand, the patients would likely have survived only about 6-9 months.
“These results in 50 men provide further confidence to our previously published 30-patient cohort, demonstrating high response rates and low toxicity in men with mCRPC who have progressed after multiple conventional therapies,” Dr. Hofman said. The findings also “support a novel mechanism of action for this therapy compared to existing therapies.”
The favorable data have led to initiation of two randomized controlled trials: the phase 2 TheraP trial (NCT03392428) comparing LuPSMA with cabazitaxel (Jevtana), and the phase 3 VISION trial (NCT03511664), comparing LuPSMA with best standard of care. “We really need the larger trials ... to get a confident assessment on whether it improves survival and by how much,” he maintained. “But my impression, seeing these patients come into the clinic very sick and seeing them improve on the therapy, and knowing those averages [for survival without this therapy], is that these trials are likely to be positive.”
“As a clinician, I will tell you that this is a very intriguing agent, and the VISION study, which is a registration trial, is open in the U.S.,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Of the 76 patients screened for the LuPSMA trial, 16 (21%) were ineligible because of insufficient PSMA uptake on a PSMA–FDG PET scan. “The majority of patients with this disease are suitable. Probably somewhere in the range of 20% to 30%, depending on how you measure it, may not be suitable,” Dr. Hofman said.
The 50 patients ultimately enrolled had aggressive disease, as indicated by a median PSA doubling time of 2.6 months. Most had previously received abiraterone (Zytiga), enzalutamide (Xtandi), or both (90%), as well as docetaxel (84%) or cabazitaxel (48%). “Many of these men had no further treatment options, and without this study open, they probably would have received end-of-life palliative care,” he said.
The median number of LuPSMA cycles administered was four, according to data reported in the presscast leading up to the symposium. Eight patients received fewer than four cycles because they had an exceptional response, while 10 patients did not complete all planned cycles because of disease progression.
Main results showed that PSA levels fell by at least 30% in 74% of patients, at least 50% in 64% of patients, and at least 80% in 44% of patients. Only two patients did not see any reduction. “We think this is probably a feature of our careful selection of patients with the PET scanning up front to really enrich the study for patients who are likely to benefit from the treatment,” Dr. Hofman said. The reductions in PSA were accompanied by reductions in positive lesions on PSMA–FDG PET.
For the entire cohort, median overall survival was 13.3 months. But it was significantly longer for those with versus without at least a 50% PSA decline (18.0 vs. 8.7 months; P = .001).
Fourteen patients who experienced progression on LuPSMA were given additional doses after the trial ended, as part of an off-trial expanded-access program. Fully 64% of these patients achieved a PSA reduction of at least 50%, and median overall survival in all of the retreated patients was 33 months.
Dr. Hofman disclosed that he has a consulting or advisory role with Endocyte; receives research funding (institutional) from Endocyte; and receives travel, accommodations, and/or expenses from Ipsen and Sanofi. The trial received research funding from the Peter MacCallum Cancer Centre.
SOURCE: Hofman M et al. GUCS 2019, Abstract 228.
SAN FRANCISCO – (LuPSMA), finds a single-center phase 2 trial to be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“Whilst there have been major advances in the last few years with several drugs that prolong survival in these men, the disease remains fatal in a relatively short period of time, and there is an urgent need for new effective therapies,” said lead study author Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne.
LuPSMA is a radiolabeled small molecule that binds with high affinity to PSMA (prostate-specific membrane antigen), enabling targeted delivery of beta radiation to lesions throughout the body. To be eligible for the trial, patients had to have PSMA-positive disease. Results among the first 30 patients treated showed good activity and acceptable toxicity (Lancet Oncol. 2018;19:825-33), leading to enrollment of an expansion cohort of 20 patients.
With a median follow-up of 23.5 months among all 50 patients, nearly two-thirds achieved a 50% or greater reduction in their PSA level, Dr. Hofman reported in a presscast held before the symposium. Median overall survival exceeded 12 months for the whole cohort and was especially good for the subset achieving that level of PSA reduction, at 18 months.
“This is a single-arm study with no control arm. So whilst my impression is that this is a life-prolonging therapy, this is not a claim that we can make yet because there is no comparator arm with an existing treatment or therapy,” he acknowledged. However, data from the literature suggest that in the absence of this novel radioligand, the patients would likely have survived only about 6-9 months.
“These results in 50 men provide further confidence to our previously published 30-patient cohort, demonstrating high response rates and low toxicity in men with mCRPC who have progressed after multiple conventional therapies,” Dr. Hofman said. The findings also “support a novel mechanism of action for this therapy compared to existing therapies.”
The favorable data have led to initiation of two randomized controlled trials: the phase 2 TheraP trial (NCT03392428) comparing LuPSMA with cabazitaxel (Jevtana), and the phase 3 VISION trial (NCT03511664), comparing LuPSMA with best standard of care. “We really need the larger trials ... to get a confident assessment on whether it improves survival and by how much,” he maintained. “But my impression, seeing these patients come into the clinic very sick and seeing them improve on the therapy, and knowing those averages [for survival without this therapy], is that these trials are likely to be positive.”
“As a clinician, I will tell you that this is a very intriguing agent, and the VISION study, which is a registration trial, is open in the U.S.,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Of the 76 patients screened for the LuPSMA trial, 16 (21%) were ineligible because of insufficient PSMA uptake on a PSMA–FDG PET scan. “The majority of patients with this disease are suitable. Probably somewhere in the range of 20% to 30%, depending on how you measure it, may not be suitable,” Dr. Hofman said.
The 50 patients ultimately enrolled had aggressive disease, as indicated by a median PSA doubling time of 2.6 months. Most had previously received abiraterone (Zytiga), enzalutamide (Xtandi), or both (90%), as well as docetaxel (84%) or cabazitaxel (48%). “Many of these men had no further treatment options, and without this study open, they probably would have received end-of-life palliative care,” he said.
The median number of LuPSMA cycles administered was four, according to data reported in the presscast leading up to the symposium. Eight patients received fewer than four cycles because they had an exceptional response, while 10 patients did not complete all planned cycles because of disease progression.
Main results showed that PSA levels fell by at least 30% in 74% of patients, at least 50% in 64% of patients, and at least 80% in 44% of patients. Only two patients did not see any reduction. “We think this is probably a feature of our careful selection of patients with the PET scanning up front to really enrich the study for patients who are likely to benefit from the treatment,” Dr. Hofman said. The reductions in PSA were accompanied by reductions in positive lesions on PSMA–FDG PET.
For the entire cohort, median overall survival was 13.3 months. But it was significantly longer for those with versus without at least a 50% PSA decline (18.0 vs. 8.7 months; P = .001).
Fourteen patients who experienced progression on LuPSMA were given additional doses after the trial ended, as part of an off-trial expanded-access program. Fully 64% of these patients achieved a PSA reduction of at least 50%, and median overall survival in all of the retreated patients was 33 months.
Dr. Hofman disclosed that he has a consulting or advisory role with Endocyte; receives research funding (institutional) from Endocyte; and receives travel, accommodations, and/or expenses from Ipsen and Sanofi. The trial received research funding from the Peter MacCallum Cancer Centre.
SOURCE: Hofman M et al. GUCS 2019, Abstract 228.
SAN FRANCISCO – (LuPSMA), finds a single-center phase 2 trial to be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“Whilst there have been major advances in the last few years with several drugs that prolong survival in these men, the disease remains fatal in a relatively short period of time, and there is an urgent need for new effective therapies,” said lead study author Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne.
LuPSMA is a radiolabeled small molecule that binds with high affinity to PSMA (prostate-specific membrane antigen), enabling targeted delivery of beta radiation to lesions throughout the body. To be eligible for the trial, patients had to have PSMA-positive disease. Results among the first 30 patients treated showed good activity and acceptable toxicity (Lancet Oncol. 2018;19:825-33), leading to enrollment of an expansion cohort of 20 patients.
With a median follow-up of 23.5 months among all 50 patients, nearly two-thirds achieved a 50% or greater reduction in their PSA level, Dr. Hofman reported in a presscast held before the symposium. Median overall survival exceeded 12 months for the whole cohort and was especially good for the subset achieving that level of PSA reduction, at 18 months.
“This is a single-arm study with no control arm. So whilst my impression is that this is a life-prolonging therapy, this is not a claim that we can make yet because there is no comparator arm with an existing treatment or therapy,” he acknowledged. However, data from the literature suggest that in the absence of this novel radioligand, the patients would likely have survived only about 6-9 months.
“These results in 50 men provide further confidence to our previously published 30-patient cohort, demonstrating high response rates and low toxicity in men with mCRPC who have progressed after multiple conventional therapies,” Dr. Hofman said. The findings also “support a novel mechanism of action for this therapy compared to existing therapies.”
The favorable data have led to initiation of two randomized controlled trials: the phase 2 TheraP trial (NCT03392428) comparing LuPSMA with cabazitaxel (Jevtana), and the phase 3 VISION trial (NCT03511664), comparing LuPSMA with best standard of care. “We really need the larger trials ... to get a confident assessment on whether it improves survival and by how much,” he maintained. “But my impression, seeing these patients come into the clinic very sick and seeing them improve on the therapy, and knowing those averages [for survival without this therapy], is that these trials are likely to be positive.”
“As a clinician, I will tell you that this is a very intriguing agent, and the VISION study, which is a registration trial, is open in the U.S.,” said ASCO expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, deputy director and associate director of clinical research at the University of Virginia Cancer Center and professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Of the 76 patients screened for the LuPSMA trial, 16 (21%) were ineligible because of insufficient PSMA uptake on a PSMA–FDG PET scan. “The majority of patients with this disease are suitable. Probably somewhere in the range of 20% to 30%, depending on how you measure it, may not be suitable,” Dr. Hofman said.
The 50 patients ultimately enrolled had aggressive disease, as indicated by a median PSA doubling time of 2.6 months. Most had previously received abiraterone (Zytiga), enzalutamide (Xtandi), or both (90%), as well as docetaxel (84%) or cabazitaxel (48%). “Many of these men had no further treatment options, and without this study open, they probably would have received end-of-life palliative care,” he said.
The median number of LuPSMA cycles administered was four, according to data reported in the presscast leading up to the symposium. Eight patients received fewer than four cycles because they had an exceptional response, while 10 patients did not complete all planned cycles because of disease progression.
Main results showed that PSA levels fell by at least 30% in 74% of patients, at least 50% in 64% of patients, and at least 80% in 44% of patients. Only two patients did not see any reduction. “We think this is probably a feature of our careful selection of patients with the PET scanning up front to really enrich the study for patients who are likely to benefit from the treatment,” Dr. Hofman said. The reductions in PSA were accompanied by reductions in positive lesions on PSMA–FDG PET.
For the entire cohort, median overall survival was 13.3 months. But it was significantly longer for those with versus without at least a 50% PSA decline (18.0 vs. 8.7 months; P = .001).
Fourteen patients who experienced progression on LuPSMA were given additional doses after the trial ended, as part of an off-trial expanded-access program. Fully 64% of these patients achieved a PSA reduction of at least 50%, and median overall survival in all of the retreated patients was 33 months.
Dr. Hofman disclosed that he has a consulting or advisory role with Endocyte; receives research funding (institutional) from Endocyte; and receives travel, accommodations, and/or expenses from Ipsen and Sanofi. The trial received research funding from the Peter MacCallum Cancer Centre.
SOURCE: Hofman M et al. GUCS 2019, Abstract 228.
REPORTING FROM GUCS 2019
Key clinical point: Lutetium-177 PSMA-617 (LuPSMA) is highly active in PSMA-positive metastatic castrate-resistant prostate cancer.
Major finding: PSA level fell by at least 50% in 64% of men, and median overall survival was 13.3 months.
Study details: A single-center, single-arm phase 2 trial among 50 men with PSMA-positive metastatic castrate-resistant prostate cancer (LuPSMA trial).
Disclosures: Dr. Hofman disclosed that he has a consulting or advisory role with Endocyte; receives research funding (institutional) from Endocyte; and receives travel, accommodations, and/or expenses from Ipsen and Sanofi. The trial received research funding from the Peter MacCallum Cancer Centre.
Source: Hofman M et al. GUCS 2019, Abstract 228.
Pancreatic cancer expression signature is linked to chemoresistance
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Molecular features of pancreatic cancer may help estimate prognosis and predict response to chemotherapy.
Major finding: Compared with peers whose tumors had a classic RNA expression signature, patients whose tumors had a basal-like RNA expression signature had poorer overall survival when given mFOLFIRINOX (hazard ratio, 0.33; P = .0005).
Study details: Prospective trial with whole-genome sequencing and RNA sequencing of tumors in 150 patients with advanced pancreatic ductal adenocarcinoma before start of first-line therapy (COMPASS trial).
Disclosures: Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
Source: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
Gastrectomy does not alter benefit of new oral chemo in gastric cancer
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
SAN FRANCISCO – suggests a preplanned subgroup analysis of the global phase 3 randomized controlled TAGS trial. Results were reported at the 2019 GI Cancers Symposium.
“The standard of care for early-stage gastric cancer is surgery, which is the only potentially curative treatment,” noted lead investigator David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York. “Forty percent of patients with metastatic disease have had a history of previous gastrectomy.”
The TAGS trial assessed efficacy of combined trifluridine and tipiracil (Lonsurf) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens. (This combination chemotherapy is currently approved in the United States as later-line therapy for metastatic colorectal cancer.)
Compared with placebo, trifluridine/tipiracil prolonged overall survival by 2.6 months in the subgroup who had previously undergone gastrectomy, a benefit slightly greater than the 2.1 months previously reported for the entire trial population (Lancet Oncol. 2018;19:1437-48). And although the gastrectomy subgroup experienced more grade 3 or 4 adverse events, they were not more likely to stop treatment because of toxicity.
“The data from this analysis reinforce the benefit for trifluridine/tipiracil as prolonging survival versus placebo, and this is regardless of prior gastrectomy,” Dr. Ilson summarized. “Hematologic adverse events, such as neutropenia and leukopenia, may have been somewhat more frequent among the trifluridine/tipiracil–treated patients with gastrectomy than in the overall population, but this did not result in more treatment discontinuations. Exposure to the drug was similar between patients with gastrectomy and those in the overall population.”
“Trifluridine/tipiracil is an effective treatment option with a manageable toxicity profile for patients with metastatic gastric cancer, regardless of prior gastrectomy status,” he concluded.
Still fit for treatment
The disconnect between toxicity and treatment discontinuation seen in the TAGS trial is not new, according to invited discussant Martine Extermann, MD, PhD, leader of the Senior Adult Oncology Program at the Moffitt Cancer Center in Tampa. Previous data among geriatric cancer patients have similarly shown that, despite substantial chemotherapy toxicity, by and large, there are only modest effects on health-related quality of life, performance status, and instrumental activities of daily living, she noted.
“The CTCAE [Common Terminology Criteria for Adverse Events] toxicity differences do not always translate into functional impact and treatment cessation. So this is only part of the picture. It’s a convenient part. It’s easily measurable. It’s well acknowledged as a measurement of side effects. But it does not tell the whole story. Quality of life and functional status add to the picture,” Dr. Extermann elaborated. “What the TAGS study is telling us is, despite a gastrectomy, these patients can be treated as a third-line treatment population for gastric cancer, which is not necessarily obvious to every oncologist.”
At the same time, she added that it would be helpful to have nutritional data on the study patients – and on all patients in similar trials, for that matter – because nutritional status is one of the components of the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score used to predict chemotherapy toxicity in older adults.
“I would support that [trifluridine/tipiracil] is an effective third-line chemotherapy in gastric cancer patients with or without prior gastrectomy, and this can be given safely,” Dr. Extermann concluded.
Study details
Patients in TAGS were randomized 2:1 to trifluridine/tipiracil (formerly TAS-102) or placebo, each added to best supportive care. (Trifluridine is a novel oral thymidine analogue, and tipiracil prevents trifluridine degradation.) Overall, 44% had undergone gastrectomy before entering the trial.
In the entire trial population, overall survival was 5.7 months with trifluridine/tipiracil and 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.85; P = .0006), as previously reported.
Among the subgroup who had undergone prior gastrectomy, overall survival was 6.0 months with trifluridine/tipiracil and 3.4 months with placebo (HR, 0.57; 95% CI, 0.41-0.79), Dr. Ilson reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The combination also netted better progression-free survival (2.2 vs. 1.8 months; HR, 0.48; 95% CI, 0.35-0.65). “These data mirror the data seen in the overall treatment population,” he commented.
In a multivariate analysis including all prespecified factors, prior gastrectomy was neither prognostic nor predictive. Moreover, the treatment effect size remained the same after adjustment for potential prognostic factors.
Exposure to trifluridine/tipiracil was similar for the gastrectomy subgroup and the entire trial population in terms of relative dose intensity, median number of cycles, and treatment duration.
The rate of grade 3 or 4 treatment-related adverse events with trifluridine/tipiracil in the gastrectomy subgroup, 64%, was higher than that in the entire trial population, 53%, but the rate of discontinuation because of any-grade adverse events was similar, at 10% and 13%, respectively.
The difference in grade 3 or 4 adverse events between the gastrectomy subgroup and the entire trial population was mainly driven by higher rates of neutropenia (44% vs. 34%) and leukopenia (14% vs. 9%) in the former.
Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
SOURCE: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Patients with metastatic gastric cancer experience largely similar efficacy and safety outcomes with oral trifluridine/tipiracil regardless of prior gastrectomy.
Major finding: Compared with placebo, trifluridine/tipiracil improved overall survival in the gastrectomy subgroup (hazard ratio, 0.57) with a higher rate of grade 3/4 adverse events in that subgroup (64% vs. 53%) but similar rate of discontinuation because of adverse events (10% vs. 13%).
Study details: Preplanned subgroup analysis of a phase 3 randomized controlled trial (TAGS trial) among 507 patients with metastatic gastric or gastroesophageal junction cancer who had received at least two prior chemotherapy regimens.
Disclosures: Dr. Ilson disclosed that he has a consulting role with Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, Pieris, Roche/Genentech, and Taiho and that he receives research support from Taiho. The study was funded by Taiho Oncology and Taiho Pharmaceutical.
Source: Ilson DH et al. 2019 GI Cancers Symposium, Abstract 3.
Cancer vaccine fails in CRC but trial yields lessons
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
SAN FRANCISCO – , according to final results of the German and Austrian phase 2 randomized LICC trial. However, information gleaned from the results, which were reported at the 2019 GI Cancers Symposium, will help inform future research.
“Hepatic metastectomy … is deemed the only potential curative treatment for stage IV colorectal cancer with limited liver disease. However, high recurrence rates after resection remain a major challenge: They range up to 50%-75% within the first 2 years,” said lead investigator Carl C. Schimanski, MD, PhD, of the Klinikum Darmstadt GmbH in Darmstadt, Germany.
Tecemotide is a liposome carrying mucin 1 (MUC1) antigen and an adjuvant that is taken up by antigen-presenting cells, ultimately leading to production of MUC1-specific cytotoxic T lymphocytes that target tumors. “MUC1 has been described to be expressed in up to 100% of colorectal cancer metastasis, so we thought this might be a good target,” Dr. Schimanski explained.
All 121 patients in the LICC trial had recently undergone primary or secondary resection, with either R0 or R1 outcome, for liver-only metastases of colorectal cancer. They were treated on a double-blind basis with a single dose of cyclophosphamide to reduce regulatory T cells, followed by tecemotide (weekly for 8 weeks, then every 6 weeks for up to 2 years) or with placebo.
Results showed that recurrence-free survival was actually shorter, by more than 5 months, with the vaccine versus placebo. In addition, the 3-year rate of overall survival was lower by an absolute 10%. Interestingly, tumor expression of MUC1 did not influence benefit from the vaccine.
But Dr. Schimanski noted that survival was better than expected at the trial’s outset. For example, the 65-month median overall survival among all patients in LICC undergoing secondary resection was about a year longer than that of similar patients in the CELIM trial (54 months) and the FIRE-3 trial (56 months).
“The LICC trial failed to meet its primary endpoint of significantly improving recurrence-free survival or overall survival with tecemotide. We had unexpectedly high overall survival in both arms, highlighting the critical importance of accurate staging and intensive surveillance, in our eyes,” he concluded. “We have further analysis of a very large translational program, and we hope to learn a lot about recurrence independent of tecemotide.”
A good space for testing immune therapies
In 2009, a consensus panel of immunologists ranked MUC1 as the second-best cancer antigen for translational research, “so there was clearly a feeling that this was a good target at that time for going forward,” noted invited discussant Michael J. Overman, MD, a professor in the department of gastrointestinal medical oncology, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston.
He agreed with the LICC investigators’ conclusions that the trial was negative and that MUC1 expression does not appear to predict outcome. “Whether that’s the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know. I do think that survival was encouraging,” he said.
“There’s many unanswered questions in regards to the LICC study and in regards to cancer vaccines in general,” Dr. Overman noted. Among them, what are the optimal antigens to target, what are the optimal vaccine formulations and adjuvant agents, what is the best way to address the immunosuppressive tumor microenvironment, and what is the correct disease setting for vaccine testing?
“The LICC study is very impressive in demonstrating that we can enroll in this posthepatectomy space, postmetastectomy space. It’s a very increasingly interesting space for, potentially, drug development and immunologic exploration,” he maintained. “One of the benefits of this space when we talk about a minimal residual disease setting is that you potentially do not have the suppressive effects from the tumor microenvironment that potentially are hindering success in regards to having immune therapy response. So I would say that this is a space we should consider for drug development going forward.”
Study details
In the LICC trial, tecemotide and placebo yielded a respective median recurrence-free survival of 6.1 months and 11.4 months (P = .1754) and a respective overall survival of 62.8 months and not reached (P = .2141), Dr. Schimanski reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The 3-year overall survival rate was 69.1% with tecemotide and 79.1% with placebo.
That survival “was astonishing for us,” Dr. Schimanski said. “We think – but we cannot prove it – that has resulted from careful staging due to the retrospective radiological review and the initial staging, and a very tight surveillance program.”
Findings were similar regardless of whether patients had low, medium, or high tumor MUC1 expression; therefore, “we have to conclude that the target is not really validated.”
Patients in the tecemotide arm had higher rates of any-grade nausea, fatigue, diarrhea, and viral upper respiratory tract infections, at least some of which was likely attributable to the single dose of cyclophosphamide, according to Dr. Schimanski. They also had higher (but still low) rates of grade 3 or 4 back pain, anemia, ileus, cholestatic jaundice, and increased blood uric acid levels (2.5% for each). There was a single death in that arm from Merkel cell carcinoma that was deemed potentially related to the vaccine.
Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
SOURCE: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Tecemotide did not improve outcomes among patients with resected liver-only metastases of CRC.
Major finding: Tecemotide was not superior to placebo with respect to median recurrence-free survival (6.1 vs. 11.4 months; P = .1754) or overall survival (62.8 months vs. not reached; P = .2141).
Study details: A phase 2 randomized controlled trial among 121 patients having had R0/R1 resection of isolated liver CRC metastases (LICC trial).
Disclosures: Dr. Schimanski disclosed that an immediate family member is employed by Merck and that he receives research funding from Merck KGaA (institutional). The trial was funded by Merck KGaA.
Source: Schimanski CC et al. GI Cancers Symposium, Abstract 480.
Dual BRAF, MEK inhibition proves highly active in biliary tract cancer
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
SAN FRANCISCO – Simultaneously targeting two components of the same signaling pathway in BRAF V600E–mutated biliary tract cancer is a winning strategy, suggests an analysis of the multicenter phase 2 ROAR basket trial.
“Recently, a number of genetic targets have been identified with distinct rates of frequency in intrahepatic, extrahepatic, and gallbladder cancer that are the subject of a number of ongoing clinical trials. In retrospective studies, mutations in BRAF have been identified in about 5%-7% of patients, predominantly in the intrahepatic cohort,” lead investigator Zev A. Wainberg, MD, noted at the 2019 GI Cancers Symposium. Previous research has shown combined inhibition of BRAF and MEK – two sequential proteins on the MAP kinase signaling pathway – to be efficacious in BRAF V600E–mutated melanoma, non–small cell lung cancer, and anaplastic thyroid cancer.
In the ROAR trial, 178 patients with advanced or metastatic BRAF V600E–mutated rare cancers who had exhausted standard treatment options were treated with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist). Dr. Wainberg reported results for the 35 patients having biliary tract cancer, most of whom were heavily pretreated.
With a median duration of follow-up of 8 months, the overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers. More than half of patients had a grade 3 or 4 adverse event, but just one had to permanently stop treatment because of toxicity.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E–mutated biliary tract cancers treated with the combination of BRAF and MEK inhibition. Efficacy in this patient population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” pointed out Dr. Wainberg, codirector of the GI oncology program and an assistant professor of medicine at the University of California, Los Angeles.
“Dabrafenib and trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancers and should be considered a meaningful therapeutic option for these patients,” he contended. “BRAF V600E is one of several actionable driver mutations in this disease and should be considered for routine testing in patients with biliary tract cancers. In addition, among all the other data [that are] emerging in molecular analysis of this malignancy, perhaps among all the GI malignancies, this has the potential to undergo multiple studies of other targeted therapies.”
Why stop there?
“I don’t think there is anything needed to convince you that this treatment is very effective. It’s incredibly impressive,” commented invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the gastrointestinal cancers program, University of Southern California Norris Comprehensive Cancer Center in Los Angeles.
But experience with other BRAF-mutant malignancies, such as BRAF-mutant colorectal cancer, suggests that further benefit can accrue from hitting additional molecular targets, he said. For example, rationally selected triplet combinations can suppress emergence of resistant clones up front.
“How can we do even better? I think we need to be smart in how we inhibit downstream signaling of BRAF-mutant disease,” Dr. Lenz maintained, as downstream targeting is potentially more effective. Therefore, a logical candidate for improving on the combination of BRAF and MEK inhibitors in biliary tract cancer is an ERK inhibitor. Alternatively, the combination may be synergistic when used with immune checkpoint inhibitors that target programmed death-1 or programmed death–ligand 1.
Oncologists should perform next-generation sequencing for all patients with biliary tract cancer, in Dr. Lenz’s opinion. “Biliary cancer is one of these cancers where we have many potentially actionable mutations. I know there is no drug approved, but many trials are ongoing,” he elaborated. “So I just encourage you to do that in order to identify potential trials or treatment options.”
Study details
In the ROAR trial, patients received open-label dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) until unacceptable toxicity, disease progression, or death.
All 35 patients with biliary cancer had received gemcitabine, and 80% had received at least two lines of prior systemic therapy.
The median treatment duration was 6 months, Dr. Wainberg reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. Fully 86% of patients were on treatment for longer than 3 months.
In addition to the impressive response rates, the patients had a median progression-free survival of 9.2 months, and a median overall survival of 11.7 months.
Adverse events were as expected based on previous experience with these targeted therapies, according to Dr. Wainberg. The rate of grade 3 or 4 adverse events was 57%. “These were predominantly pyrexia, a known side effect of BRAF inhibitors, which is managed with antipyretic therapy and dexamethasone,” he noted. Rash and gastrointestinal toxicity were also common.
Although adverse events often led to dose reductions and dose interruptions, only a single patient (3% of the cohort) had to stop treatment early because of an event (cholangitis).
SOURCE: Wainberg ZA et al. 2019 GI Cancers Symposium, Abstract 187.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The overall response rate was 42% as assessed by investigators and 36% as assessed by independent reviewers.
Study details: A multicenter, single-arm, open-label phase 2 basket trial with reporting of data for 35 patients having BRAF V600E–mutated biliary tract cancer (ROAR trial).
Disclosures: Dr. Wainberg disclosed that he has a consulting or advisory role with and receives research funding from numerous pharmaceutical companies including Novartis. The trial was sponsored by GlaxoSmithKline and Novartis.
Source: Wainberg ZA et al. GI Cancers Symposium, Abstract 187.
mRECIST response to kinase inhibitors predicts survival in HCC
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
SAN FRANCISCO – Patients with hepatocellular carcinoma (HCC) who have a response to first-line kinase inhibitors based on modified RECIST (mRECIST) criteria live almost a year longer than counterparts who have stable or progressive disease, finds a retrospective post hoc analysis of the REFLECT trial.
“The inability to accurately evaluate response to targeted or locoregional therapies resulted in the adaptation of RECIST to mRECIST, guidelines specifically designed to evaluate response to treatment in HCC,” noted lead investigator Masatoshi Kudo, MD, PhD, of the department of gastroenterology and hepatology, Kindai University Faculty of Medicine, Osaka, Japan. “Based on recommendations from the EASL [European Association for the Study of the Liver] consensus conference in 2000, mRECIST was developed to assess response based on the reduction of viable tumor burden … rather than overall tumor shrinkage. However, EASL clinical practice guidelines also suggested additional studies are needed to validate this approach.”
The investigators analyzed data from REFLECT, a global phase 3 noninferiority, randomized, controlled trial that showed overall survival with the novel kinase inhibitor lenvatinib (Lenvima) was not inferior to that with the older kinase inhibitor sorafenib (Nexavar) in 954 patients with untreated, unresectable HCC (Lancet. 2018;391:1163-73).
The new analysis, reported at the 2019 GI Cancers Symposium, showed that, among all randomized patients, those having an objective response according to mRECIST criteria were 39% less likely to die after other factors were taken into account. The finding was consistent in a landmark analysis, which addresses the issue of lead-time bias.
“Objective response by mRECIST was an independent predictor of overall survival in patients with HCC regardless of treatment,” Dr. Kudo concluded, adding that the findings are consistent with those of several previous studies. “Thus, patients who achieve an objective response can potentially expect a longer overall survival. However, additional studies are needed to further validate the correlation between objective response and overall survival.”
Findings in context
Although the mRECIST criteria overcome some issues with the size-based RECIST criteria in assessing HCC, the former are not without their limitations, noted invited discussant Andrew X. Zhu, MD, PhD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
These limitations include, for example, the need for more stringent selection of target lesions and the potential for antiangiogenic agents to cause vasoconstriction, complicating measurement. “There is tremendous intraobserver and interobserver variability, and a tremendous learning curve,” he added, noting that in REFLECT the mRECIST overall response rate assessed by independent reviewers was considerably higher than that assessed by investigators.
To date, three other trials of targeted therapies have similarly found an association between mRECIST response and overall survival. But a fourth did not.
“In the era of immunotherapy being actively applied to HCC, it’s important to recognize that this association actually may be agent dependent,” Dr. Zhu said. “Even though the TKIs with antiangiogenic [activity] have shown an improved overall response [going] from RECIST to mRECIST, this has not been recapitulated, at least based on the current experience that we have, with checkpoint inhibitors.”
The REFLECT investigators’ conclusion “is certainly backed by the large dataset from a positive phase 3 trial. It has very sound statistical methodology, and it may actually provide the initial evidence that this biomarker may serve as a potentially relevant surrogate to predict overall survival,” he said.
At the same time, there is reason to be cautious given the post hoc, retrospective nature of the study; the lack of a comparison with conventional RECIST response; absence of analysis of the potential correlation of stable disease with overall survival; and the lumping together of two agents, among other issues.
“For these reasons, I do think additional studies are warranted for prospective validation of the findings,” Dr. Zhu concluded.
Study details
REFLECT patients had an investigator-assessed mRECIST objective response rate of 16.7% overall (24.1% with lenvatinib and 9.2% with sorafenib) and a median overall survival of 13.0 months (13.6 months with lenvatinib and 12.3 months with sorafenib).
Median overall survival was 22.4 months for mRECIST responders and 11.4 months for nonresponders (P less than .001), Dr. Kudo reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In a multivariate analysis, this difference translated to a 39% reduction in risk of death for responders (hazard ratio, 0.61; P less than .0001).
Moreover, the survival advantage of response was evident in landmark analyses, whether response was assessed at 2 months (HR, 0.75; P = .033), at 4 months (HR, 0.72; P = .009), or at 6 months (HR, 0.73; P = .010).
Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 186.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: .
Major finding: Median overall survival was a respective 22.4 months and 11.4 months in patients who did and did not have a response according to mRECIST criteria (HR, 0.61; P less than .0001).
Study details: A retrospective post hoc analysis of a phase 3 randomized controlled trial of lenvatinib versus sorafenib among 954 patients with untreated, unresectable HCC (REFLECT trial).
Disclosures: Dr. Kudo disclosed that he receives honoraria or has a consulting or advisory role with several pharmaceutical companies. The presentation was sponsored by Eisai and Merck.
Source: Kudo M et al. 2019 GI Cancers Symposium, Abstract 186.
Pembrolizumab bests chemo in PD-L1-positive esophageal cancer
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) may soon unseat chemotherapy as standard second-line therapy for certain advanced cancers of the esophagus or gastroesophageal junction, according to data from the global phase 3 KEYNOTE-181 trial.
“Patients with advanced esophageal cancer after first-line therapy have a poor prognosis and limited treatment options,” said lead investigator Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan. “Taxanes and irinotecan are commonly used after first-line chemotherapy; however, no overall survival benefit has been demonstrated for chemotherapy in a phase 3 study.”
The 628 patients in KEYNOTE-181 were randomly assigned to chemotherapy (paclitaxel, docetaxel, or irinotecan, left to investigator’s choice) or pembrolizumab, an antibody to programmed death 1 (PD-1). Currently, pembrolizumab is approved in the United States for use as third- or later-line therapy for gastric or gastroesophageal junction cancer that is positive for programmed death ligand 1 (PD-L1) as defined by a combined positive score (CPS) of 1 or greater, among many other indications.
Main trial results reported at the 2019 GI Cancers Symposium showed that among patients with high PD-L1 expression, defined by a CPS of 10 or higher, pembrolizumab reduced risk of death by about one-third, prolonging survival by 2.6 months. The difference met the predefined threshold for statistical significance.
There was a more modest, nonsignificant benefit among patients with tumors having squamous cell carcinoma histology and among the entire intention-to-treat population.
The rate of treatment-related adverse events of grade 3-5 was roughly half as high with pembrolizumab versus chemotherapy (18.2% vs. 40.9%).
“These data suggest that pembrolizumab should be considered a new standard of care for patients with PD-L1 CPS of 10 or greater metastatic esophageal cancer in the second-line setting,” Dr. Kojima concluded.
Implications for practice
“In the intention-to-treat population, the KEYNOTE-181 study failed to meet its primary endpoint of overall survival, so pembrolizumab is not indicated in unselected esophageal cancer patients,” said invited discussant Harry H. Yoon, MD, cochair of the Esophageal/Gastric Cancer Disease Group at the Mayo Clinic Cancer Center, Rochester, Minn.
For the patients with squamous histology, the negative findings are unlikely to be due to underpowering and may instead be related to the trial’s use of multiple primary endpoints, in his opinion. “Some may advocate using pembrolizumab off protocol [in this population], particularly for patients who cannot tolerate chemotherapy, because it is after all better tolerated than chemo. This can be a discussion point for guideline committees,” he said.
The results for the group with PD-L1 CPS scores of 10 or higher are statistically significant and clinically meaningful, as well as internally valid – with the caveat that patients were not stratified by PD-L1 status and some favorable risk factors were more common in the pembrolizumab group, according to Dr. Yoon. The 43% survival rate at 12 months translates to a number needed to treat of just four patients for one patient to be alive at that time point.
“A multivariate analysis could help clarify whether the positive results in the PD-L1 CPS 10-or-higher subgroup are explained by a higher frequency of favorable patient characteristics in the pembrolizumab arm,” he noted. “The strength of those results could influence guideline recommendations and implementation in clinical practice.”
Subgroup analyses suggested benefit was mainly seen in Asian patients, who tend to have higher prevalence of squamous tumors, Dr. Yoon said. Potential molecular differences at play here may be elucidated by ongoing research.
Ultimately, the findings in the PD-L1 CPS 10-or-higher group have potential implications for biomarker testing. “For the patient in front of me, I currently order PD-L1 and HER2 at first metastatic diagnosis in gastroesophageal adenocarcinomas,” he elaborated. “It’s reasonable to consider a practice change. This means ordering PD-L1 at first metastatic diagnosis in patients with squamous carcinoma of the esophagus. This would also mean some pathology labs may need to report a more detailed PD-L1 CPS score, if they don’t already.”
These findings also have potential implications for treatment. “For the second-line setting, for squamous carcinoma of the esophagus, esophageal adenocarcinomas, and Siewert 1 adenocarcinomas with a PD-L1 CPS of 10 or more, it’s reasonable to consider pembrolizumab,” Dr. Yoon noted. “This should be discussed within guideline committees, and the results will be submitted to regulatory authorities, who will have access to more detailed data. It’s possible that these recommendations could be modified in the near future.”
Study details
As KEYNOTE-181 had three primary endpoints (overall survival in each of three populations), P values required for statistical significance were defined accordingly. “The study was positive if one of the primary endpoints was met,” Dr. Kojima explained at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Some 35% of trial patients had a PD-L1 CPS of 10 or greater. In this population, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy. The hazard ratio was 0.69, with the P value (.0074) meeting that predefined for statistical significance in this population (less than or equal to .0085). The 12-month rate of overall survival was 43% and 20%, respectively.
About 64% of trial patients had squamous cell carcinoma histology. In this population, median overall survival was 8.2 months with pembrolizumab and 7.1 months with chemotherapy. The hazard ratio was 0.78, but the P value (.0095) did not meet that predefined for statistical significance in this group (less than or equal to .0077).
Finally, in the entire intention-to-treat population, median overall survival was identical, at 7.1 months, with pembrolizumab and with chemotherapy. The hazard ratio was 0.89 in favor of the antibody, but the P value (.0560) did not meet that predefined for statistical significance in this population (less than or equal to .0077).
A similar pattern was seen for other outcomes, with patients having PD-L1 CPS greater than or equal to 10 deriving greatest benefit from pembrolizumab over chemotherapy in terms of progression-free survival (hazard ratio, 0.73), response rate (21.5% vs. 6.1%), and median duration of response (9.3 vs. 7.7 months).
“Toxicity profiles were in line with previous reports of each treatment. No new safety signals were observed,” Dr. Kojima reported. Pembrolizumab was associated with a higher rate of immune-mediated and infusion reactions (23.2% vs. 7.4%), but lower rates of most gastrointestinal and hematologic adverse events.
Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
SOURCE: Kojima T et al. GI Cancers Symposium Abstract 2, https://meetinglibrary.asco.org/record/169377/abstract.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: .
Major finding: Among patients with a PD-L1 combined positive score of 10 or higher, median overall survival was 9.3 months with pembrolizumab and 6.7 months with chemotherapy (hazard ratio, 0.69; P = .0074).
Study details: A phase 3 randomized controlled trial among 628 patients having progression after first-line therapy for advanced cancer of the esophagus or GEJ (KEYNOTE-181).
Disclosures: Dr. Kojima disclosed ties to Oncolys BioPharma, Astellas, Amgen, MSD, Ono Pharmaceutical, and Shionogi. Merck Sharp & Dohme sponsored the trial.
Source: Kojima T et al. GI Cancers Symposium, Abstract 2.
Age may dictate benefit of andecaliximab in gastric cancer
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”
Study details
Patients in GAMMA-1 were randomized evenly to receive the mFOLFOX-6 regimen plus either placebo or andecaliximab given intravenously every 2 weeks.
Median overall survival, the primary outcome, was 12.5 months with the antibody and 11.8 months with placebo, a nonsignificant difference (hazard ratio, 0.93; P = .56), Dr. Shah reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
However, exploratory analyses showed benefit increased with quartile of age, and the difference in overall survival was significant for those 65 years and older at 13.9 months versus 10.5 months (HR, 0.64; P = .029).
The pattern was similar for progression-free survival, with only a trend among all patients (7.5 vs. 7.1 months; HR, 0.84; P = .10) but a significant reduction in risk for the older subgroup (8.7 vs 5.6 months; HR, 0.5; P less than .001).
Overall response rate was better with andecaliximab than with placebo in the entire trial population (51% vs. 41%; odds ratio, 1.47; P = .049). The rate of complete response was 8.3% and 4.7%, respectively.
“There were no meaningful differences in the safety profile of andecaliximab versus placebo in the groups treated,” Dr. Shah said. Rates and types of treatment-emergent adverse events of any grade and of grade 3 or higher were similar, with gastrointestinal and hematologic events predominating.
“We were intrigued with this phenomenon by age,” he said, and the investigators therefore assessed factors differing by age. “We looked at chemotherapy treatment and toxicity, things like that, and it didn’t appear that we could find any factor that was really associated. We did find that older patients actually received more treatment, but that’s likely because they had somewhat of a benefit with andecaliximab.”
Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck, and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
SOURCE: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.
This article was updated 1/24/19.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Benefit of first-line andecaliximab in advanced gastric/gastroesophageal junction cancer may be age dependent.
Major finding: Compared with placebo plus mFOLFOX-6, andecaliximab plus mFOLFOX-6 did not improve overall survival among all patients, but it did among those aged 65 years and older in exploratory analyses (hazard ratio, 0.64; P = .029).
Study details: A phase 3, randomized, controlled trial among 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (GAMMA-1 trial).
Disclosures: Dr. Shah reported receiving research funding from Boston Biomedical, Gilead Sciences, Merck (institutional), and Oncolys BioPharma. The trial was sponsored by Gilead Sciences.
Source: Shah MA et al. GI Cancers Symposium 2019, Abstract 4.