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Durvalumab fails to advance in pancreatic cancer
, according to results of a phase 2 randomized controlled trial.
“Immune checkpoint blockade in PDAC as a single-agent therapy was not currently indicated beyond the subgroup of patients with microsatellite instability or mismatch repair deficiency ... however, a precedent existed for evaluating a combination of 2 immune checkpoint antagonists in this setting,” noted the investigators, led by Eileen M. O’Reilly, MD, gastrointestinal medical oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Cornell University, New York. In particular, a combination of agents that inhibit programmed cell death-1 ligand 1 (PD-L1) and the human T-cell receptor protein cytotoxic T-lymphocyte-associated protein 4 (CTLA4), nonredundant mechanisms, has shown promise.
Dr. O’Reilly and coinvestigators treated 65 patients in the trial’s initial cohort who had received only a single first-line fluorouracil- or gemcitabine-based chemotherapy regimen for recurrent or metastatic PDAC. Patients were randomized to combination therapy with durvalumab (Imfinzi), an anti-PD-L1 antibody, and tremelimumab, an investigational anti-CTLA4 antibody, followed by durvalumab alone, or to durvalumab monotherapy.
The objective response rate was just 3.1% with combination therapy and 0% with monotherapy—values that fell far short of the predefined 10% rate needed to initiate a planned expansion cohort. Both groups had a median progression-free survival of 1.5 months, Dr. O’Reilly and associates wrote. Their report is in JAMA Oncology.
The rate of grade 3 or higher treatment-related adverse events was 22% in the combination therapy group and 6% in the monotherapy group. In both groups, the most common events were fatigue and diarrhea. Some 6% and 3% of patients, respectively, stopped treatment because of a treatment-related adverse event.
The small trial population precluded detailed analyses of associations between treatment response and PD-L1 expression or microsatellite instability status.
“The observed efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy was reflective of a population of patients with [metastatic PDAC] who had poor prognoses and rapidly progressing disease; however, treatment was well tolerated,” Dr. O’Reilly and coinvestigators wrote.
“Future studies are needed to evaluate how to best combine immune checkpoint blockade with other agents, including cytotoxic and targeted therapies, with the intention of overcoming the unique immunosuppressive, hypoxic, and fibrotic tumor microenvironment of PDAC. Such studies should evaluate biomarker expression to identify patients most likely to benefit from immune checkpoint blockade,” they recommended.
Dr. O’Reilly disclosed holding a consulting or advisory role or receiving grants from numerous pharmaceutical companies, including AstraZeneca, which funded the study.
SOURCE: O’Reilly EM et al. JAMA Oncol. 2019 July 18. doi:10.1001/jamaoncol.2019.1588.
“This study clearly and soberly demonstrates that despite the observed clinical benefits of dual ICI [immune check-point inhibition] therapy appreciated in other tumor types, PDAC remains refractory to standalone dual ICI therapy,” Dan A. Laheru, MD, and colleagues wrote in an invited commentary. “The priming of antitumor T-cell responses in the draining lymph nodes by anti-CTLA-4 therapy, tremelimumab, appears to be insufficient in priming T cells in PDAC for the addition of PD-L1 therapy.”
Current evidence suggests two main challenges will have to be overcome to pave the way for effective ICI therapy in PDAC and similarly nonimmunogenic cancers, they proposed. One will be inducing high-quality effector T cells into the tumor microenvironment (TME); the other will be reprogramming this “extremely immunosuppressive” milieu.
“Although there remains a rationale for testing dual checkpoint blockade therapy in patients with PDAC, this strategy will likely need to include agents that will first trigger the trafficking of T cells into the otherwise T-cell-poor tumor so that T cells are available for activation by ICIs. Furthermore, other agents need to be further tested in combination that would effectively reprogram the otherwise immunosuppressive PDAC TME to optimize T-cell function by turning off inhibitory signals,” Dr. Laheru and colleagues noted. “This study also strongly suggests that we should no longer test stand-alone ICI monotherapy or dual ICI in patients with PDAC without a T-cell inducing agent, whether that is a personalized vaccine-based therapy, small-molecule/antibody immunomodulator, or another immunotherapy agent altogether.
“The road to developing improved immunotherapy for patients with PDAC remains challenging,” they concluded. “Through the results of such work presented by the authors along with a greater understanding of the immune microenvironment, it is our hope that subsequent trials will allow future patients with PDAC to realize the benefits of immunotherapy that have helped so many in other cancer types.”
Arsen Osipov, MD, Neeha Zaidi, MD, and Dan A. Laheru, MD, are with the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.
“This study clearly and soberly demonstrates that despite the observed clinical benefits of dual ICI [immune check-point inhibition] therapy appreciated in other tumor types, PDAC remains refractory to standalone dual ICI therapy,” Dan A. Laheru, MD, and colleagues wrote in an invited commentary. “The priming of antitumor T-cell responses in the draining lymph nodes by anti-CTLA-4 therapy, tremelimumab, appears to be insufficient in priming T cells in PDAC for the addition of PD-L1 therapy.”
Current evidence suggests two main challenges will have to be overcome to pave the way for effective ICI therapy in PDAC and similarly nonimmunogenic cancers, they proposed. One will be inducing high-quality effector T cells into the tumor microenvironment (TME); the other will be reprogramming this “extremely immunosuppressive” milieu.
“Although there remains a rationale for testing dual checkpoint blockade therapy in patients with PDAC, this strategy will likely need to include agents that will first trigger the trafficking of T cells into the otherwise T-cell-poor tumor so that T cells are available for activation by ICIs. Furthermore, other agents need to be further tested in combination that would effectively reprogram the otherwise immunosuppressive PDAC TME to optimize T-cell function by turning off inhibitory signals,” Dr. Laheru and colleagues noted. “This study also strongly suggests that we should no longer test stand-alone ICI monotherapy or dual ICI in patients with PDAC without a T-cell inducing agent, whether that is a personalized vaccine-based therapy, small-molecule/antibody immunomodulator, or another immunotherapy agent altogether.
“The road to developing improved immunotherapy for patients with PDAC remains challenging,” they concluded. “Through the results of such work presented by the authors along with a greater understanding of the immune microenvironment, it is our hope that subsequent trials will allow future patients with PDAC to realize the benefits of immunotherapy that have helped so many in other cancer types.”
Arsen Osipov, MD, Neeha Zaidi, MD, and Dan A. Laheru, MD, are with the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.
“This study clearly and soberly demonstrates that despite the observed clinical benefits of dual ICI [immune check-point inhibition] therapy appreciated in other tumor types, PDAC remains refractory to standalone dual ICI therapy,” Dan A. Laheru, MD, and colleagues wrote in an invited commentary. “The priming of antitumor T-cell responses in the draining lymph nodes by anti-CTLA-4 therapy, tremelimumab, appears to be insufficient in priming T cells in PDAC for the addition of PD-L1 therapy.”
Current evidence suggests two main challenges will have to be overcome to pave the way for effective ICI therapy in PDAC and similarly nonimmunogenic cancers, they proposed. One will be inducing high-quality effector T cells into the tumor microenvironment (TME); the other will be reprogramming this “extremely immunosuppressive” milieu.
“Although there remains a rationale for testing dual checkpoint blockade therapy in patients with PDAC, this strategy will likely need to include agents that will first trigger the trafficking of T cells into the otherwise T-cell-poor tumor so that T cells are available for activation by ICIs. Furthermore, other agents need to be further tested in combination that would effectively reprogram the otherwise immunosuppressive PDAC TME to optimize T-cell function by turning off inhibitory signals,” Dr. Laheru and colleagues noted. “This study also strongly suggests that we should no longer test stand-alone ICI monotherapy or dual ICI in patients with PDAC without a T-cell inducing agent, whether that is a personalized vaccine-based therapy, small-molecule/antibody immunomodulator, or another immunotherapy agent altogether.
“The road to developing improved immunotherapy for patients with PDAC remains challenging,” they concluded. “Through the results of such work presented by the authors along with a greater understanding of the immune microenvironment, it is our hope that subsequent trials will allow future patients with PDAC to realize the benefits of immunotherapy that have helped so many in other cancer types.”
Arsen Osipov, MD, Neeha Zaidi, MD, and Dan A. Laheru, MD, are with the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.
, according to results of a phase 2 randomized controlled trial.
“Immune checkpoint blockade in PDAC as a single-agent therapy was not currently indicated beyond the subgroup of patients with microsatellite instability or mismatch repair deficiency ... however, a precedent existed for evaluating a combination of 2 immune checkpoint antagonists in this setting,” noted the investigators, led by Eileen M. O’Reilly, MD, gastrointestinal medical oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Cornell University, New York. In particular, a combination of agents that inhibit programmed cell death-1 ligand 1 (PD-L1) and the human T-cell receptor protein cytotoxic T-lymphocyte-associated protein 4 (CTLA4), nonredundant mechanisms, has shown promise.
Dr. O’Reilly and coinvestigators treated 65 patients in the trial’s initial cohort who had received only a single first-line fluorouracil- or gemcitabine-based chemotherapy regimen for recurrent or metastatic PDAC. Patients were randomized to combination therapy with durvalumab (Imfinzi), an anti-PD-L1 antibody, and tremelimumab, an investigational anti-CTLA4 antibody, followed by durvalumab alone, or to durvalumab monotherapy.
The objective response rate was just 3.1% with combination therapy and 0% with monotherapy—values that fell far short of the predefined 10% rate needed to initiate a planned expansion cohort. Both groups had a median progression-free survival of 1.5 months, Dr. O’Reilly and associates wrote. Their report is in JAMA Oncology.
The rate of grade 3 or higher treatment-related adverse events was 22% in the combination therapy group and 6% in the monotherapy group. In both groups, the most common events were fatigue and diarrhea. Some 6% and 3% of patients, respectively, stopped treatment because of a treatment-related adverse event.
The small trial population precluded detailed analyses of associations between treatment response and PD-L1 expression or microsatellite instability status.
“The observed efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy was reflective of a population of patients with [metastatic PDAC] who had poor prognoses and rapidly progressing disease; however, treatment was well tolerated,” Dr. O’Reilly and coinvestigators wrote.
“Future studies are needed to evaluate how to best combine immune checkpoint blockade with other agents, including cytotoxic and targeted therapies, with the intention of overcoming the unique immunosuppressive, hypoxic, and fibrotic tumor microenvironment of PDAC. Such studies should evaluate biomarker expression to identify patients most likely to benefit from immune checkpoint blockade,” they recommended.
Dr. O’Reilly disclosed holding a consulting or advisory role or receiving grants from numerous pharmaceutical companies, including AstraZeneca, which funded the study.
SOURCE: O’Reilly EM et al. JAMA Oncol. 2019 July 18. doi:10.1001/jamaoncol.2019.1588.
, according to results of a phase 2 randomized controlled trial.
“Immune checkpoint blockade in PDAC as a single-agent therapy was not currently indicated beyond the subgroup of patients with microsatellite instability or mismatch repair deficiency ... however, a precedent existed for evaluating a combination of 2 immune checkpoint antagonists in this setting,” noted the investigators, led by Eileen M. O’Reilly, MD, gastrointestinal medical oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Cornell University, New York. In particular, a combination of agents that inhibit programmed cell death-1 ligand 1 (PD-L1) and the human T-cell receptor protein cytotoxic T-lymphocyte-associated protein 4 (CTLA4), nonredundant mechanisms, has shown promise.
Dr. O’Reilly and coinvestigators treated 65 patients in the trial’s initial cohort who had received only a single first-line fluorouracil- or gemcitabine-based chemotherapy regimen for recurrent or metastatic PDAC. Patients were randomized to combination therapy with durvalumab (Imfinzi), an anti-PD-L1 antibody, and tremelimumab, an investigational anti-CTLA4 antibody, followed by durvalumab alone, or to durvalumab monotherapy.
The objective response rate was just 3.1% with combination therapy and 0% with monotherapy—values that fell far short of the predefined 10% rate needed to initiate a planned expansion cohort. Both groups had a median progression-free survival of 1.5 months, Dr. O’Reilly and associates wrote. Their report is in JAMA Oncology.
The rate of grade 3 or higher treatment-related adverse events was 22% in the combination therapy group and 6% in the monotherapy group. In both groups, the most common events were fatigue and diarrhea. Some 6% and 3% of patients, respectively, stopped treatment because of a treatment-related adverse event.
The small trial population precluded detailed analyses of associations between treatment response and PD-L1 expression or microsatellite instability status.
“The observed efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy was reflective of a population of patients with [metastatic PDAC] who had poor prognoses and rapidly progressing disease; however, treatment was well tolerated,” Dr. O’Reilly and coinvestigators wrote.
“Future studies are needed to evaluate how to best combine immune checkpoint blockade with other agents, including cytotoxic and targeted therapies, with the intention of overcoming the unique immunosuppressive, hypoxic, and fibrotic tumor microenvironment of PDAC. Such studies should evaluate biomarker expression to identify patients most likely to benefit from immune checkpoint blockade,” they recommended.
Dr. O’Reilly disclosed holding a consulting or advisory role or receiving grants from numerous pharmaceutical companies, including AstraZeneca, which funded the study.
SOURCE: O’Reilly EM et al. JAMA Oncol. 2019 July 18. doi:10.1001/jamaoncol.2019.1588.
FROM JAMA ONCOLOGY
IL-6, CRP are prognostic for checkpoint inhibition in melanoma
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
REPORTING FROM ASCO 2019
Bispecific CAR T-cell therapy yields complete responses in relapsed/refractory non-Hodgkin lymphomas
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.
Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.
“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.
Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.
Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.
Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.
“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.
The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.
In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.
A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.
There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.
Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.
To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.
Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.
Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.
SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.
This article was updated on 7/8/2019
REPORTING FROM ASCO 2019
APHINITY trial: Biomarker analysis IDs predictive, prognostic factors
CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.
APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.
TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.
Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).
As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.
“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.
The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.
The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.
As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).
HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).
A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.
However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.
“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.
“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.
Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.
SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .
CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.
APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.
TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.
Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).
As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.
“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.
The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.
The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.
As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).
HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).
A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.
However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.
“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.
“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.
Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.
SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .
CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.
APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.
TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.
Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).
As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.
“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.
The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.
The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.
As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).
HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).
A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.
However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.
“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.
“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.
Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.
SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .
REPORTING FROM ASCO 2019
Chemo-free neoadjuvant approaches emerge in NSCLC and breast cancer
In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.
NEOSTAR in NSCLC
With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.
Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).
Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
What this means in practice
Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.
If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.
PREDIX in HER2-positive breast cancer
As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.
Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.
In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.
PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.
What this means in practice
Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.
Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.
NEOSTAR in NSCLC
With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.
Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).
Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
What this means in practice
Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.
If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.
PREDIX in HER2-positive breast cancer
As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.
Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.
In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.
PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.
What this means in practice
Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.
Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.
NEOSTAR in NSCLC
With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.
Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).
Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
What this means in practice
Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.
If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.
PREDIX in HER2-positive breast cancer
As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.
Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.
In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.
PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.
What this means in practice
Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.
Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
FDA approves pembrolizumab for advanced SCLC
The Food and Drug Administration has granted accelerated approval to pembrolizumab for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
Approval was based on an overall response rate of 19% among 83 patients with SCLC who had disease progression on or after two or more prior lines of therapy enrolled in two nonrandomized trials, according to the FDA.
SCLC cohorts in KEYNOTE-028 and KEYNOTE-158 received either pembrolizumab 200 mg intravenously every 3 weeks (n = 64) or 10 mg/kg intravenously every 2 weeks (n = 19). Treatment continued until documented disease progression, unacceptable toxicity, or for a maximum of 24 months.
The ORR was 19% (95% confidence interval, 11%-29%), while the complete response rate was 2%. Responses were durable for 6 months or longer in 94% of the 16 responding patients.
Common adverse reactions included fatigue, decreased appetite, cough, nausea, and constipation. The most frequent serious adverse reactions were pneumonia and pleural effusion.
The recommended dosage for SCLC treatment is 200 mg, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression, the FDA said.
Pembrolizumab is marketed as Keytruda by Merck.
The Food and Drug Administration has granted accelerated approval to pembrolizumab for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
Approval was based on an overall response rate of 19% among 83 patients with SCLC who had disease progression on or after two or more prior lines of therapy enrolled in two nonrandomized trials, according to the FDA.
SCLC cohorts in KEYNOTE-028 and KEYNOTE-158 received either pembrolizumab 200 mg intravenously every 3 weeks (n = 64) or 10 mg/kg intravenously every 2 weeks (n = 19). Treatment continued until documented disease progression, unacceptable toxicity, or for a maximum of 24 months.
The ORR was 19% (95% confidence interval, 11%-29%), while the complete response rate was 2%. Responses were durable for 6 months or longer in 94% of the 16 responding patients.
Common adverse reactions included fatigue, decreased appetite, cough, nausea, and constipation. The most frequent serious adverse reactions were pneumonia and pleural effusion.
The recommended dosage for SCLC treatment is 200 mg, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression, the FDA said.
Pembrolizumab is marketed as Keytruda by Merck.
The Food and Drug Administration has granted accelerated approval to pembrolizumab for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
Approval was based on an overall response rate of 19% among 83 patients with SCLC who had disease progression on or after two or more prior lines of therapy enrolled in two nonrandomized trials, according to the FDA.
SCLC cohorts in KEYNOTE-028 and KEYNOTE-158 received either pembrolizumab 200 mg intravenously every 3 weeks (n = 64) or 10 mg/kg intravenously every 2 weeks (n = 19). Treatment continued until documented disease progression, unacceptable toxicity, or for a maximum of 24 months.
The ORR was 19% (95% confidence interval, 11%-29%), while the complete response rate was 2%. Responses were durable for 6 months or longer in 94% of the 16 responding patients.
Common adverse reactions included fatigue, decreased appetite, cough, nausea, and constipation. The most frequent serious adverse reactions were pneumonia and pleural effusion.
The recommended dosage for SCLC treatment is 200 mg, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression, the FDA said.
Pembrolizumab is marketed as Keytruda by Merck.
Niraparib-pembrolizumab combo finds niche in breast, ovarian cancers
The strategy of simultaneously exploiting deficient DNA damage repair and unleashing the immune response could expand treatment options for hard-to-treat breast and ovarian cancers, findings of the TOPACIO/KEYNOTE-162 trial suggest.
Triple-negative breast cancer (TNBC) and high-grade serous ovarian carcinoma share a number of genomic features, including a high frequency of BRCA1 and BRCA2 inactivation (Nature. 2012;490:61-70), as well as potential immunoreactivity (Lancet Oncol. 2018;19:40-50).
The open-label, single-arm phase 1/2 trial therefore tested the combination of niraparib (Zejula), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab (Keytruda), an antibody to programmed death 1 (PD-1), among more than 100 patients with advanced or metastatic TNBC or recurrent platinum-resistant ovarian carcinoma. Patients were enrolled irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression.
Main results, reported in JAMA Oncology, showed that the combination was safe, and about a fifth of patients with each type of cancer had an objective response. Median progression-free survival (PFS) was about 2 months in those with TNBC overall (although it exceeded 8 months in the subset with a tumor BRCA mutation) and about 3 months in those with ovarian cancer.
TNBC cohort
Investigators led by Shaveta Vinayak, MD, of the division of oncology at Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, studied 55 patients with TNBC treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 47 patients, the objective response rate (ORR) was 21%, and the disease control rate (DCR) was 49%. With a median duration of follow-up of 14.8 months, the median duration of response was not reached.
Activity of the combination varied by tumor BRCA mutation status. Compared with counterparts having BRCA wild-type tumors, patients having tumors with BRCA mutations had a numerically higher ORR (47% vs. 11%), DCR (80% vs. 33%), and PFS (8.3 vs. 2.1 months).
Some 18% of patients had treatment-related anemia, 15% thrombocytopenia, and 7% fatigue. In addition, 15% of patients had immune-related adverse events, with 4% having grade 3 immune-related adverse events.
“Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations,” Dr. Vinayak and colleagues conclude. “The combination therapy was safe with a tolerable safety profile, warranting further investigation.”
Ovarian cancer cohort
Investigators led by Panagiotis A. Konstantinopoulos, MD, PhD, of the division of gynecologic oncology, department of medical oncology at Dana-Farber Cancer Institute, Harvard Medical School, Boston, studied 62 patients with ovarian carcinoma treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 60 patients, the ORR was 18% and the DCR was 65%. The ORRs were similar regardless of patients’ platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status.
With a median duration of follow-up of 12.4 months, the median duration of response was not reached, ranging from 4.2 to roughly 14.5 months. Median progression-free survival was 3.4 months.
The leading treatment-related adverse events of grade 3 or higher in this cohort were anemia (21%) and thrombocytopenia (9%). In addition, 19% of patients had immune-related adverse events, with 9% having grade 3 or higher immune-related adverse events.
“Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab,” Dr. Konstantinopoulos and colleagues conclude. “Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.”
Dr. Vinayak disclosed receiving clinical trial funding from TESARO; serving on an advisory board for TESARO; and serving on an advisory board for OncoSec Medical (uncompensated). Dr. Konstantinopoulos disclosed serving on advisory boards for AstraZeneca, Pfizer, and Merck. The trial was supported by TESARO: a GSK company and Merck, and in part by Stand Up to Cancer (a program of the Entertainment Industry Foundation); the Ovarian Cancer Research Fund Alliance; and National Ovarian Cancer Coalition Dream Team Translational Research.
SOURCE: Vinayak A et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1029. Konstantinopoulos PA et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1048.
“Targeting DNA repair and immune checkpoint pathways has emerged as an important concept in cancer therapy, well supported by preclinical and clinical data in ovarian cancer and TNBC. However, there are some limitations to the two studies presented herein,” maintain editorialists Kunle Odunsi, MD, PhD, and Tanja Pejovic, MD, PhD.
Patients varied considerably with respect to number of prior chemotherapy regimens, they elaborate. Also, there may have been some misclassification of patients into DNA damage repair (DDR) groups, and small sample sizes precluded rigorous subgroup analyses.
“Because DDR and, by extension, tumor mutational burden and PD-L1 status do not fully explain the effects of the combination of PARP inhibitors and anti–PD-1 therapy, additional predictive biomarkers based on tumor intrinsic or adaptive mechanisms of resistance are needed for both cancer types,” the editorialists contend. In particular, knowledge of the tumor microenvironment could be used to tailor therapy for individual patients.
“The TOPACIO clinical studies are clearly steps in the right direction for patients with [platinum-resistant ovarian carcinoma] and TNBC,” they conclude. “However, larger confirmatory randomized clinical trials are needed that use panels of integrated biomarkers that would allow identification of patients most likely to respond.”
Dr. Odunsi is the deputy director and chair of the department of gynecologic oncology, executive director of the Center for Immunotherapy, and co-leader of the Tumor Immunology and Immunotherapy Research Program–Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Dr. Pejovic is associate professor, division of gynecologic oncology, department of obstetrics & gynecology, Knight Cancer Institute, Oregon Health & Science University, Portland, Ore. These remarks are adapted from a related editorial (JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1009 ).
“Targeting DNA repair and immune checkpoint pathways has emerged as an important concept in cancer therapy, well supported by preclinical and clinical data in ovarian cancer and TNBC. However, there are some limitations to the two studies presented herein,” maintain editorialists Kunle Odunsi, MD, PhD, and Tanja Pejovic, MD, PhD.
Patients varied considerably with respect to number of prior chemotherapy regimens, they elaborate. Also, there may have been some misclassification of patients into DNA damage repair (DDR) groups, and small sample sizes precluded rigorous subgroup analyses.
“Because DDR and, by extension, tumor mutational burden and PD-L1 status do not fully explain the effects of the combination of PARP inhibitors and anti–PD-1 therapy, additional predictive biomarkers based on tumor intrinsic or adaptive mechanisms of resistance are needed for both cancer types,” the editorialists contend. In particular, knowledge of the tumor microenvironment could be used to tailor therapy for individual patients.
“The TOPACIO clinical studies are clearly steps in the right direction for patients with [platinum-resistant ovarian carcinoma] and TNBC,” they conclude. “However, larger confirmatory randomized clinical trials are needed that use panels of integrated biomarkers that would allow identification of patients most likely to respond.”
Dr. Odunsi is the deputy director and chair of the department of gynecologic oncology, executive director of the Center for Immunotherapy, and co-leader of the Tumor Immunology and Immunotherapy Research Program–Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Dr. Pejovic is associate professor, division of gynecologic oncology, department of obstetrics & gynecology, Knight Cancer Institute, Oregon Health & Science University, Portland, Ore. These remarks are adapted from a related editorial (JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1009 ).
“Targeting DNA repair and immune checkpoint pathways has emerged as an important concept in cancer therapy, well supported by preclinical and clinical data in ovarian cancer and TNBC. However, there are some limitations to the two studies presented herein,” maintain editorialists Kunle Odunsi, MD, PhD, and Tanja Pejovic, MD, PhD.
Patients varied considerably with respect to number of prior chemotherapy regimens, they elaborate. Also, there may have been some misclassification of patients into DNA damage repair (DDR) groups, and small sample sizes precluded rigorous subgroup analyses.
“Because DDR and, by extension, tumor mutational burden and PD-L1 status do not fully explain the effects of the combination of PARP inhibitors and anti–PD-1 therapy, additional predictive biomarkers based on tumor intrinsic or adaptive mechanisms of resistance are needed for both cancer types,” the editorialists contend. In particular, knowledge of the tumor microenvironment could be used to tailor therapy for individual patients.
“The TOPACIO clinical studies are clearly steps in the right direction for patients with [platinum-resistant ovarian carcinoma] and TNBC,” they conclude. “However, larger confirmatory randomized clinical trials are needed that use panels of integrated biomarkers that would allow identification of patients most likely to respond.”
Dr. Odunsi is the deputy director and chair of the department of gynecologic oncology, executive director of the Center for Immunotherapy, and co-leader of the Tumor Immunology and Immunotherapy Research Program–Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Dr. Pejovic is associate professor, division of gynecologic oncology, department of obstetrics & gynecology, Knight Cancer Institute, Oregon Health & Science University, Portland, Ore. These remarks are adapted from a related editorial (JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1009 ).
The strategy of simultaneously exploiting deficient DNA damage repair and unleashing the immune response could expand treatment options for hard-to-treat breast and ovarian cancers, findings of the TOPACIO/KEYNOTE-162 trial suggest.
Triple-negative breast cancer (TNBC) and high-grade serous ovarian carcinoma share a number of genomic features, including a high frequency of BRCA1 and BRCA2 inactivation (Nature. 2012;490:61-70), as well as potential immunoreactivity (Lancet Oncol. 2018;19:40-50).
The open-label, single-arm phase 1/2 trial therefore tested the combination of niraparib (Zejula), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab (Keytruda), an antibody to programmed death 1 (PD-1), among more than 100 patients with advanced or metastatic TNBC or recurrent platinum-resistant ovarian carcinoma. Patients were enrolled irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression.
Main results, reported in JAMA Oncology, showed that the combination was safe, and about a fifth of patients with each type of cancer had an objective response. Median progression-free survival (PFS) was about 2 months in those with TNBC overall (although it exceeded 8 months in the subset with a tumor BRCA mutation) and about 3 months in those with ovarian cancer.
TNBC cohort
Investigators led by Shaveta Vinayak, MD, of the division of oncology at Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, studied 55 patients with TNBC treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 47 patients, the objective response rate (ORR) was 21%, and the disease control rate (DCR) was 49%. With a median duration of follow-up of 14.8 months, the median duration of response was not reached.
Activity of the combination varied by tumor BRCA mutation status. Compared with counterparts having BRCA wild-type tumors, patients having tumors with BRCA mutations had a numerically higher ORR (47% vs. 11%), DCR (80% vs. 33%), and PFS (8.3 vs. 2.1 months).
Some 18% of patients had treatment-related anemia, 15% thrombocytopenia, and 7% fatigue. In addition, 15% of patients had immune-related adverse events, with 4% having grade 3 immune-related adverse events.
“Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations,” Dr. Vinayak and colleagues conclude. “The combination therapy was safe with a tolerable safety profile, warranting further investigation.”
Ovarian cancer cohort
Investigators led by Panagiotis A. Konstantinopoulos, MD, PhD, of the division of gynecologic oncology, department of medical oncology at Dana-Farber Cancer Institute, Harvard Medical School, Boston, studied 62 patients with ovarian carcinoma treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 60 patients, the ORR was 18% and the DCR was 65%. The ORRs were similar regardless of patients’ platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status.
With a median duration of follow-up of 12.4 months, the median duration of response was not reached, ranging from 4.2 to roughly 14.5 months. Median progression-free survival was 3.4 months.
The leading treatment-related adverse events of grade 3 or higher in this cohort were anemia (21%) and thrombocytopenia (9%). In addition, 19% of patients had immune-related adverse events, with 9% having grade 3 or higher immune-related adverse events.
“Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab,” Dr. Konstantinopoulos and colleagues conclude. “Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.”
Dr. Vinayak disclosed receiving clinical trial funding from TESARO; serving on an advisory board for TESARO; and serving on an advisory board for OncoSec Medical (uncompensated). Dr. Konstantinopoulos disclosed serving on advisory boards for AstraZeneca, Pfizer, and Merck. The trial was supported by TESARO: a GSK company and Merck, and in part by Stand Up to Cancer (a program of the Entertainment Industry Foundation); the Ovarian Cancer Research Fund Alliance; and National Ovarian Cancer Coalition Dream Team Translational Research.
SOURCE: Vinayak A et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1029. Konstantinopoulos PA et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1048.
The strategy of simultaneously exploiting deficient DNA damage repair and unleashing the immune response could expand treatment options for hard-to-treat breast and ovarian cancers, findings of the TOPACIO/KEYNOTE-162 trial suggest.
Triple-negative breast cancer (TNBC) and high-grade serous ovarian carcinoma share a number of genomic features, including a high frequency of BRCA1 and BRCA2 inactivation (Nature. 2012;490:61-70), as well as potential immunoreactivity (Lancet Oncol. 2018;19:40-50).
The open-label, single-arm phase 1/2 trial therefore tested the combination of niraparib (Zejula), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab (Keytruda), an antibody to programmed death 1 (PD-1), among more than 100 patients with advanced or metastatic TNBC or recurrent platinum-resistant ovarian carcinoma. Patients were enrolled irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression.
Main results, reported in JAMA Oncology, showed that the combination was safe, and about a fifth of patients with each type of cancer had an objective response. Median progression-free survival (PFS) was about 2 months in those with TNBC overall (although it exceeded 8 months in the subset with a tumor BRCA mutation) and about 3 months in those with ovarian cancer.
TNBC cohort
Investigators led by Shaveta Vinayak, MD, of the division of oncology at Fred Hutchinson Cancer Research Center, and University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, studied 55 patients with TNBC treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 47 patients, the objective response rate (ORR) was 21%, and the disease control rate (DCR) was 49%. With a median duration of follow-up of 14.8 months, the median duration of response was not reached.
Activity of the combination varied by tumor BRCA mutation status. Compared with counterparts having BRCA wild-type tumors, patients having tumors with BRCA mutations had a numerically higher ORR (47% vs. 11%), DCR (80% vs. 33%), and PFS (8.3 vs. 2.1 months).
Some 18% of patients had treatment-related anemia, 15% thrombocytopenia, and 7% fatigue. In addition, 15% of patients had immune-related adverse events, with 4% having grade 3 immune-related adverse events.
“Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations,” Dr. Vinayak and colleagues conclude. “The combination therapy was safe with a tolerable safety profile, warranting further investigation.”
Ovarian cancer cohort
Investigators led by Panagiotis A. Konstantinopoulos, MD, PhD, of the division of gynecologic oncology, department of medical oncology at Dana-Farber Cancer Institute, Harvard Medical School, Boston, studied 62 patients with ovarian carcinoma treated with niraparib-pembrolizumab in the trial.
In the efficacy-evaluable population of 60 patients, the ORR was 18% and the DCR was 65%. The ORRs were similar regardless of patients’ platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status.
With a median duration of follow-up of 12.4 months, the median duration of response was not reached, ranging from 4.2 to roughly 14.5 months. Median progression-free survival was 3.4 months.
The leading treatment-related adverse events of grade 3 or higher in this cohort were anemia (21%) and thrombocytopenia (9%). In addition, 19% of patients had immune-related adverse events, with 9% having grade 3 or higher immune-related adverse events.
“Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab,” Dr. Konstantinopoulos and colleagues conclude. “Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.”
Dr. Vinayak disclosed receiving clinical trial funding from TESARO; serving on an advisory board for TESARO; and serving on an advisory board for OncoSec Medical (uncompensated). Dr. Konstantinopoulos disclosed serving on advisory boards for AstraZeneca, Pfizer, and Merck. The trial was supported by TESARO: a GSK company and Merck, and in part by Stand Up to Cancer (a program of the Entertainment Industry Foundation); the Ovarian Cancer Research Fund Alliance; and National Ovarian Cancer Coalition Dream Team Translational Research.
SOURCE: Vinayak A et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1029. Konstantinopoulos PA et al. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1048.
FROM JAMA ONCOLOGY
Skin plus GI adverse events with checkpoint inhibitors linked to risk of additional adverse events
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
REPORTING FROM WCD2019
EULAR issues guidelines on managing rheumatic complications of cancer immunotherapies
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
REPORTING FROM EULAR 2019 CONGRESS
Adding ipilimumab to nivolumab provides no benefit in SCC trial
CHICAGO – Phase 3 results suggest ipilimumab plus nivolumab is no more effective than nivolumab alone in previously treated patients with metastatic squamous cell lung cancer and no matching biomarker.
However, there is evidence to suggest that patients with a high tumor mutational burden (TMB) and low programmed death–ligand 1 (PD-L1) tumor proportion score (TPS) may derive a benefit from the combination.
Lyudmila Bazhenova, MD, of the University of California, San Diego, and her colleagues presented results from this trial (NCT02785952) in a poster at the annual meeting of the American Society for Clinical Oncology. Kathryn C. Arbour, MD, of Memorial Sloan Kettering Cancer Center in New York reviewed the data in a poster discussion session.
Patients and treatment
The researchers reported on 275 previously treated patients with stage IV or recurrent squamous cell lung cancer who were naive to checkpoint inhibitors. Patients were randomized to receive nivolumab (nivo) at 3 mg/m2 once every 2 weeks (n = 137) or the same dose of nivolumab plus ipilimumab (ipi + nivo) at 1 mg/m2 once every 6 weeks (n = 138).
The patients were stratified by gender and number of prior therapies (one vs. two or more), but they were not stratified by TMB or PD-L1 expression.
The PD-L1 TPS was unknown in 36% of patients, less than 5% in 57%, and 5% or greater in 43% of patients. TMB was unknown in 8% of patients, less than 10 mutations per megabase in 52%, and 10 mutations per megabase or greater in 48%.
Baseline characteristics were similar between the treatment arms. The median age was 67.5 years (range, 42-83 years) in the ipi + nivo arm and 68.1 years (range, 49-90 years) in the nivo arm. Most patients had received only one prior therapy – 85% and 83%, respectively – and most had a performance status of 1 – 71% and 72%, respectively.
Efficacy
There were no significant differences in outcomes between the treatment arms, and the study was closed early for futility.
The overall response rate was 18% in the ipi + nivo arm and 17% in the nivo arm, with one complete response occurring in each arm. The median duration of response was 9.1 months in the ipi + nivo arm and 8.6 months in the nivo arm.
The median progression-free survival was 3.8 months in the ipi + nivo arm and 2.9 months in the nivo arm (hazard ratio, 0.84; P = .19). The 24-month progression-free survival was 8.2% and 5.9%, respectively.
The median overall survival was 10.0 months in the ipi + nivo arm and 11.0 months in the nivo arm (HR, 0.97; P = .82). The 24-month overall survival was 27.6% and 20.1%, respectively.
There were no significant differences in outcomes by TMB or PD-L1 with the cutoffs used in this study, according to Dr. Bazhenova and colleagues, but different cutoffs are being explored.
The median progression-free survival was 4.4 months in TMB-high/PD-L1-low patients in the ipi + nivo arm, compared with 1.7 months in the TMB-high/PD-L1-low patients in the nivo arm. The median overall survival was 15.9 months and 10.3 months, respectively.
“It is slightly challenging to interpret the results without knowing the PD-L1 data of all patients in the cohort, and biomarker selection remains crucial for this combination,” Dr. Arbour said.
Safety
There were no differences in individual toxicities between the treatment arms, but cumulative toxicities were higher in the combination arm, according to the researchers.
The incidence of treatment-related adverse events (AEs) was 88% in the ipi + nivo arm and 90% in the nivo arm. The incidence of grade 3-5 treatment-related AEs was 39% and 31%, respectively.
The incidence of immune-mediated AEs was 65% in the ipi + nivo arm and 57% in the nivo arm. The incidence of immune-mediated grade 3-5 AEs was 20% and 11%, respectively.
There were six AEs leading to death in the ipi + nivo arm – two due to dyspnea, one due to colitis, and one due to respiratory failure. The attribution of one death is under review. For the remaining death, the exact cause is unknown.
There were two AEs leading to death in the nivo arm, both due to pneumonitis.
This study was supported by grants from the National Institutes of Health and by AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health in partnership with Friends of Cancer Research.
Dr. Bazhenova reported relationships with Epic Sciences, AbbVie, AstraZeneca, Boston Biomedical, Genentech/Roche, Lilly, Loxo, Pfizer, Takeda, and BeyondSpring Pharmaceuticals. Her colleagues reported relationships with these and other companies. Dr. Arbour reported a relationship with AstraZeneca.
SOURCE: Bazhenova L et al. ASCO 2019, Abstract 9014.
CHICAGO – Phase 3 results suggest ipilimumab plus nivolumab is no more effective than nivolumab alone in previously treated patients with metastatic squamous cell lung cancer and no matching biomarker.
However, there is evidence to suggest that patients with a high tumor mutational burden (TMB) and low programmed death–ligand 1 (PD-L1) tumor proportion score (TPS) may derive a benefit from the combination.
Lyudmila Bazhenova, MD, of the University of California, San Diego, and her colleagues presented results from this trial (NCT02785952) in a poster at the annual meeting of the American Society for Clinical Oncology. Kathryn C. Arbour, MD, of Memorial Sloan Kettering Cancer Center in New York reviewed the data in a poster discussion session.
Patients and treatment
The researchers reported on 275 previously treated patients with stage IV or recurrent squamous cell lung cancer who were naive to checkpoint inhibitors. Patients were randomized to receive nivolumab (nivo) at 3 mg/m2 once every 2 weeks (n = 137) or the same dose of nivolumab plus ipilimumab (ipi + nivo) at 1 mg/m2 once every 6 weeks (n = 138).
The patients were stratified by gender and number of prior therapies (one vs. two or more), but they were not stratified by TMB or PD-L1 expression.
The PD-L1 TPS was unknown in 36% of patients, less than 5% in 57%, and 5% or greater in 43% of patients. TMB was unknown in 8% of patients, less than 10 mutations per megabase in 52%, and 10 mutations per megabase or greater in 48%.
Baseline characteristics were similar between the treatment arms. The median age was 67.5 years (range, 42-83 years) in the ipi + nivo arm and 68.1 years (range, 49-90 years) in the nivo arm. Most patients had received only one prior therapy – 85% and 83%, respectively – and most had a performance status of 1 – 71% and 72%, respectively.
Efficacy
There were no significant differences in outcomes between the treatment arms, and the study was closed early for futility.
The overall response rate was 18% in the ipi + nivo arm and 17% in the nivo arm, with one complete response occurring in each arm. The median duration of response was 9.1 months in the ipi + nivo arm and 8.6 months in the nivo arm.
The median progression-free survival was 3.8 months in the ipi + nivo arm and 2.9 months in the nivo arm (hazard ratio, 0.84; P = .19). The 24-month progression-free survival was 8.2% and 5.9%, respectively.
The median overall survival was 10.0 months in the ipi + nivo arm and 11.0 months in the nivo arm (HR, 0.97; P = .82). The 24-month overall survival was 27.6% and 20.1%, respectively.
There were no significant differences in outcomes by TMB or PD-L1 with the cutoffs used in this study, according to Dr. Bazhenova and colleagues, but different cutoffs are being explored.
The median progression-free survival was 4.4 months in TMB-high/PD-L1-low patients in the ipi + nivo arm, compared with 1.7 months in the TMB-high/PD-L1-low patients in the nivo arm. The median overall survival was 15.9 months and 10.3 months, respectively.
“It is slightly challenging to interpret the results without knowing the PD-L1 data of all patients in the cohort, and biomarker selection remains crucial for this combination,” Dr. Arbour said.
Safety
There were no differences in individual toxicities between the treatment arms, but cumulative toxicities were higher in the combination arm, according to the researchers.
The incidence of treatment-related adverse events (AEs) was 88% in the ipi + nivo arm and 90% in the nivo arm. The incidence of grade 3-5 treatment-related AEs was 39% and 31%, respectively.
The incidence of immune-mediated AEs was 65% in the ipi + nivo arm and 57% in the nivo arm. The incidence of immune-mediated grade 3-5 AEs was 20% and 11%, respectively.
There were six AEs leading to death in the ipi + nivo arm – two due to dyspnea, one due to colitis, and one due to respiratory failure. The attribution of one death is under review. For the remaining death, the exact cause is unknown.
There were two AEs leading to death in the nivo arm, both due to pneumonitis.
This study was supported by grants from the National Institutes of Health and by AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health in partnership with Friends of Cancer Research.
Dr. Bazhenova reported relationships with Epic Sciences, AbbVie, AstraZeneca, Boston Biomedical, Genentech/Roche, Lilly, Loxo, Pfizer, Takeda, and BeyondSpring Pharmaceuticals. Her colleagues reported relationships with these and other companies. Dr. Arbour reported a relationship with AstraZeneca.
SOURCE: Bazhenova L et al. ASCO 2019, Abstract 9014.
CHICAGO – Phase 3 results suggest ipilimumab plus nivolumab is no more effective than nivolumab alone in previously treated patients with metastatic squamous cell lung cancer and no matching biomarker.
However, there is evidence to suggest that patients with a high tumor mutational burden (TMB) and low programmed death–ligand 1 (PD-L1) tumor proportion score (TPS) may derive a benefit from the combination.
Lyudmila Bazhenova, MD, of the University of California, San Diego, and her colleagues presented results from this trial (NCT02785952) in a poster at the annual meeting of the American Society for Clinical Oncology. Kathryn C. Arbour, MD, of Memorial Sloan Kettering Cancer Center in New York reviewed the data in a poster discussion session.
Patients and treatment
The researchers reported on 275 previously treated patients with stage IV or recurrent squamous cell lung cancer who were naive to checkpoint inhibitors. Patients were randomized to receive nivolumab (nivo) at 3 mg/m2 once every 2 weeks (n = 137) or the same dose of nivolumab plus ipilimumab (ipi + nivo) at 1 mg/m2 once every 6 weeks (n = 138).
The patients were stratified by gender and number of prior therapies (one vs. two or more), but they were not stratified by TMB or PD-L1 expression.
The PD-L1 TPS was unknown in 36% of patients, less than 5% in 57%, and 5% or greater in 43% of patients. TMB was unknown in 8% of patients, less than 10 mutations per megabase in 52%, and 10 mutations per megabase or greater in 48%.
Baseline characteristics were similar between the treatment arms. The median age was 67.5 years (range, 42-83 years) in the ipi + nivo arm and 68.1 years (range, 49-90 years) in the nivo arm. Most patients had received only one prior therapy – 85% and 83%, respectively – and most had a performance status of 1 – 71% and 72%, respectively.
Efficacy
There were no significant differences in outcomes between the treatment arms, and the study was closed early for futility.
The overall response rate was 18% in the ipi + nivo arm and 17% in the nivo arm, with one complete response occurring in each arm. The median duration of response was 9.1 months in the ipi + nivo arm and 8.6 months in the nivo arm.
The median progression-free survival was 3.8 months in the ipi + nivo arm and 2.9 months in the nivo arm (hazard ratio, 0.84; P = .19). The 24-month progression-free survival was 8.2% and 5.9%, respectively.
The median overall survival was 10.0 months in the ipi + nivo arm and 11.0 months in the nivo arm (HR, 0.97; P = .82). The 24-month overall survival was 27.6% and 20.1%, respectively.
There were no significant differences in outcomes by TMB or PD-L1 with the cutoffs used in this study, according to Dr. Bazhenova and colleagues, but different cutoffs are being explored.
The median progression-free survival was 4.4 months in TMB-high/PD-L1-low patients in the ipi + nivo arm, compared with 1.7 months in the TMB-high/PD-L1-low patients in the nivo arm. The median overall survival was 15.9 months and 10.3 months, respectively.
“It is slightly challenging to interpret the results without knowing the PD-L1 data of all patients in the cohort, and biomarker selection remains crucial for this combination,” Dr. Arbour said.
Safety
There were no differences in individual toxicities between the treatment arms, but cumulative toxicities were higher in the combination arm, according to the researchers.
The incidence of treatment-related adverse events (AEs) was 88% in the ipi + nivo arm and 90% in the nivo arm. The incidence of grade 3-5 treatment-related AEs was 39% and 31%, respectively.
The incidence of immune-mediated AEs was 65% in the ipi + nivo arm and 57% in the nivo arm. The incidence of immune-mediated grade 3-5 AEs was 20% and 11%, respectively.
There were six AEs leading to death in the ipi + nivo arm – two due to dyspnea, one due to colitis, and one due to respiratory failure. The attribution of one death is under review. For the remaining death, the exact cause is unknown.
There were two AEs leading to death in the nivo arm, both due to pneumonitis.
This study was supported by grants from the National Institutes of Health and by AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health in partnership with Friends of Cancer Research.
Dr. Bazhenova reported relationships with Epic Sciences, AbbVie, AstraZeneca, Boston Biomedical, Genentech/Roche, Lilly, Loxo, Pfizer, Takeda, and BeyondSpring Pharmaceuticals. Her colleagues reported relationships with these and other companies. Dr. Arbour reported a relationship with AstraZeneca.
SOURCE: Bazhenova L et al. ASCO 2019, Abstract 9014.
REPORTING FROM ASCO 2019
Key clinical point: Ipilimumab plus nivolumab appears no more effective than nivolumab alone in previously treated patients with metastatic squamous cell lung cancer and no matching biomarker.
Major finding: The median progression-free survival was 3.8 months in the ipilimumab plus nivolumab arm and 2.9 months in the nivolumab arm (P = .19). The median overall survival was 10.0 months and 11.0 months, respectively (P = .82).
Study details: A phase 3 trial of 275 previously treated patients with stage IV or recurrent squamous cell lung cancer.
Disclosures: This study was supported by grants from the National Institutes of Health and by AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health in partnership with Friends of Cancer Research. The researchers reported relationships with a range of companies. Source: Bazhenova L et al. ASCO 2019, Abstract 9014.