TY - JOUR
T1 - Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer
T2 - Preliminary Analysis of Patients in the CheckMate 650 Trial
AU - Sharma, Padmanee
AU - Pachynski, Russell K.
AU - Narayan, Vivek
AU - Fléchon, Aude
AU - Gravis, Gwenaelle
AU - Galsky, Matthew D.
AU - Mahammedi, Hakim
AU - Patnaik, Akash
AU - Subudhi, Sumit K.
AU - Ciprotti, Marika
AU - Simsek, Burcin
AU - Saci, Abdel
AU - Hu, Yanhua
AU - Han, G. Celine
AU - Fizazi, Karim
N1 - Funding Information:
M.D.G. reports personal fees from BioMotiv, Janssen, Astellas, Pfizer, EMD Serono, Seattle Genetics, Incyte, Dracen, Inovio, Dragonfly, and Aileron; research grants from Dendreon and Novartis ; and research grants and personal fees from Merck , Genentech , BMS , and AstraZeneca , outside the submitted work.
Funding Information:
A.P. reports funding support for this clinical trial from BMS during the conduct of the study; grants from Prostate Cancer Foundation, Phi Beta Psi Charity Trust Research Organization, National Cancer Institute, BMS, and Progenics; grants and personal fees from Clovis; and personal fees from Exelixis, PRIME, Janssen, Jounce Therapeutics, Guidepoint, Merck, and Gerson Lehrman Group, outside of the submitted work.
Funding Information:
We thank the patients and their families for making this study possible; the clinical study teams who participated in the study; Dako, an Agilent Technologies, Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay (Santa Clara, CA, USA); and Bristol Myers Squibb (Princeton, NJ, USA) and ONO Pharmaceutical Co. Ltd. (Osaka, Japan). We also acknowledge the assistance of Bilal Siddiqui from MD Anderson Cancer Center for assistance in developing the manuscript. Professional medical writing and editorial assistance was provided by Richard Daniel, PhD, of Parexel, funded by Bristol Myers Squibb. FUNDING/SUPPORT: Supported by Bristol Myers Squibb and ONO Pharmaceutical Company Limited. The authors received no financial support or compensation for publication of this article. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672). All authors conceived and designed the study, collected and assembled the data, analyzed and interpreted the data, were involved in writing the article, and approved the final version of the article. B.S. performed the statistical analyses. P.S. reports stock options and advisory fees from Oncolytics, Jounce, BioAlta, Forty-Seven, Polaris, Marker Therapeutics, Codiak, ImaginAB, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, Infinity, and Glympse, and stock options with BioNTx and Constellation, outside the submitted work. R.P. reports personal fees and non-financial support from Bristol Myers Squibb (BMS) and Genentech/Roche; personal fees from Dendreon, EMD Serono/Pfizer, Genomic Health, AstraZeneca, Sanofi, Merck, Bayer, and Jounce Therapeutics; and institutional grants from Janssen, outside the submitted work. V.N. reports research grants paid to the institution from BMS, during the conduct of the study; research grants paid to the institution from Pfizer and Peloton Therapeutics; research grants paid to the institution and personal fees from Janssen; and personal fees from AstraZeneca, outside the submitted work. A.F. reports personal fees from Astellas, Sanofi, Janssen, AAA, and BMS, outside the submitted work. G.G. reports personal fees from Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer, Sanofi, and Ipsen, outside the submitted work. M.D.G. reports personal fees from BioMotiv, Janssen, Astellas, Pfizer, EMD Serono, Seattle Genetics, Incyte, Dracen, Inovio, Dragonfly, and Aileron; research grants from Dendreon and Novartis; and research grants and personal fees from Merck, Genentech, BMS, and AstraZeneca, outside the submitted work. H.M. reports personal fees and travel fees from BMS and Sanofi, travel fees from Bayer, congress fees from Roche, and personal fees from Ipsen, Janssen, and Astellas, outside the submitted work. A.P. reports funding support for this clinical trial from BMS during the conduct of the study; grants from Prostate Cancer Foundation, Phi Beta Psi Charity Trust Research Organization, National Cancer Institute, BMS, and Progenics; grants and personal fees from Clovis; and personal fees from Exelixis, PRIME, Janssen, Jounce Therapeutics, Guidepoint, Merck, and Gerson Lehrman Group, outside of the submitted work. S.K.S reports personal fees from Exelixis, Dava Oncology, Cancer Now, Polaris, and MEDACorp; grants and non-financial support from Parker Institute for Cancer Immunotherapy; grants, personal fees, and non-financial support from Janssen Oncology, AstraZeneca, and BMS; personal fees and non-financial support from Dendreon, Amgen, Bayer, and Society for Immunotherapy of Cancer; and personal fees and ownership interests from Apricity Health, outside the submitted work. M.C. is an employee of and shareholder in BMS. B.S. is an employee of and shareholder in BMS. G.C.H. is an employee of BMS. A.S. is a former employee of and shareholder in BMS. Y.H. is an employee of and shareholder in BMS. K.F. reports personal fees from Amgen, Astellas, AstraZeneca, AAA, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Orion, and Sanofi, outside the submitted work.
Funding Information:
S.K.S reports personal fees from Exelixis, Dava Oncology, Cancer Now, Polaris, and MEDACorp; grants and non-financial support from Parker Institute for Cancer Immunotherapy ; grants, personal fees, and non-financial support from Janssen Oncology , AstraZeneca , and BMS ; personal fees and non-financial support from Dendreon , Amgen , Bayer , and Society for Immunotherapy of Cancer ; and personal fees and ownership interests from Apricity Health, outside the submitted work.
Funding Information:
We thank the patients and their families for making this study possible; the clinical study teams who participated in the study; Dako, an Agilent Technologies, Inc., company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay (Santa Clara, CA, USA); and Bristol Myers Squibb (Princeton, NJ, USA) and ONO Pharmaceutical Co. Ltd. (Osaka, Japan). We also acknowledge the assistance of Bilal Siddiqui from MD Anderson Cancer Center for assistance in developing the manuscript. Professional medical writing and editorial assistance was provided by Richard Daniel, PhD, of Parexel, funded by Bristol Myers Squibb . FUNDING/SUPPORT: Supported by Bristol Myers Squibb and ONO Pharmaceutical Company Limited . The authors received no financial support or compensation for publication of this article. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672 ).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10/12
Y1 - 2020/10/12
N2 - Metastatic castration-resistant prostate cancer (mCRPC) is immunologically “cold” and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3–4 treatment-related adverse events have occurred in ∼42%–53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented. From a preliminary phase II clinical trial on metastatic castration-resistant prostate cancer with anti-CTLA-4 plus anti-PD-1, Sharma et al. report ORR of 25% and 10%, median rPFS of 5.5 and 3.8 months, and median OS of 19.0 and 15.2 months in pre- and post-chemotherapy patients. Additional analyses with modified dosing are needed to optimize safety.
AB - Metastatic castration-resistant prostate cancer (mCRPC) is immunologically “cold” and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3–4 treatment-related adverse events have occurred in ∼42%–53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented. From a preliminary phase II clinical trial on metastatic castration-resistant prostate cancer with anti-CTLA-4 plus anti-PD-1, Sharma et al. report ORR of 25% and 10%, median rPFS of 5.5 and 3.8 months, and median OS of 19.0 and 15.2 months in pre- and post-chemotherapy patients. Additional analyses with modified dosing are needed to optimize safety.
KW - DNA damage repair
KW - biomarkers
KW - clinical trial
KW - immunotherapy
KW - ipilimumab
KW - metastatic castration-resistant prostate cancer
KW - nivolumab
KW - tumor mutational burden
UR - http://www.scopus.com/inward/record.url?scp=85092128610&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2020.08.007
DO - 10.1016/j.ccell.2020.08.007
M3 - Article
C2 - 32916128
AN - SCOPUS:85092128610
SN - 1535-6108
VL - 38
SP - 489-499.e3
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -