Suzanne L Topalian1, Mario Sznol, David F McDermott, Harriet M Kluger, Richard D Carvajal, William H Sharfman, Julie R Brahmer, Donald P Lawrence, Michael B Atkins, John D Powderly, Philip D Leming, Evan J Lipson, Igor Puzanov, David C Smith, Janis M Taube, Jon M Wigginton, Georgia D Kollia, Ashok Gupta, Drew M Pardoll, Jeffrey A Sosman, F Stephen Hodi. 1. Suzanne L. Topalian, William H. Sharfman, Julie R. Brahmer, Evan J. Lipson, Janis M. Taube, and Drew M. Pardoll, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol and Harriet M. Kluger, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; David F. McDermott, Beth Israel Deaconess Medical Center; Donald P. Lawrence, Massachusetts General Hospital Cancer Center; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York, NY; Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC; John D. Powderly, Carolina BioOncology Institute, Huntersville, NC; Philip D. Leming, The Christ Hospital Cancer Center, Cincinnati, OH; Igor Puzanov and Jeffrey A. Sosman, Vanderbilt University Medical Center, Nashville, TN; David C. Smith, University of Michigan, Ann Arbor, MI; and Jon M. Wigginton, Georgia D. Kollia, and Ashok Gupta, Bristol-Myers Squibb, Princeton, NJ.
Abstract
PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
Authors: Evan J Lipson; William H Sharfman; Charles G Drake; Ira Wollner; Janis M Taube; Robert A Anders; Haiying Xu; Sheng Yao; Alice Pons; Lieping Chen; Drew M Pardoll; Julie R Brahmer; Suzanne L Topalian Journal: Clin Cancer Res Date: 2012-11-20 Impact factor: 12.531
Authors: Julie R Brahmer; Charles G Drake; Ira Wollner; John D Powderly; Joel Picus; William H Sharfman; Elizabeth Stankevich; Alice Pons; Theresa M Salay; Tracee L McMiller; Marta M Gilson; Changyu Wang; Mark Selby; Janis M Taube; Robert Anders; Lieping Chen; Alan J Korman; Drew M Pardoll; Israel Lowy; Suzanne L Topalian Journal: J Clin Oncol Date: 2010-06-01 Impact factor: 44.544
Authors: Suzanne L Topalian; F Stephen Hodi; Julie R Brahmer; Scott N Gettinger; David C Smith; David F McDermott; John D Powderly; Richard D Carvajal; Jeffrey A Sosman; Michael B Atkins; Philip D Leming; David R Spigel; Scott J Antonia; Leora Horn; Charles G Drake; Drew M Pardoll; Lieping Chen; William H Sharfman; Robert A Anders; Janis M Taube; Tracee L McMiller; Haiying Xu; Alan J Korman; Maria Jure-Kunkel; Shruti Agrawal; Daniel McDonald; Georgia D Kollia; Ashok Gupta; Jon M Wigginton; Mario Sznol Journal: N Engl J Med Date: 2012-06-02 Impact factor: 91.245
Authors: Jeffrey A Sosman; Kevin B Kim; Lynn Schuchter; Rene Gonzalez; Anna C Pavlick; Jeffrey S Weber; Grant A McArthur; Thomas E Hutson; Stergios J Moschos; Keith T Flaherty; Peter Hersey; Richard Kefford; Donald Lawrence; Igor Puzanov; Karl D Lewis; Ravi K Amaravadi; Bartosz Chmielowski; H Jeffrey Lawrence; Yu Shyr; Fei Ye; Jiang Li; Keith B Nolop; Richard J Lee; Andrew K Joe; Antoni Ribas Journal: N Engl J Med Date: 2012-02-23 Impact factor: 91.245
Authors: Jedd D Wolchok; Axel Hoos; Steven O'Day; Jeffrey S Weber; Omid Hamid; Celeste Lebbé; Michele Maio; Michael Binder; Oliver Bohnsack; Geoffrey Nichol; Rachel Humphrey; F Stephen Hodi Journal: Clin Cancer Res Date: 2009-11-24 Impact factor: 12.531
Authors: Jedd D Wolchok; Harriet Kluger; Margaret K Callahan; Michael A Postow; Naiyer A Rizvi; Alexander M Lesokhin; Neil H Segal; Charlotte E Ariyan; Ruth-Ann Gordon; Kathleen Reed; Matthew M Burke; Anne Caldwell; Stephanie A Kronenberg; Blessing U Agunwamba; Xiaoling Zhang; Israel Lowy; Hector David Inzunza; William Feely; Christine E Horak; Quan Hong; Alan J Korman; Jon M Wigginton; Ashok Gupta; Mario Sznol Journal: N Engl J Med Date: 2013-06-02 Impact factor: 91.245
Authors: Kathleen M Kokolus; Ying Zhang; Jeffrey M Sivik; Carla Schmeck; Junjia Zhu; Elizabeth A Repasky; Joseph J Drabick; Todd D Schell Journal: Oncoimmunology Date: 2017-12-21 Impact factor: 8.110