title: Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma.
abstract: Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n= 32) and 11% (n= 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of patients,n= 28) and occurred while receiving therapy (78%,n= 28). The median PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P= 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P= 0.036). Two patients experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption.Cancer Immunol Res; 5(5); 357-62. ©2017 AACR.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Wang
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Eroglu
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Ozgun
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Leger
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Luke
authors.affiliation: Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Melanoma Disease Center, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.affiliation: Melanoma Disease Center, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Melanoma Disease Center, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. douglas.b.johnson@vanderbilt.edu elizabeth_buchbinder@dfci.harvard.edu.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Melanoma Disease Center, Dana Farber Cancer Institute, Boston, Massachusetts. douglas.b.johnson@vanderbilt.edu elizabeth_buchbinder@dfci.harvard.edu.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Buchbinder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy / Q000601:surgery; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab