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Cited by 1,069Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma

Open access
Ribas, Antoni, Hamid, Omid, Daud, Adil, Hodi, F. Stephen, Wolchok, Jedd D., Kefford, Richard, Joshua, Anthony M., Patnaik, Amita, Hwu, Wen-Jen, Weber, Jeffrey S., Gangadhar, Tara C., Hersey, Peter, Dronca, Roxana, Joseph, Richard W., Zarour, Hassane, Chmielowski, Bartosz, Lawrence, Donald P., Algazi, Alain, Rizvi, Naiyer A., Hoffner, Brianna, Mateus, Christine, Gergich, Kevin, Lindia, Jill A., Giannotti, Maxine, Li, Xiaoyun Nicole, Ebbinghaus, Scot, Kang, S. Peter, Robert, Caroline·2016·JAMA
DOI 10.1001/jama.2016.4059
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Abstract

IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

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Research works printed but not linked: 4

  1. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma. Lancet. 2014;384(9948):1109-1117.
  2. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002). Lancet Oncol. 2015;16(8):908-918.
  3. Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size (BTS) and PD-L1 expression are independently associated with clinical outcomes in patients (pts) with metastatic melanoma (MM) treated with pembrolizumab (pembro; MK-3475). Abstract presented at: Society for Melanoma Research 2014 Congress; November 13-16, 2014; Zurich, Switzerland. Pigment Cell Melanoma Res. 2014;27:1188.
  4. Kluger HM, Sznol M, Callahan MK et al. Survival, response duration and activity by BRAF mutation status in a phase 1 trial of nivolumab (anti-PD-1; BMS-936558,ONO-4538) and ipilimumab concurrent therapy in advanced melanoma (MEL). Abstract presented at: Society for Melanoma Research 2014 Congress; November 13-16, 2014; Zurich, Switzerland. Pigment Cell Melanoma Res. 2014;27:1203.

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Authors
Ribas, A., Hamid, O., Daud, A., Hodi, F. S., Wolchok, J. D., Kefford, R., Joshua, A. M., Patnaik, A., Hwu, W.-J., Weber, J. S., Gangadhar, T. C., Hersey, P., Dronca, R., Joseph, R. W., Zarour, H., Chmielowski, B., Lawrence, D. P., Algazi, A., Rizvi, N. A., Hoffner, B., Mateus, C., Gergich, K., Lindia, J. A., Giannotti, M., Li, X. N., Ebbinghaus, S., Kang, S. P., & Robert, C.
Affiliations
  • University of California, Los Angeles (US)
  • Angeles Clinic and Research Institute (US)
  • University of California, San Francisco (US)
  • Dana-Farber Cancer Institute (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Westmead Hospital (AU)
  • Princess Margaret Cancer Centre (CA)
  • South Texas Accelerated Research Therapeutics (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Moffitt Cancer Center (US)
  • Abramson Cancer Center (US)
  • The University of Sydney (AU)
  • Mayo Clinic (US)
  • Mayo Clinic in Florida (US)
  • University of Pittsburgh (US)
  • Massachusetts General Hospital (US)
  • Institut Gustave Roussy (FR)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Ribas, Antoni
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2016-04-19
Volume
315
Issue
15
Pages
1600
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2016.4059
OpenAlex
W2338494814
Cited by
1,069
References
22
Citations by year
2026: 33 · 2025: 66 · 2024: 67 · 2023: 99 · 2022: 63 · 2021: 123 · 2020: 139 · 2019: 139 · 2018: 145 · 2017: 153 · 2016: 39
FWCI
85.72
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
Funders
National Cancer Institute (P30CA008748)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
pembrolizumab, advanced melanoma, metastatic melanoma, anti-PD-1 therapy, anti-PD-1 monoclonal antibody, objective response rate, overall survival, progression-free survival, duration of response, ipilimumab, immune checkpoint inhibitors, treatment-naive patients, treatment-emergent adverse events, immune-related adverse events, immune-related pneumonitis, immune-related colitis
MeSH terms
Ipilimumab, Adult, Aged, Aged, 80 and over, Algorithms, Antibodies, Monoclonal, Antineoplastic Agents, Drug Administration Schedule, Female, Humans, Male, Melanoma, Middle Aged, Skin Neoplasms, Survival Rate, Treatment Outcome, Disease Progression, Disease-Free Survival, Young Adult, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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