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 accessAbstract
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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In the citing paper
“Immune checkpoint blockade with monoclonal antibodies (mAbs) targeting programmed cell death protein 1 (PD-1) provides long-term clinical benefits to nearly 40% of patients with advanced melanoma (1–5).”
From Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients (2021) · cites this paper as [2]
In the citing paper
“Both CTLA-4 and PD-1 act independently as brakes on CD3/CD28-dependent signaling, suggesting that underlying immune responses are required for checkpoint inhibitor treatment to take effect (66).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [66]
In the citing paper
“In melanoma, anti-PD-1 treatment was more effective in patients with smaller tumors (66).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [66]
In the citing paper
“Both CTLA-4 and PD-1 act independently as brakes on CD3/CD28-dependent signaling, suggesting that underlying immune responses are required for checkpoint inhibitor treatment to take effect (66).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [66]
In the citing paper
“For example, patients with smaller tumors or low serum lactate dehydrogenase (LDH) levels at baseline have a better prognosis and are also more likely to respond to anti-PD-1 treatment (66).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [66]
In the citing paper
“Patients more likely to benefit from checkpoint immunotherapy include those with tumors demonstrating a high density of somatic mutations, elevated PD-L1 expression and/or are enriched with IFNγ transcriptional profiles (8–13).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [11]
In the citing paper
“The degree of tumor inflammation, as assessed by the presence of type I/II IFN signaling and infiltrating effector T cells, is associated with an improved response to checkpoint immunotherapy (8–11,13).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [11]
In the citing paper
“Anti-PD-1 immunotherapy has shown efficacy in melanoma, but fewer than half of all melanoma patients treated with anti-PD-1 immunotherapy have a prolonged response5.”
From Mechanisms and prevention of UV‐induced melanoma (2018) · cites this paper as [5]
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Citations
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Self-citation
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Cited by
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Cancer immunotherapy using checkpoint blockade
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Metadata
- 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
- 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.
- Hersey, Peter
- Dronca, Roxana
- Joseph, Richard W.
- Zarour, Hassane
- Chmielowski, Bartosz
- Lawrence, Donald P.
- Algazi, Alain
- Rizvi, Naiyer A.
- Mateus, Christine
- Li, Xiaoyun Nicole
- Robert, Caroline
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-04-19
- Volume
- 315
- Issue
- 15
- Pages
- 1600
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- 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
- bronze
- doi.org
- 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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