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Original Investigation |

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

Antoni Ribas, MD, PhD1; Omid Hamid, MD2; Adil Daud, MD3; F. Stephen Hodi, MD4; Jedd D. Wolchok, MD, PhD5; Richard Kefford, MD, PhD6,7; Anthony M. Joshua, MBBS, PhD8; Amita Patnaik, MD9; Wen-Jen Hwu, MD, PhD10; Jeffrey S. Weber, MD, PhD11; Tara C. Gangadhar, MD12; Peter Hersey, MD, PhD13; Roxana Dronca, MD14; Richard W. Joseph, MD15; Hassane Zarour, MD16; Bartosz Chmielowski, MD, PhD1; Donald P. Lawrence, MD17; Alain Algazi, MD3; Naiyer A. Rizvi, MD5; Brianna Hoffner, BA, RN, MSN2; Christine Mateus, MD18; Kevin Gergich, MA19; Jill A. Lindia, MS19; Maxine Giannotti, BS19; Xiaoyun Nicole Li, PhD20; Scot Ebbinghaus, MD19; S. Peter Kang, MD19; Caroline Robert, MD, PhD18
[+] Author Affiliations
1Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles
2Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California
3Department of Hematology/Oncology, University of California-San Francisco, San Francisco
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
6Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia
7Department of Clinical Medicine, Macquarie University, Sydney, Australia
8Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
9Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio
10Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston
11Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
12Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia
13Department of Medicine, University of Sydney, Sydney, Australia
14Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
15Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida
16Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
17Department of Hematology/Oncology, Massachusetts General Hospital, Boston
18Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France
19Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey
20BARDS, Merck & Co, Inc, Kenilworth, New Jersey
JAMA. 2016;315(15):1600-1609. doi:10.1001/jama.2016.4059.
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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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Figure 1.
Flowchart of Enrolled Participants and Progress Through the Trial

There was 1 nonrandomized cohort with 5 sequential, nonoverlapping treatment groups,6 and there were 3 randomized cohorts.7,10,11 In all 3 randomized cohorts, patients were randomized prior to assignment to a treatment group. The enrolled group consists of patients with and without measurable disease by independent review who received at least 1 dose of pembrolizumab.

The group comprising the full analysis set consists of patients with measurable disease at baseline (per independent review) who received at least 1 dose of pembrolizumab; those without measurable disease at baseline were excluded.

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Figure 2.
Objective Response Rate Assessed in Patients With Measurable Disease at Baseline in Subgroups (n = 581)

Data were assessed by independent central review using RECIST v1.1. ULN indicates upper limit of normal.

aObjective response rate was defined as the percentage of patients with a complete or partial response.

bImmunotherapy category excludes ipilimumab.

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Figure 3.
Duration of Response to Pembrolizumab Among Responders

Reports estimates of duration of response among responders in the total population (n = 205) and the treatment-naive population (n = 65), as assessed by RECIST v1.1 by independent central review for patients with confirmed response who had at least 1 dose of study treatment, regardless of whether they had measurable disease per central RECIST v1.1 at baseline. Small vertical tick marks represent patients who were censored at that specific time in the analysis. Tick marks appear to be floating when multiple events occurred at the same time.

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Figure 4.
Maximum Percentage of Change From Baseline in Sum of the Longest Diameter of Each Target Lesion in the Full Analysis Set

Reports maximum percentage change from baseline in the sum of the longest diameter of each target lesion, as assessed by RECIST v1.1 by independent central review for patients who had measurable disease at baseline by the same and at least 1 postbaseline tumor assessment (full analysis set, N = 510). Target lesions were defined as all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total. Changes greater than 100% were truncated at 100%.

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Figure 5.
Progression-Free and Overall Survival in Patients Treated With Pembrolizumab in Total and Treatment-Naive Populations

The small vertical tick marks represent patients who were censored at that specific time in the survival analysis. Tick marks appear to be floating when multiple events occurred at the same time. Data were assessed by independent central review using RECIST v1.1.

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