Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma

Abstract

Background: Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort.

Methods: Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016.

Results: Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD-L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC.

Conclusion: Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806).

Conflict of interest statement

Competing Interests: B H O’Neil disclosed travel, accommodations, and expenses from Amgen. D Lorente disclosed consultant or advisory role for Janssen Pharma and Sanofi Aventis; D Lorente also received travel, accommodations, and expenses from Janssen Pharma and Sanofi Aventis. J Raimbourg received honoraria from Bristol-Myers Squibb, Roche, and Boehringer Ingelheim; she also received travel, accomodations, and expenses from Roche, Pierre Fabre, and Novartis. C Gomez-Roca disclosed consultant or advisory role for Novartis, Erytech Pharma, Sanofi Aventis; he also received travel, accomodations, and expenses from Roche, Amgen, and Bristol-Myers Squibb. SA Piha-Paul disclosed research funding from GlaxoSmithKline, Puma Biotechnology, Inc., Novartis, Merck & Co., Inc., Medivation, Inc., Principia Biopharma Inc., AbbVie, XuanZhu Biopharma, Helix BioPharma Corp., and Incyte, Inc. MN Stein received research funding from Merck & Co., Inc., AbbVie, Janssen Pharma, Medivation/Astellas, Oncoceutics, Inc., Bavarian Nordic, and Abraxis BioScience. A Santoro disclosed consultant or advisory role for Takeda, Eli Lilly, Amgen, Bayer, and ArQule. R B Cohen disclosed research funding to his institution from Merck & Co., Inc. M Gould, S Saraf, and K Stein are currently (or were at the time the study was conducted) employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, who may own stock and/or hold stock options in Merck & Co., Inc. J Wallmark, E Elez, S Ejadi, AR Abdul Razak, K Dotti, and S-W Han claimed no conflicts of interest. There are no additional declarations from the authors relevant to this research relating to employment, consultancy, products in development, patents, or revenues from marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials, with the exception declared in the data availability statement.

Figures

Fig 1. CONSORT diagram.

Fig 2. Treatment exposure and response duration.

Includes patients evaluable for best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review (n = 20). The length of each bar represents the time to the last imaging assessment.

Fig 3. Change from baseline in tumor size.

(A) Maximum change from baseline. (B) Longitudinal change from baseline.Both panels include patients with ≥1 evaluable postbaseline tumor assessment per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review (n = 19).

Fig 4. Kaplan-Meier estimates of survival.

(A) Progression-free survival. (B) Overall survival.