A high level of microsatellite instability (MSI-H) is indicative of a tumor deficient in mismatch repair (dMMR). Prior reports suggest that anti-PD-1 antibody therapy provides durable responses in patients (pts) with MSI-H cancers. Here we assessed efficacy of PD-1 blockade using pembrolizumab in pts with dMMR/MSI-H (hereafter termed MSI-H) advanced cancer enrolled in two ongoing, global, multicenter phase 2 studies KEYNOTE (KN)164 and KN158. We report results in 61 pts with MSI-H CRC and 77 pts with MSI-H non-CRC across 20 tumor types.
KN164 enrolled pts with MSI-H colorectal cancer (CRC) and ≥2 prior therapies, whereas the multicohort KN158 study included pts with MSI-H non-CRC and ≥1 prior therapy. MSI-H status was determined locally by IHC or PCR or centrally by PCR. Eligible pts in both studies received pembrolizumab 200 mg Q3W. Tumor response was assessed every 9 wk. Primary endpoint was ORR by independent central review per RECIST v1.1. Database cut-off date was Feb 10, 2017 for KN164 (≥54 wk follow-up) and Jan 27, 2017 for KN158 (≥27 wk follow-up).
KN164 enrolled 61 pts with MSI-H CRC (90% with ≥2 prior therapies) and KN158 enrolled 77 pts with MSI-H non-CRC (52% with ≥2 prior therapies), at data cutoff. Tumor types represented in KN158 in at least 2 pts included endometrial (n = 17), gastric (n = 11), small intestinal (n = 10), pancreatic (n = 9), biliary (n = 8), mesothelioma and small cell lung (n = 3 each), adrenocortical, bladder, and thyroid (n = 2 each) cancers. ORR was 27.9% (n = 17 [all confirmed]; 95% CI 17.1%-40.8%) for MSI-H CRC and 37.7% (n = 29 [23 confirmed and 6 unconfirmed]; 95% CI 26.9%-49.4%) for MSI-H non-CRC. Median DOR was not reached for MSI-H CRC (range 2.9+ to 12.5+) or MSI-H non-CRC (range 2.4+ to 9.2+). Median OS was not reached for either MSI-H CRC or MSI-H non-CRC, with 6-mo OS rates of 87% and 73%, respectively.
6-mo PFS rates were 43% for MSI-H CRC and 45% for MSI-H non-CRC. 4 (7%) pts with MSI-H CRC and 7 (9%) with MSI-H non-CRC had serious drug-related AEs. The safety profile was consistent with that previously seen for pembrolizumab.
Pembrolizumab provides robust antitumor activity with durable responses in heavily pretreated pts with MSI-H cancers.
Clinical trial identification
ClinicalTrials.gov NCT02460198. MK-3475 164 First received: May 29, 2015 Last updated: February 16, 2017 Last verified: February 2017 AND ClinicalTrials.gov NCT02628067. MK-3475 158 First received: December 9, 2015 Last updated: February 23, 2017 Last verified: February 2017
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
L. Diaz: Travel expenses from Merck & Co., Inc. A. Marabelle: Advisory board for Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, Bristol-Myers Squibb, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche-Genentech. Speakers’ bureau for MSD. T.W. Kim: Advisory board member for Amgen. Research funding from Taiho, Bayer. R. Geva: RG: Advisory board member for Bayer, MSD & Novartis. Honoraria from Bristol-Myers Squibb, Lilly, Medison, Roche, Novartis and Janssen. E. Van Cutsem: Research funding from Amgen, Bayer, Boehringer, Celgene, Ipsen, Lilly, MSD, Merckserono, Novartis, Roche, Sanofi and Servier. T. André: Honoraria from Bohrigner Ingenheim, Merck, Serono, Baxter, Bayer and Roche. P.A. Ascierto: Advisory board member for Bristol-Myers Squibb, Roche-Genentech, MSD, Novartis, Array, Amgen, Merck Serono, and Pierre Fabre. M. Maio: Honoraria, travel expenses and consulting fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, GSK, & Medimmune. R. Guimbaud: Advisory board member for Novartis. Travel expenses, including accommodations from Roche, Ipsen, Lilly and Sanofi. D. Jaeger: Consulting or advisory roles and Roche, Bristol-Myers Squibb & Bayer. T. Yoshino, A. Joe, B. Lam, J. Ding, S. Pruitt, S.P. Kang: SPK is employed by Merck & Co., Inc. and may own stock options in the company. D.T. Le: Research grants and honoraria from Merck & Co., Inc. All other authors have declared no conflicts of interest.