Efficacy of pembrolizumab in phase 2 KEYNOTE-164 and KEYNOTE-158 studies of microsatellite instability high cancers

Abstract

Background: 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 termedMSI-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-HCRC and 77 pts with MSI-Hnon-CRC across 20 tumor types. Methods: 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). Results: 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. Conclusions: Pembrolizumab provides robust antitumor activity with durable responses in heavily pretreated pts with MSI-H cancers.