Pembrolizumab in microsatellite instability high cancers: Updated analysis of the phase II KEYNOTE-164 and KEYNOTE-158 studies

Abstract

Background: Pembrolizumab (pembro) is indicated for patients (pts) with microsatellite instability-high (MSI-H) solid tumors after 1 prior therapy, and MSI-H colorectal cancer (CRC) after prior fluoropyrimidine, oxaliplatin, and irinotecan, based in part on data showing durable clinical benefit with pembro in the phase II studies KEYNOTE (KN)164 ([NCT02460198] in 61 pts (cohort A) with MSI-H CRC) and KN158 ([NCT02628067] in19 pts with MSI-H non-CRC). Here, we report results of the antitumor activity of pembro in pts with MSI-H tumors from a pooled analysis of KN164 and KN158, with >=18 mo of additional follow-up across 28 tumor types. Method(s): KN164 enrolled pts with MSI-HCRC (cohort A [>=2 prior], cohort B [>=1 prior therapy]), while KN158 included pts with MSI-H non-CRC (>=1 prior therapy). MSI-H status was determined locally by IHC or PCR or centrally by PCR. Eligible pts in both received pembro 200 mg Q3W. Tumor response was assessed every 9 wk. Primary endpoint was ORR by central review per RECIST v1.1. Data cutoff date was Sept 4, 2018 for KN164 and Dec 6, 2018 for KN158. Result(s): At data cutoff, 357 pts (124 with MSI-H CRC, 233 with MSI-H non-CRC) were enrolled. Pts had median age of 59 years (range 20-87) and 350 (98%) had >=1 prior therapy. Common MSI-H non-CRC tumor types included endometrial (n=49), gastric (n=24), cholangiocarcinoma (n=22), pancreatic (n=22), small intestinal (n=19), ovarian (n=15), brain (n=13), sarcoma (n=9), neuroendocrine (n=7), cervical and prostate (n=6) cancers. Median follow-up was 18.0mo (range 0.1-35.6). Confirmed ORR was 34% (n=121; 95% CI 29-39); 30 (8%) pts had CR. Median DOR was not reached (range 2.9 to 31.3+); 54% of pts had response duration >=18 mo. Median OS was 27.8 monthsmo (95% CI 21.3 to not reached), with 2-year OS rate of 52%. Median PFS was 4.0 mo (95% CI 2.5-4.3) with 2-year PFS rate of 31%. Serious drug-related events occurred in 11 (9%) pts with MSI-H CRC and 18 (8%) pts with MSI-H non-CRC. The safety profile was consistent with that previously seen for pembro. A pooled safety analysis will be presented. Conclusion(s): Pembro provides robust antitumor activity with durable responses and a manageable safety profile in pts with MSI-H cancers independent of tumor type.