Background
KEYNOTE-158 was a phase II, open-label, multi-cohort basket trial evaluating pembrolizumab 200 mg q3w as second-line or later monotherapy across 10 pre-specified MSI-H/dMMR solid tumor types. It was the pivotal study supporting the landmark FDA tissue-agnostic approval of pembrolizumab for MSI-H/dMMR solid tumors (June 2020) — the first tumor-agnostic approval based on a biomarker rather than site of origin.
Interventions and follow up
Regimen: Pembrolizumab 200 mg IV q3w monotherapy in MSI-H/dMMR advanced solid tumors (10 pre-specified cohorts) until progression, up to 35 cycles
Primary endpoint: ORR per central BICR (RECIST v1.1) in each tumor-type cohort and the overall MSI-H population
mFollow-up: 37.5 months
Primary endpoint: ORR per central BICR (RECIST v1.1) in each tumor-type cohort and the overall MSI-H population
mFollow-up: 37.5 months
Results
Overall MSI-H (n=233): ORR 34.3% (80/233; 95% CI 28.3–40.8); CR 9.9%; median DOR not reached; 69.6% still responding at 12 months
Gyn/onc cohorts: endometrial (cohort K, n=49) ORR 57.1%; cervical (cohort C, n=21) ORR 14.3%; ovarian (cohort G, n=15) ORR 33.3%
Other cohorts: biliary (n=22) 40.9%; colorectal (n=27) 33.3%
Gyn/onc cohorts: endometrial (cohort K, n=49) ORR 57.1%; cervical (cohort C, n=21) ORR 14.3%; ovarian (cohort G, n=15) ORR 33.3%
Other cohorts: biliary (n=22) 40.9%; colorectal (n=27) 33.3%
Adverse events
Overall: Grade ≥3 TRAEs 16%; treatment discontinuation 4.3%; no treatment-related deaths in MSI-H cohorts; profile consistent with pembrolizumab monotherapy
Immune-mediated: 20% any grade; most common Grade ≥3 — colitis (2.5%), hypothyroidism (0.9%)
Immune-mediated: 20% any grade; most common Grade ≥3 — colitis (2.5%), hypothyroidism (0.9%)
Conclusions
Pembrolizumab achieved durable ORR (34.3% overall, up to 57.1% in endometrial) across MSI-H/dMMR tumor types, establishing the first tissue-agnostic biomarker-guided cancer treatment approval and validating MSI-H/dMMR as a pan-tumor predictive biomarker for PD-1 blockade.
Key Limitations
Single-arm, uncontrolled design across heterogeneous tumor types; small per-cohort sample sizes (n=15–49) limit statistical precision; ORR varies widely by tumor type (14.3% cervical to 57.1% endometrial), precluding uniform clinical inference; MSI-H rate varies by tumor type, affecting real-world applicability; second-line-only setting (later superseded by first-line approvals in specific tumor types); local MSI testing variability; ORR (not OS) as primary endpoint.
Clinical Context
KEYNOTE-158, combined with KEYNOTE-016 and the KEYNOTE-158 colorectal cohort, led to FDA accelerated approval (2017) then full tissue-agnostic approval (2020) of pembrolizumab for MSI-H/dMMR solid tumors — a regulatory landmark. For gyn/onc specifically, the endometrial cohort ORR of 57.1% is among the highest across tumor types and supports pembrolizumab as a second-line option in dMMR endometrial cancer not amenable to targeted therapy. The tissue-agnostic framework established by KEYNOTE-158 subsequently influenced approvals of dostarlimab (GARNET), larotrectinib (TRK fusions), and entrectinib.