Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164

Abstract

Purpose: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).

Methods: This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.

Results: A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.

Conclusion: Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

FIG 1.

Best percent change from baseline in target lesion size (RECIST version 1.1 by central review) by prior lines of therapy in patients with microsatellite instability–high colorectal cancer in (A) cohort A and (B) cohort B. (*) Two patients in cohort A did not have postbaseline assessments and are not included. (†) One patient in cohort B did not have postbaseline assessments and is not included.

FIG 2.

Kaplan-Meier estimates of progression-free survival (RECIST version 1.1 by central review) in patients with microsatellite instability–high colorectal cancer (MSI-H CRC) in (A) cohort A and (B) cohort B.

FIG 3.

Kaplan-Meier estimates of overall survival in patients with microsatellite instability–high colorectal cancer (MSI-H CRC) in (A) cohort A and (B) cohort B. NR, not reached.

FIG A1.

Percent change from baseline in target lesion size (RECIST v1.1) with time in patients with microsatellite instability–high/mismatch repair–deficient colorectal cancer in (A) Cohort A and (B) Cohort B. CR, complete response; PD, disease progression; PR, partial response; SD, stable disease.

FIG A2.

Treatment exposure and duration of response by BRAF status in patients with microsatellite instability–high/mismatch repair–deficient colorectal cancer in (A) Cohort A and (B) Cohort B. CR, complete response; PR, partial response.

FIG A3.

Treatment exposure and duration of response by RAS status in patients with microsatellite instability–high/mismatch repair–deficient colorectal cancer in (A) Cohort A and (B) Cohort B. CR, complete response; PR, partial response.