As reported in the Journal of Clinical Oncology by Dung T. Le, MD, and colleagues, the phase II KEYNOTE-164 trial demonstrated activity of pembrolizumab in previously treated metastatic microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) colorectal cancer.
Dung T. Le, MD
Findings from the trial supported the May 2017 accelerated approval of pembrolizumab for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or patients with MSI-H or dMMR colorectal cancer progressing following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Study Details
A total of 123 patients from seven countries were enrolled in the trial between September 2015 and September 2017. Eligible patients had metastatic MSI-H/dMMR colorectal cancer and were treated with either two or more prior lines of standard therapy including a fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-VEGF/EGFR antibody treatment (cohort A = 61) or one or more prior lines of therapy (cohort B).
Patients received pembrolizumab at 200 mg every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response on Response Evaluation Criteria in Solid Tumors, version 1.1, on independent central review.
At data cutoff, the median follow-up was 31.3 months in cohort A and 24.2 months in cohort B. In cohort A, response was observed in 20 patients (33%), with a complete response in 2; an additional 11 patients (16%) had stable disease. The median time to response was 4.3 months. The median duration of response was not reached (range = 6.2–31.3 months); 85% of responses were ongoing at the time of analysis, with 95% being ≥ 12 months in duration.
In cohort B, response was observed in 21 patents (33%), with a complete response in 5; an additional 15 (24%) had stable disease. The median time to response was 3.9 months. The median duration of response was not reached (range = 4.4–23.6 months); 76% of responses were ongoing at the time of analysis, with 95% being ≥ 12 months in duration.
KEY POINTS
- The objective response rate was 33% in patients treated with two or more prior lines of standard therapy including a fluoropyrimidine, oxaliplatin, and irinotecan.
- The objective response rate was 33% in a separate cohort who had received one or more prior line of therapy.
The median progression-free survival was 2.3 months in cohort A and 4.1 months in cohort B. The median overall survival was 31.4 months (95% confidence interval [CI] = 21.4 months–not reached) and not reached (95% CI = 19.2 months–not reached).
Adverse Events
Treatment-related grade 3 or 4 adverse events were observed in 10 patients (16%) in cohort A and 8 (13%) in cohort B. Treatment-related adverse events led to treatment discontinuation in two patients in cohort A (increased alanine aminotransferase and pneumonitis in one each) and two patients in cohort B (pneumonitis in both).
Immune-mediated adverse events or infusion reactions occurred in 21% of patients in cohort A and 37% in cohort B. Grade 3 or 4 events occurred in four patients in cohort A (pancreatitis in two patients and hepatitis, pneumonitis, and severe skin toxicity in one patient each) and two patients in cohort B (colitis and pneumonitis in one patient each).
The investigators concluded, “Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR colorectal cancer.”
Dr. Le, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co Inc. For full disclosures of the study authors, visit jco.ascopubs.org.
