Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164
Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, Burge M, O’Neil B, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Crocenzi T, Atreya CE, Cui Y, Dai T, Marinello P, Diaz LA Jr, André T.
Colorectal cancer (CRC) is the 3rd leading cause of cancer death worldwide. It is responsible for more than 16,000 deaths per year in France. 5% of metastatic CRCs present an MSI (microsatellite instability) tumor phenotype related to a deficiency in the DNA mismatch repair system (dMMR). It has recently been shown that newer immunotherapy drugs (immune checkpoint inhibitors) are particularly effective in patients whose cancer has the MSI/dMMR phenotype. Thus pembrolizumab (anti-PD1 antibodies) has been approved by the American authorities (FDA: Food and Drug Administration) for the treatment of patients with metastatic MSI/dMMR CCR resistant to conventional treatments, based on preliminary data from the KEYNOTE-164 study.
This publication presents the complete results of the KEYNOTE-164 study. This is a Phase 2 study that included patients with metastatic MSI/dMMR CRC previously treated with a minimum of two lines (Cohort A) or one line of standard therapy (Cohort B). Patients received pembrolizumab 200 mg intravenous every 3 weeks until unacceptable progression or toxicity, for a maximum total of 2 years.
124 patients were included. Respectively 44% and 30% of patients in cohorts A (N=61) and B (N=63) had received more than 3 lines of treatment previously, and more than half of the patients in each cohort had an impaired performance index. With a median follow-up of 31 months (cohort A) and 24 months (cohort B), the objective response rate (defined as more than 30% reduction in tumour mass) was 33% in each of the 2 cohorts. The median duration of response was not reached (time from first documentation of response to tumour progression or death). The median overall survival was 31 months in cohort A and was not reached in cohort B. Treatment had to be discontinued in 2 patients in each cohort due to side effects (hepatic cytolysis, pneumonitis). 16% and 13% of patients in cohorts A and B respectively experienced treatment-related side effects, including dysthyroidism and colitis.
Updated data from the KEYNOTE-164 study confirms that immunotherapy is an effective therapeutic strategy, with lasting clinical benefit, in patients with metastatic MSI/dMMR CRC.
By Dr Romain COHEN