Data Support Use of Pembrolizumab as Frontline Treatment for MSI-H/dMMR mCRC
Although there was no significant overall survival benefit shown with pembrolizumab in the KEYNOTE-177 study, response and safety findings still support its use as a frontline option for patients with microsatellite instability high and mismatch repair deficient metastatic colorectal cancer.
Pembrolizumab (Keytruda) treatment in patients with metastatic colorectal cancer (mCRC) with microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) achieved durable antitumor activity and less toxicity compared with chemotherapy, despite not showing overall survival (OS) benefit, according to findings from the phase 3 KEYNOTE-177 clinical trial (NCT02563002).
The final overall analysis for the KEYNOTE-177 published in the Lancet Oncology sought to shed light on OS outcomes in the population of MSI-H/dMMR. Prior to this study, little was known about OS outcomes in this patient population. There was no significant OS benefit shown with pembrolizumab in the study; however, response and safety findings still support its use as a frontline option for patients with MSI-H/dMMR mCRC.
“These data show that pembrolizumab results in a durable antitumor response and fewer treatment-related adverse events in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the first-line setting compared with chemotherapy, and support pembrolizumab as a standard first-line treatment in this population,” wrote the study authors, led by Luis A Diaz Jr, MD, head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center.
The objective response rate (ORR) observed with pembrolizumab in the study was 45% (95% CI, 37%-53%) compared with 33% (95% CI, 26%-41%) in the chemotherapy arm. Response to pembrolizumab included 20 complete responses vs 6 in the chemotherapy arm. The median duration of response observed with pembrolizumab was not reached (NR; interquartile range [IQR], 36.1-NR) vs 10.6 months (IQR, 8.1-28.8) with chemotherapy.
Further, ongoing responses to pembrolizumab were observed after 36 months in 76% of patients (95% CI, 62%-85%). In comparison, the chemotherapy arm had ongoing responses to therapy after 36 months in 24% of patients (95% CI, 12%-38%).
KEYNOTE-177 included 307 patients who were randomized 1:1 to receive pembrolizumab 200 mg via intravenous infusion on day 1 of each 21-day cycle or 1 of 6 possible standard-of-care chemotherapy regimens. Those in the chemotherapy arm were permitted to crossover to the pembrolizumab arm for up to 35 cycles after disease progression.
Coprimary end points explored in the study were OS and progression-free survival (PFS). The secondary end points of the study were overall response rate per RECIST v1.1, the number of patients with adverse events (AEs), and the number of patients who discontinued study treatment due to an AE.
At a median follow-up of 44.5 months (interquartile range, 39.7-49.8), the median OS was not reached (NR) with pembrolizumab (95% CI, 49.2-NR) vs 36.7 months (95% CI, 27.6-NR) with chemotherapy (HR, 0.74; 95% CI, 0.53-1.03; P =.036), missing 1 of the key end points. However, the study was positive for the coprimary end point of PFS.
The median PFS in the pembrolizumab arm was 16.5 months (95% CI, 5.4-38.1) compared with 8.2 months (95% CI, 6.1-10.2) in the chemotherapy arm (HR, 0.59; 95% CI, 0.45-0.79).
Safety results showed that ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 22% of the pembrolizumab arm vs 66% of the chemotherapy arm. The most common TRAES in the pembrolizumab arm were increased alanine aminotransferase, colitis, diarrhea, and fatigue, which each occurred in 3% of patients. The most common TRAEs resulting from chemotherapy were decreased neutrophil count (17%), neutropenia (15%), diarrhea (10%), and fatigue (19%).
Sixteen percent of patients in the pembrolizumab arm experienced serious AEs compared with 29% of the chemotherapy arm. There were no deaths related to pembrolizumab in the study, but 1 death occurred as a result of intestinal perforation in the chemotherapy arm.
“The safety profile was favorable at final analysis, with fewer high-grade treatment-related adverse events observed with pembrolizumab than with chemotherapy,” wrote Diaz et al.
REFERENCE:
Diaz LA, Shiu K, Kim T, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022; 23(5):659-670.
