As reported in The Lancet Oncology by Diaz et al, the final overall survival analysis of the phase III KEYNOTE-177 trial did not show a significant improvement with pembrolizumab vs chemotherapy in patients with newly diagnosed microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer. However, 60% of the chemotherapy group crossed over to receive anti–PD-1 or anti–PD-L1 therapy upon disease progression.
The trial supported the June 2020 approval of pembrolizumab in this setting on the basis of improved progression-free survival. Progression-free survival results were previously reported.
Study Details
In the open-label trial, 307 patients were randomly assigned between February 2016 and February 2018 to receive pembrolizumab at 200 mg every 3 weeks (n = 153) or investigator’s choice of chemotherapy (n = 154) with mFOLFOX6 (oxaliplatin, leucovorin, fluorouracil) or FOLFIRI (irinotecan, leucovorin, fluorouracil) with or without bevacizumab or cetuximab.
Pembrolizumab was given until disease progression, unacceptable toxicity, or for a maximum of 35 cycles. Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 cycles after disease progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population.
Major Findings
Median follow-up for the final overall survival analysis was 44.5 months (interquartile range = 39.7–49.8 months). A total of 93 patients (60%) crossed over from chemotherapy to anti–PD-1 or anti–PD-L1 therapy, including 56 who crossed over to on-study pembrolizumab and 37 who received off-study therapy.
These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer.— Diaz et al
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Median overall survival was not reached (95% confidence interval [CI] = 49.2 months to not reached) in the pembrolizumab group vs 36.7 months (95% CI = 27.6 months to not reached) in the chemotherapy group. The hazard ratio (HR) was 0.74 (95% CI = 0.53–1.03, P = .036); superiority was not achieved since the prespecified α of .025 needed for statistical significance was not met. In a post hoc analysis, estimated 36-month overall survival was 61.4% (95% CI = 53.2%–68.6%) in the pembrolizumab group vs 50.3% (95% CI = 42.0%–58.0%) in the chemotherapy group.
In the updated analysis, median progression-free survival was 16.5 months (95% CI = 5.4–38.1 months) in the pembrolizumab group vs 8.2 months (95% CI = 6.1–10.2 months) in the chemotherapy group (HR = 0.59, 95% CI = 0.45–0.79). In post hoc analysis, estimated 36-month progression-free survival was 42.3% (95% CI = 34.0%–50.4%) vs 11.1% (95% CI = 6.1%–17.9%). Median second progression-free survival was 54.0 months (95% CI = 44.4 months to not reached) vs 24.9 months (95% CI = 16.6–32.6 months); HR = 0.61, 95% CI = 0.44–0.83, P = .0008).
Grade ≥ 3 treatment-related adverse events occurred in 22% of the pembrolizumab group vs 66% of the chemotherapy group.
The investigators concluded: “In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer.”
Luis A. Diaz Jr, MD, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by MSD. For full disclosures of the study authors, visit thelancet.com.
