KEY TAKEAWAYS
- The KEYNOTE-177 trial is a phase 3, randomized, open-label study conducted across 23 countries, which aimed to evaluate the efficacy and safety of pembrolizumab as first-line therapy.
- The study’s primary aim was to compare the OS and PFS of patients receiving pembrolizumab versus those receiving standard chemotherapy.
- Patients meeting the eligibility criteria were randomly assigned to receive pembrolizumab or the investigator’s choice of chemotherapy with or without bevacizumab or cetuximab.
- At the final analysis with a median follow-up of 44.5 months, the median OS was not reached with pembrolizumab versus 36.7 months with chemotherapy.
- Pembrolizumab exhibited fewer treatment-related adverse events of grade 3 or worse than chemotherapy.
- Although pembrolizumab continued to show durable antitumor activity, no significant difference was observed in OSl between the two treatment groups.
Patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer have shown improved progression-free survival (PFS) with pembrolizumab compared to chemotherapy. However, the treatment’s impact on patients’ overall survival (OS) was unclear. This was a randomized, open-label, third-phase study conducted at 193 hospitals and medical schools across 23 countries. Patients with untreated, microsatellite instability-high or mismatch repair-deficient, metastatic colorectal cancer were enrolled if they were at least 18 years old and had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients were randomly assigned (1:1) in blocks of four using an IVR or IR system to receive either intravenous pembrolizumab 200 mg every 3 weeks or the investigator’s choice of either intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per following progression during chemotherapy, patients could switch to pembrolizumab for up to 35 treatment cycles. OS and PFS were the primary endpoints in the intent-to-treat population. The trial is no longer accepting new participants.
A total of 852 patients were screened between February 11, 2016, and February 19, 2018, and 307 (36%) were randomly assigned to receive either pembrolizumab (n=153) or chemotherapy (n=154). Ninety-three patients, or 60%, switched from chemotherapy to anti-PD-1 or anti-PD-L1 treatment (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). Median OS was not reached (NR; 95% CI 49.2-NR) with pembrolizumab versus 36.7 months (27.6-NR) with chemotherapy (hazard ratio [HR] 0.74; 95% CI 0.53-1.03; p=0.036) at the time of the final analysis (median follow-up of 44.5 months [IQR 39.7-49.8]). The OS benefit of pembrolizumab over chemotherapy could not be established because the prespecified requirement α of 0.025 was unmet.
Pembrolizumab significantly increased the median PFS over chemotherapy (HR 0.59, 95% CI 0.45-0.79) from 8.2 months (6.1-10.2) to 16.5 months (95% CI 5.4-38.1). Of the 153 patients treated with pembrolizumab, 33 (22%) experienced treatment-related adverse events of grade 3 or worse, compared to 95 (66%) of the 143 patients treated with chemotherapy. In three (2%) patients, pembrolizumab was responsible for grade 3 or worse adverse events, including increased alanine aminotransferase, colitis, diarrhea, and fatigue. In comparison, in twenty-four (17%) patients, chemotherapy was responsible for grade 3 or worse adverse events, including neutropenia, diarrhea, and fatigue. Twenty-five patients (16%) in the pembrolizumab group and forty-one patients (29%) in the chemotherapy group experienced serious adverse events attributed to the study treatment. Pembrolizumab was not linked to fatalities, but chemotherapy was blamed for one death caused by intestinal perforation.
In this updated analysis, there was no significant difference in OS between the two treatment groups, even though pembrolizumab continued to show durable antitumor activity and fewer treatment-related adverse events compared to chemotherapy. These results lend credence to pembrolizumab’s use as a first-line therapy for patients with metastatic colorectal cancer, high microsatellite instability, or a lack of mismatch repair.
Source: https://pubmed.ncbi.nlm.nih.gov/35427471/
Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT02563002
Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomized, open-label, phase 3 study. Lancet Oncol. 2022 May;23(5):659-670. doi: 10.1016/S1470-2045(22)00197-8. Epub 2022 Apr 12. PMID: 35427471; PMCID: PMC9533375.
