The monoclonal antibody pembrolizumab (Keytruda; Merck) provides statistically significant improvements in progression-free survival relative to standard chemotherapy as first-line treatment in patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer, new research has concluded.
Results of the final progression-free survival analysis from the international, multi-center KEYNOTE-177 trial (NCT02563002) also found fewer treatment-related adverse events among individuals treated with pembrolizumab.
In a presentation to the 2021 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (abstract 6), the authors explained that KEYNOTE-177 sought to evaluate the anti-tumor activity of pembrolizumab and chemotherapy with or without bevacizumab (Avastin; Genentech) or cetuximab (Erbitux; Lilly) as first-line therapy among patients with MSI-H/dMMR metastatic colorectal cancer. In the current study, they presented the results of the final progression-free survival analysis.
According to lead author Kai-Keen Shiu, PhD, of University College London Hospitals, NHS Foundation Trust, United Kingdom, the trial comprised 307 patients with locally-determined MSI-H/dMMR metastatic colorectal cancer and an Eastern Cooperative Oncology Group performance status of either 0 or 1. These individuals were randomized to receive first-line therapy with either 200 mg pembrolizumab every three weeks for up to two years (n=153) or the investigator’s choice of either mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI therapy (folinic acid, fluorouracil, and irinotecan) every two weeks with or without bevacizumab or cetuximab (n=154).
Each treatment was continued until one of four benchmarks occurred: disease progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembrolizumab only). Patients in the chemotherapy group were allowed to cross over to pembrolizumab for up to 35 cycles after confirmed progressive disease.
The trial’s primary endpoints were progression-free survival and overall survival; secondary endpoints were objective response rate and treatment safety. The study also had several exploratory endpoints: duration of response, health-related quality of life, and what the investigators called PFS2, which represented the time from randomization to progression on the next line of therapy or death from any cause.
Over a median follow-up period of 32.4 months (range 24.0-48.3 months), patients who received pembrolizumab had a median progression-free survival of 16.5 months, significantly greater than the 8.2 months for their counterparts who underwent chemotherapy (hazard ratio 0.60; p=0.0002). Similarly, the 12-month and 24-month progression-free survival rates were 55.3% and 48.3% with pembrolizumab, compared with vs 37.3% and 18.6% with chemotherapy. Pembrolizumab’s progression-free survival advantages were consistent across a variety of patient subgroups, including age, gender, ECOG performance score, geographic region, stage, and tumor site.
Overall survival analysis is ongoing.
Pembrolizumab also proved superior with respect to secondary endpoints. Indeed, confirmed objective response rate was 43.8% in pembrolizumab patients and 33.1% in chemotherapy patients. Furthermore, 11.1% of pembrolizumab patients had a complete response, 32.7% had a partial response, 20.9% had stable disease, and 29.4% had progressive disease, markedly better than the 1.9%, 29.2%, 42.2%, and 12.3%, respectively, observed in chemotherapy patients.
PFS2 was also longer with pembrolizumab (median not reached vs 23.5 months; HR 0.63). Finally, median duration of response was not reached with pembrolizumab, compared with 10.6 months among chemotherapy patients. Rates of response at a minimum of 24 months were 83% with pembrolizumab and 35% with chemotherapy. Median time to response was 2.2 months with pembrolizumab and 2.1 months with chemotherapy.
Tolerability analyses demonstrated that rates of treatment-related adverse events of at least grade 3 were 22% in pembrolizumab patients and 66% for chemotherapy patients. Nevertheless, 10% of pembrolizumab patients and 6% of chemotherapy patients discontinued treatment.
No grade 5 treatment-related adverse events occurred in pembrolizumab patients, compared with one chemotherapy patient (a grade 5 intestinal perforation). Health-related quality of life scores were also improved with pembrolizumab.
The investigators concluded that pembrolizumab is superior to chemotherapy as first-line treatment of patients with MSI-H/dMMR metastatic colorectal cancer.
“We have a lot of work to do,” Dr. Shiu said in a recording of the presentation. “We wait for the overall survival analysis of this trial eagerly later this year, because there's a lot of biomarker work we have to do. And I also think in a lot of upcoming trials, in the same setting, but also in the earlier setting, the agent will keep on giving us more answers.”
