ASCO 2020: Pembrolizumab Offers Better Outcomes Than Chemotherapy for High Microsatellite Instability Metastatic Colorectal Carcinoma
Pembrolizumab should become the new standard of care for these patients, says study author
May 29, 2020—The programmed cell death ligand 1 (PD-L1) inhibitor pembrolizumab as a first-line therapy for high microsatellite instability/mismatch repair deficient metastatic colorectal carcinoma offers superior progression-free survival outcomes than chemotherapy, according to an interim analysis of the KEYNOTE-177 trial. Results were given during a virtual presentation as part of the 2020 International Conference of the American Society of Clinical Oncology. The conference, scheduled to take place in Chicago from May 29 to June 2, was shifted to an online platform due to the COVID-19 pandemic.
“Microsatellite instability occurs in cells with high levels of mutations in short, repeated DNA sequences caused by deficiency in the mismatch repair system,” Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, France said during his presentation. “Mismatch repair status and microsatellite instability high status have predicted clinical benefit of immune checkpoint blockades with pembrolizumab and other anti-PD-1 therapies.”
“In phase II studies, pembrolizumab demonstrated durable antitumor activity with an acceptable safety profile in previously treated high microsatellite instability metastatic colorectal cancer,” he continued. “[Here], we report results from the first phase III study of pembrolizumab versus standard of care as first-line therapy in high microsatellite instability metastatic colorectal cancer.”
As of February 19, 2020, the time of data cut-off, a total of 307 patients with high microsatellite instability/mismatch repair deficient metastatic colorectal carcinoma were included in the study. Of these patients, 153 were randomized to first-line pembrolizumab 200 mg every 3 weeks for up to 35 cycles, and 154 were randomized to the investigator’s choice of one of six standard chemotherapy regimens, which were selected prior to randomization. Investigators selected from the following chemotherapy regimens: MFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin), MFOLFOX6 plus bevacizumab, MFOLFOX6 plus cetuximab, FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan), FOLFIRI plus bevacizumab, or FOLFIRI plus cetuximab. Patients in the chemotherapy arm had the option to cross over to the pembrolizumab arm after disease progression.
The primary endpoints were progression-free survival and overall survival. Key secondary endpoints included overall response rate and safety.
Median progression-free survival with first-line pembrolizumab was 16.5 months (95% confidence interval 5.4–32.4), compared with 8.2 months (95% confidence interval 6.1–10.2) with chemotherapy, for a hazard ratio of 0.60 (95% confidence interval 0.45–0.80; P = .0002).
Progression-free survival at 12 months follow-up was 55.3% with pembrolizumab and 37.3% with chemotherapy. At 24 months, progression-free survival was 48.3% for the pembrolizumab arm versus 18.6% for the chemotherapy arm.
For patients treated with pembrolizumab, overall response rate was 43.8%. This included 11% of patients with a complete response and 32.7% with a partial response. Another 30.9% had stable disease. Among chemotherapy patients, overall response rate was 33.1%, with a complete response rate of 3.9%, partial response rate of 29.2%, and stable disease rate of 42.2%. The response period was longer for patients given pembrolizumab, with 83% of these patients having a response longer than 2 years, compared with 35% of chemotherapy patients.
Grade 3 or higher severe treatment-related adverse events were less common among patients in the pembrolizumab arm (22% vs 66%). Toxicity profiles of pembrolizumab and chemotherapy differed greatly, with pembrolizumab-related adverse events being typically immune-mediated, such as colitis and hepatitis. For patients in the chemotherapy arm, adverse events were most commonly diarrhea, neutropenia, fatigue, nausea, vomiting, stomatitis, alopecia, and neurotoxicity.
“Pembrolizumab provided a clinically meaningful and statistically significant improvement in progression-free survival versus chemotherapy as first-line therapy for [high] microsatellite instability metastatic colorectal cancer, with different and less treatment-predicted events. The study will continue to evaluate overall survival at final analysis,” said Dr. André. “In the past, no medical treatment has shown such a difference in terms of improvement of progression-free survival in metastatic colorectal cancer.”
“Today, this study demonstrates that the majority of the 5% of patients with metastatic colorectal cancer, selected by microsatellite instability high status, benefited greatly [from] anti-PD-L1 pembrolizumab compared to standard of care. Pembrolizumab should be the new standard of care for these patients,” he concluded.
KEYNOTE-177 is sponsored by Merck Sharp & Dohme Corp.
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Oncology
ASCO 2020 reported the long-awaited data of the first-line, randomized KEYNOTE-177 trial of pembrolizumab compared with standard chemotherapy +/− biologics in MSI-H/MMR-D colorectal cancer. In the US and Japan, anti–PD-1 antibodies have long been approved in this patient population in later-line settings based on single-arm studies with demonstration of durable responses. European regulators, however, have been waiting for randomized data to show superiority of PD-1 inhibition over standard approaches. This alone underscores the importance of this trial. KEYNOTE-177 met its co-primary endpoint of progression-free survival (PFS), which more than doubled by median with a hazard ratio of 0.60; at 2 years, more than twice as many patients on pembrolizumab had not yet progressed compared with the chemotherapy arm (48% vs 19%). A plateau for PFS seems to emerge long term around 30% to 40%.
Response rates were also 10% higher for pembrolizumab with remarkable durability of response, the median of which was not reached at data cutoff. As expected, serious adverse events were lower with the anti–PD-1 antibody compared with combination chemotherapy. Interestingly, though, 2.5 times more patients on pembrolizumab had progression of disease as best response (29.4% vs 12.3%), which resulted in a drop of the PFS curve in the initial phase with crossing of the curves, a phenomenon seen in various other trials with anti–PD-1 antibodies in gastrointestinal malignancies, such as gastroesophageal cancers. It appears that there is a subgroup within the MSI-H/MMR-D population that does not respond to immune checkpoint inhibitors, which has yet to be clearly defined.
Prior studies have indicated that in MSI-H/MMR-D cancers tumor mutational burden (TMB) could be used as a predictive marker in the sense that higher TMB is associated with a very high likelihood of response to immune therapy. In addition, one could consider combination strategies with pembrolizumab plus either chemotherapy—see non–small cell lung cancer—or other checkpoint inhibitors like anti–CTLA-4 antibodies—see ipilimumab plus nivolumab (CheckMate 142)—to decrease the number of patients with early tumor progression. Data on overall survival, the second co-primary endpoint, have not been released yet; but, in view of an almost 60% crossover, it is unclear whether the results will show a statistically significant difference. For now, KEYNOTE-177 has established a new standard of care in the first-line therapy of MI-H/MMR-D colorectal cancer. The dataset will allow for a series of clinical and translational explorations, which will help us identify the mechanism of immune response in these patients and primary and secondary resistance factors.