The lead author said the findings were a step forward for biomarker studies and would change clinical practice.
Using biomarkers to connect the right patients with the right treatment at the right time is the mantra for deciding when to use immunotherapy in cancer care. Results presented Sunday at the American Society of Clinical Oncology 2020 annual meeting proved that point for certain patients with metastatic colorectal cancer (mCRC).
An interim analysis of the phase 3 KEYNOTE-177 trial, presented during ASCO's plenary session, finds that using pembrolizumab as a first-line therapy in mCRC patients with specific genetic mutations—microsatellite instability high/mismatch repair deficient (MSI-H/dMMR)—doubled progression-free survival (PFS) compared with chemotherapy (16.5 months vs 8.2 months).
The results will change clinical practice, said lead study author Thierry André MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said during the plenary session. “No medical treatment has shown such an improvement,” he said.
“Pembrolizumab works in non-randomized studies in this group of patients with advanced disease,” André said. “This randomized study demonstrates a huge benefit in first line with pembrolizumab and should be the new standard of care.”
Michael D. Overman, MD, of MD Anderson Cancer Center, a discussant for KEYNOTE-177, agreed. “These results should change clinical practice,” he said, noting that the type of tumors being treated in the study are particularly good candidates for immunotherapy. Going forward, Overman said, “It is critical that we test all colorectal cancer patients for mismatch repair or microsatellite status.”
The only caveat might involve patients for whom near term survival is the highest priority, as Overman explained how results show that the benefit of immunotherapy over chemotherapy does not start to appear until about the 6-month mark.
About 5% of mCRC patients have MSI-H/dMMR, and these patients do not fare as well with conventional chemotherapy. Pembrolizumab’s effectiveness when this mutation is present is well-recognized, and led to FDA’s first tissue-agnostic approval in May 2017.
“These data represent another step forward for biomarker driven studies,” André said.
The data cutoff for the interim analysis was February 19, 2020; at that time, the study included 307 mCRC patients with MSI-H/dMMR. Patients were randomized to receive first-line pembrolizumab for up to 2 years, or the investigator’s choice of 6 different standard chemotherapy regimens. Primary end points were PFS and overall survival (OS), while secondary end points included objective response rate (ORR) and safety.
An independent data monitoring committee had previously found statistically significant and clinically meaningful improvement, and called for the trial to continue without changes to the second co-primary end point of OS.
Patients in the chemotherapy group who progressed were allowed to cross over into the pembrolizumab group.
At 12 months, PFS was 55.3% with pembrolizumab vs 37.3% with chemotherapy; at 24 months, PFS was 48.3% with pembrolizumab and 18.6% with chemotherapy.
The ORR, a measure of how much patients’ tumors shrank, was also better for the patients treated with pembrolizumab: 43.8% compared with 33.1% for chemotherapy. The data also show:
Severe events, grade 3 or above, were less common among patients in the pembrolizumab group: 22%, compared with 66% in the chemotherapy group. The most common toxicities in the immunotherapy group were colitis and hepatitis, while chemotherapy-related toxicities were diarrhea, neutropenia, fatigue, nausea, stomatis, alopecia, and neurotoxicitiy.
Merck funded the study.
Andre T, Shiu KK, Kim TW, et al. First-line therapy of pembrolizumab versus standard of care (SOC) in microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase III, KEYNOTE-177 study. Presented at: The American Society of Clinical Oncology 2020 Annual Meeting; Alexandria, VA: May 28, 2020. Abstract LBA4.