Pembrolizumab May Change Standard of Care for Patients With Certain Type of Colorectal Cancer

Researchers have found that front-line therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda, Merck) doubled progression-free survival (PFS) vs chemotherapy in patients with an advanced colorectal cancer that has a high number of mutations. This is the first time pembrolizumab as a front-line therapy has been shown to benefit patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal carcinoma (mCRC), according to previous research.

The results of the new study were presented during the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

An interim analysis of the phase 3 KEYNOTE-177 trial found PFS with first-line pembrolizumab was 16.5 months compared with 8.2 months with chemotherapy with or without targeted therapy. According to investigators, the study results establish pembrolizumab as the new standard of care for patients with MSI-H/dMMR mCRC.

“These long-awaited trial results will change clinical practice,” said lead author Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, in a prepared statement. “Pembrolizumab works in nonrandomized studies in this group of patients with advanced disease. This randomized study demonstrates a huge benefit in first line with pembrolizumab and should be the new standard of care.”

Approximately 5% of patients with metastatic colorectal cancer have high microsatellite instability, which is the presence of high levels of mutations, according to the study. In MSI-H/dMMR, DNA repair is impaired, resulting in an increased number of mutations. For some patients, previous research suggests that the presence of MSI-H/dMMR tumors is associated with decreased survival, and patients with MSI-H/dMMR metastatic disease are less responsive to conventional chemotherapy.

Pembrolizumab blocks the activity of the programmed death-ligand 1 receptor, a protein that helps keep the immune system in check, thereby allowing the immune system to attack cancer cells. Previous research has shown good response to pembrolizumab and longer survival for MSI-H metastatic colorectal cancer, refractory to chemotherapy.

In a prepared statement, ASCO President Howard A. Burris III, MD, FACP, FASCO, also said the data presented have the potential to change the current standard of care for patients with MSI-H/dMMR mCRC.

“Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease. Now, in studies like this one, we are starting to see significant efficacy for immunotherapies as first-line treatment for advanced cancers with specific genetic signatures, in this case mCRC with microsatellite instability high/mismatch repair deficient mutations,” Burris said.

The study included 307 patients with MSI-H/dMMR mCRC. Patients were randomly assigned to receive first-line pembrolizumab for up to 2 years or the investigator’s choice of 6 different standard chemotherapy regimens, selected prior to randomization. The investigators could choose from mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin); mFOLFOX6+bevacizumab; mFOLFOX6+cetuximab; FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan); FOLFIRI+bevacizumab; or FOLFIRI+cetuximab.

Patients were allowed to cross over at progression from the chemotherapy group to the pembrolizumab group.

PFS and overall survival were the primary end points for the study. Key secondary end points included overall response rate and safety.

Study results at 12- and 24-months follow up showed PFS was 55.3% and 48.3% with pembrolizumab vs 37.3% and 18.6% with chemotherapy, respectively. The proportion of patients with a reduction in tumor size (objective responsive rate) was better with pembrolizumab as well—43.8% compared with 33.1% for chemotherapy.

Eleven percent of patients receiving pembrolizumab had complete response (no detectable cancer); 32.7% had a reduction in tumor size (partial response); and 30.9% had stable disease. In comparison, 3.9%, 29.2%, and 42.2% of patients receiving chemotherapy had complete response, partial response, and stable disease, respectively. Response with pembrolizumab was also longer lasting, with 83% of patients having a response longer than 2 years, compared with 35% of patients receiving chemotherapy.

Severe treatment-related adverse events (AEs) of grade 3 or greater were also less common with pembrolizumab than chemotherapy (22% vs. 66%). According to the researchers, the profile of toxicities is very different between both groups with immune-mediated AEs with pembrolizumab (colitis and hepatitis) and classical most frequent chemotherapy toxicities for the chemotherapy arm with diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia, and neurotoxicity.

Funded by Merck, the study will continue to evaluate overall survival.

REFERENCE

Pembrolizumab Doubles Time to Disease Progression in Patients With Advanced Colorectal Cancer With Specific DNA Mutations [news release]. Alexandria, VA; May 28, 2020: ASCO website. https://www.asco.org/about-asco/press-center/news-releases/pembrolizumab-doubles-time-disease-progression-patients Accessed June 2, 2020.