Phase III KEYNOTE-177 Study of Pembrolizumab Doubles PFS in MSI-H/dMMR mCRC

The phase III KEYNOTE-177 study demonstrated that front-line therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda) doubled progression-free survival (PFS) versus standard of care chemotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).¹

The randomized, open-label, phase III trial, presented during a 2020 ASCO Virtual Scientific Program press briefing, is the first in which pembrolizumab has been shown to benefit these patients when used as a front-line therapy. 

“These long-awaited trial results will change clinical practice,” lead author Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said in an ASCO-issued press release.² “Pembrolizumab works in non-randomized 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.”

Overall, patients with MSI-H CRC represent 5% of all patients with mCRC. The presence of MSI-H or dMMR tumors is generally associated with decreased survival rates, and patients with MSI-H or dMMR metastatic disease also tend to be less responsive to conventional chemotherapy. 

In phase II studies, pembrolizumab demonstrated durable antitumor activity with an acceptable safety profile in previously treated MSI-H mCRC. Pembrolizumab works by blocking the activity of PD-1 receptors, allowing the immune system to attack cancer cells. 

As of February 19, 2020, the time of data cutoff for this interim analysis, the phase III KEYNOTE-177 study included 307 patients with MSI-H or dMMR mCRC. Patients were randomly assigned to receive either 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 had their choice of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin), mFOLFOX6 + bevacizumab (Avastin),  mFOLFOX6 + cetuximab (Erbitux), FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan), FOLFIRI + bevacizumab, or FOLFIRI + cetuximab. 

PFS and overall survival (OS) were the primary endpoints for the trial. Key secondary endpoints included overall response rate (ORR) and safety.

At 12- and 24-months follow up, PFS was 55.3% and 48.3%, respectively, with pembrolizumab versus 37.3% and 18.6% with chemotherapy. The ORR was also better with pembrolizumab as well, with 43.8% seeing a reduction in tumor size compared with 33.1% for chemotherapy. 

Moreover, 11% of patients receiving pembrolizumab had a complete response, 32.7% had a partial response, and 30.9% had stable disease. In comparison, 3.9%, 29.2% and 42.2% of patients, respectively, receiving chemotherapy had complete response, partial response, and stable disease. 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. 

“Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease,” ASCO President Howard A. Burris III, MD, FACP, FASCO, said in the release. “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 metastatic colorectal carcinoma with microsatellite instability high/mismatch repair deficient mutations. The data presented have the potential to change the standard of care.”

Severe treatment-related adverse events (AEs; grade 3 or greater) were also less common with pembrolizumab than chemotherapy (22% vs 66%). However, the profile of toxicities was very different between both groups, with immune-mediated AEs observed with pembrolizumab (colitis and hepatitis) and the most frequent toxicities observed with standard of care chemotherapy being diarrhea, neutropenia, fatigue, nausea and vomiting, stomatis, alopecia, and neurotoxicity. 

Patients were allowed to cross over at progression from the chemotherapy group to the pembrolizumab group. The study will continue to evaluate OS. 

“In the past, no medical treatment has shown such a difference in terms of improved PFS in metastatic colorectal cancer,” André said in a pre-recorded presentation of the data. “These data represent another step forward for biomarker driven studies and will help bring this approach to target MSI-high tumor into the adjuvant and neoadjuvant setting.”

Moving forward, André indicated in the presscast that it likely won’t be long before pembrolizumab is approved in the US for use in this space. Currently, pembrolizumab is approved by the FDA for adults and pediatric patients with previously treated MSI-H metastatic tumors regardless of tumor type or site. 

References:

• Andre T, Shiu K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. Presented at: 2020 ASCO Virtual Scientific Program; May 26, 2020. Abstract LBA4.

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