“These long-awaited trial results will change clinical practice,” lead study author Dr. Thierry André, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said in an ASCO-issued press release.
Results of the phase 3 KEYNOTE-177 trial demonstrated that front-line therapy with the immune checkpoint inhibitor Keytruda (pembrolizumab) doubled progression-free survival vs. standard of care chemotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).
The randomized, open-label trial, which was presented during a 2020 ASCO Virtual Scientific Program press briefing, is the first in which Keytruda has been shown to benefit these patients when used as a front-line therapy.
“These long-awaited trial results will change clinical practice,” lead study author Dr. Thierry André, of the Sorbonne Université and Hôpital Saint Antoine in Paris, said in an ASCO-issued press release. “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 2 studies, Keytruda demonstrated durable antitumor activity with an acceptable safety profile in previously treated MSI-H mCRC. Keytruda 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 3 trial included 307 patients with MSI-H or dMMR mCRC. Patients were randomly assigned to receive either first line Keytruda for up to two years or, the investigator’s choice of six different standard of care chemotherapy regimens, selected prior to randomization. The investigators had their choice of:
- mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin)
- mFOLFOX6 plus Avastin (bevacizumab)
- mFOLFOX6 plus Erbitux (cetuximab)
- FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan)
- FOLFIRI plus Avastin, or
- FOLFIRI plus Erbitux.
Progression-free survival (PFS), or time from random assignment in a clinical trial to disease progression or death from any cause, and overall survival (OS) were the primary endpoints for the trial. Additional endpoints included overall response rate (ORR) and safety.
At 12- and 24-months follow up, PFS was 55.3% and 48.3%, respectively, with Keytruda vs. 37.3% and 18.6% with chemotherapy. The ORR was also better with Keytruda as well, with 43.8% of patients seeing a reduction in tumor size compared with 33.1% for chemotherapy.
Moreover, 11% of patients receiving Keytruda 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 study drug was also longer lasting, with 83% of patients having a response longer than two years, compared with 35% of patients receiving chemotherapy.
“Immunotherapies like pembrolizumab have proved to be effective as second-line treatments for advanced disease,” said ASCO President Dr. Howard A. Burris III 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 side effects were also less common with Keytruda than chemotherapy (22% vs 66%). However, the profile of toxicities was very different between both groups, with immune-mediated adverse events observed with Keytruda (colitis and hepatitis). The most frequent toxicities observed with standard of care chemotherapy were diarrhea, neutropenia, fatigue, nausea and vomiting, stomatitis, alopecia, and neurotoxicity.
Patients could cross over at progression from the chemotherapy group to the Keytruda 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.”
During the press briefing, André indicated that it likely will not be long before Keytruda is approved in the United States for use in this space.