Merck's Keytruda Doubled PFS In Some Colorectal Cancer Patients In ASCO Late-Breaker
Executive Summary
Pembrolizumab should be considered the new standard of care as first-line therapy in patients with microsatellite instability high (MSI-H) metastatic colorectal cancer, KEYNOTE-177 investigator André said.
Merck & Co. Inc.'s Phase III KEYNOTE-177 trial studying its PD-1 therapy Keytruda (pembrolizumab) versus chemotherapy showed the cancer immunotherapy should be the new standard of care for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer, lead investigator Thierry André, Sorbonne Université, told a press briefing ahead of the opening of the American Society of Clinical Oncology (ASCO) virtual meeting.
KEYNOTE-177 – one of seven late-breaker abstracts featured by ASCO – is the first Phase III trial to study Keytruda as a monotherapy versus standard of care (chemotherapy plus bevacizumab or cetixumab) as first-line therapy in MSI-H metastatic colorectal cancer. (Also see "Late-Breakers To Look Out For At ASCO 2020" - Scrip, 14 May, 2020.)
Merck already announced in April that the blockbuster drug significantly improved PFS over chemotherapy in the KEYNOTE-177 trial in MSI-H or dMMR unresectable or metastatic colorectal cancer, but presented the details for the first time at ASCO. Keytruda is currently approved for use in MSI-H/dMMR patients regardless of tumor origin, but only after those patients have failed other options, so the positive results of the trial will likely pave the way for earlier use in the colorectal cancer setting.
"Pembrolizumab should be the new standard of care for these patients," André said. "After stopping pembro, some patients were cured of metastatic disease. These data present another step forward for biomarker-driven studies." Impaired DNA mismatch repair and the resulting high microsatellite instability are thought to sensitize a tumor to treatment with immuno-oncology in a cancer type that may not normally be susceptible to IO, spurring research into patients with these markers regardless of tumor type.
“It is practice changing, I agree with that. It sets a new standard for that subpopulation,” MD Anderson Cancer Center's Michael Overman, who will be the discussant for the presentation at ASCO, told Scrip.
A Plea For More Biomarker-Led Research
While Overman commended that KEYNOTE-177 was a biomarker-driven study, he does argue that there should be more tumor-agnostic studies, like the indication Keytruda already has for second-line treatment. In 2017, Keytruda became the first cancer therapy approved by the US Food and Drug Administration for use based on a biomarker regardless of tumor type. At the time, the approval was hailed as a milestone in cancer treatment because it was based on a common biomarker rather than the location in the body where the tumor originated. (Also see "Biomarker-Led Claim Is Small Step For Merck's Keytruda, Giant Leap For Cancer Indications" - Pink Sheet, 23 May, 2017.)
More tumor-agnostic studies would mean “it’s not just the common cancers that get immuno-oncology earlier – it should be the same for rare cancers,” he said.
Still, KEYNOTE-177 "is really the first solid biomarker-driven success [for immuno-oncology] to some degree," Overman added. PD-L1 and tumor mutation burden (TMB) are not unequivocally successful, and "don't really cleanly define [patient selection] in a black and white scenario. MSI-H and dMMR does. We've been able to take a biomarker and move that group from a standard of chemo to a standard of immunotherapy, which itself is a pretty extreme change," the clinician said.
MSI is a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different from the number of repeats that was in the DNA when it was inherited, as defined by the National Cancer Institute. The cause of microsatellite instability may be a defect in the ability to repair mistakes made when DNA is copied in the cell. The defect is also referred to as dMMR.
Approximately 10%-15% of colorectal cancer patients have tumors that score as either MSI-H or dMMR when testing is performed, according to Merck. Treatment guidelines for CRC already call for testing for MSI or dMMR, which can be done in local labs. KEYNOTE-177 used local lab testing, which Overman commented made it a real-world study of testing.
Dramatic Improvement In PFS
The detailed KEYNOTE-177 results showed that treatment with pembrolizumab doubled progression-free survival versus standard of care (16.5 months versus 8.2 months). In the study, 48.3% of patients treated with Keytruda maintained PFS at 24 months versus 18.6% of patients treated with chemotherapy alone.
Keytruda had a higher overall response rate versus chemotherapy, at 43.8% versus 33.1%, and the responses were more durable. The median duration of response was not reached in the Keytruda arm but was 10.6 months in the chemotherapy arm. Overall survival, the dual primary endpoint, is continuing to be evaluated.
However, Overman noted that the progressive disease rates are cautionary. Chemotherapy was better until six months, "so you do have some patients that are non-responsive and progress out of the gate – there's a subset that doesn’t respond and we need to identify that." This suggests that in a patient where initial response is important - a very symptomatic patient with a high disease burden that may not be alive in a few months, "maybe do chemo first and then [immunotherapy]" either with Keytruda or Bristol-Myers Squibb Co.'s Opidvo/Yervoy, which has approval for second-line treatment in MSI-H/dMMR colorectal cancer.
Keytruda also demonstrated an improved safety profile versus chemotherapy in the KEYNOTE-177 trial, with a lower incidence of grade ≥3 treatment-related adverse events (22% versus 66%).
The safety profile is remarkable, Overman said. "We get better therapy with massively lower toxicity. That’s just amazing. The toxicity profile is just dramatically lower," especially compared to the option for second-line treatment of MSI-H or dMMR metastatic CRC. Bristol's Opidvo (nivolumab) is approved, alone or in combination with its CTLA-4 inhibitor Yervoy (ipilimumab) for MSI-H or dMMR metastatic colorectal cancer patients who have progressed following treatment with chemotherapy. In an open-label trial in that second-line setting, Opdivo had an ORR of 32% and 49% in combination with ipilimumab, according to labeling.
Overman noted that Bristol is testing Opdivo/Yervoy in first-line CRC with updated results on a 45-patient, single-arm cohort from Checkmate-142. "The data looks great, but I really have to say given this was a randomized trial, pembro is really the standard here," Overman said. "Ipilimumab/nivolumab is impressive and should be considered, but the challenge there is that the toxicity is higher."
Merck also is presenting updated results from KEYNOTE-355 at ASCO, a study in first-line triple-negative breast cancer. (Also see "ASCO: Keytruda Inches Uncertainly Towards Tecentriq In Triple-Negative Breast Cancer" - Scrip, 19 May, 2020.)
Additional reporting by Mary Jo Laffler ([email protected])