Findings from the KEYNOTE-177 study indicate that pembrolizumab is superior to the current standard of care, significantly improving progression-free survival when deployed up front to treat patients with metastatic DNA mismatch repair/microsatellite instability–high colorectal cancer.

Findings from the KEYNOTE-177 study indicate that pembrolizumab (Keytruda; Merck) is superior to the current standard of care when deployed up front against a form of metastatic colorectal cancer. Compared with chemotherapy, the PD-1 inhibitor doubled time to disease progression, according to an interim data analysis presented on May 31 at the American Society of Clinical Oncology (ASCO) Annual Meeting.

All patients in this phase III trial had tumors deficient in DNA mismatch repair (dMMR), a genotype that can be hereditary or sporadic, resulting in the phenotype of high microsatellite instability (MSI-H). These tumors accumulate multiple mutations and are highly sensitive to immune checkpoint inhibition. Both pembrolizumab and nivolumab (Opdivo; Bristol-Myers Squibb), another PD-1 inhibitor, are already approved second-line treatment options for dMMR/MSI-H colorectal cancer.

With KEYNOTE-177, however, “this is the first time [a PD-1 inhibitor] has shown benefit as monotherapy in the first-line setting for this patient population,” said trial investigator Elena Élez, MD, PhD, of Vall d'Hebron Institute of Oncology in Barcelona, Spain.

During the ASCO meeting, lead investigator Thierry André, MD, of Sorbonne Université in Paris, France, reported results for 307 patients who were randomly assigned to receive pembrolizumab or their physician's choice of standard therapy: mFOLFOX6 or FOLFIRI, with the targeted drugs bevacizumab (Avastin; Genentech) or cetuximab (Erbitux; Eli Lilly) included where appropriate.

Among patients given pembrolizumab, the objective response rate was 43.8% and the median duration of response not reached, versus 33.1% and 10.6 months in the control group. The median progression-free survival (PFS) was 16.5 months and 8.2 months, respectively. No new side effects were observed with first-line pembrolizumab, André added, and there was a lower incidence (22% versus 66%) of grade 3 or higher treatment-related toxicities compared with chemotherapy.

This much-improved safety profile is due to pembrolizumab's “monotherapy use, as opposed to adding a chemo backbone, like with many other studies of immune agents,” observed Michael Overman, MD, of The University of Texas MD Anderson Cancer Center in Houston. “It's fantastic to have a new option for these patients that's also massively less toxic.” To him, KEYNOTE-177 is “definitely practice-changing,” and pembrolizumab as the new standard of care for advanced dMMR/MSI-H colorectal cancer “is a logical transition that will happen fairly quickly, at least in the United States.”

That said, there is “a potential wrinkle in the clinical data,” Overman noted—the PFS curves suggest that “for the first 6 months, chemotherapy may be better than pembrolizumab.” Which raises the question: “What's the best option if I have patients who are symptomatic, perhaps with painful metastases, and I need to see response to treatment within 2 months or they're going to hospice? One could make a good argument that chemotherapy may be better at achieving this goal.”

Other matters of debate, Overman added, include whether dual testing for both dMMR and MSI-H—using IHC and PCR, respectively—is necessary, and, because local laboratory-developed tests are used to prospectively evaluate tumor status, whether centralized confirmation of the results is required. The latter is not always built into trial protocols, including KEYNOTE-177.

“Here, local testing results were used to enroll patients without first being centrally confirmed, and a very positive signal was still seen,” Overman said. “That's as real-world a study as it gets, which, to me, justifies the approach as a valid one.” –Alissa Poh