COMMENTARY

Pembro 'New Treatment of Choice' for MSI-H/dMMR Metastatic Colorectal Cancer

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci

Disclosures

June 15, 2020

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford in England, reporting on the American Society of Clinical Oncology (ASCO) annual meeting from my kitchen table. I don't know about you, but my bottom has got blisters by now; I spend so much time sitting here. With Zoom calls from Asia early in the morning, my European work through the day, and then a catch-up with my friends in the United States in the evening, my bottom is anchored to the kitchen table. Such is life in the time of COVID-19.

What happened at ASCO? Plenty of fantastic, important presentations by great international groups, friends of mine, who reported the KEYNOTE-177 study. This was a phase 3 randomized, open-label study comparing pembrolizumab vs standard-of-care chemotherapy plus or minus either bevacizumab or cetuximab as first-line treatment of metastatic and advanced colorectal cancer.

The chemotherapy choice was made in advance by the local investigators and driven by the patient's RAS status, among other things. They recruited 307 patients who were randomly assigned 1:1 across both arms; only patients who had microsatellite instability–high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer were included. We know from the fantastic work of researchers at Johns Hopkins that this group of patients tends to be responsive to immune checkpoint inhibitors because of the massive antigen presentation in these mismatch repair–deficient tumors, which excites an immune response.

The results of the trial are impressive and in favor of pembrolizumab, with significant prolongation of progression-free survival (PFS): 16.5 months in the pembro arm vs 8.2 months in the chemo arm. Response rates favored pembro as well: 43.8% vs 33.1%. There was also a big difference in the pattern of side effects; grade 3-5 treatment-related adverse events occurred in 22% of patients in the pembro arm vs 66% in the chemo arm.

This distinguished group of investigators believe, as do I, that pembro provided a clinically meaningful, statistically significant improvement in PFS. The drug was well tolerated, with a more favorable pattern of toxicity in those receiving pembro compared with conventional cytotoxic chemotherapy. I believe that this is the new treatment of choice, based on this practice-changing clinical research in favor of pembrolizumab.

We know that MSI-H/dMMR tumors occur in only 4% or 5% of all patients in the advanced setting. Nevertheless, for that small but important subgroup, we now have a well-tolerated new treatment. This is an exciting piece of work moving very quickly following that initial observation a couple of years ago.

There we have it: the first practice-changing piece of evidence coming from this year's ASCO for us colorectal cancerologists. I'd be very interested to know if you agree and believe that the weight of evidence presented about PFS is solid. (There was crossover from the chemo arm, and therefore we do not have meaningful overall survival results.) In your opinion, is this practice-changing? Will you move forward to offer immune checkpoint inhibitors—pembrolizumab—to this subgroup of patients? I'd be interested to know.

As always, thanks for listening. In the meantime, Medscapers, over and out.

David J. Kerr, MD, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer, and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth.

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