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Expert Discusses Phase III Trial of Frontline Pembrolizumab in MSI-H Colorectal Cancer

Danielle Bucco
Published: Friday, Jun 30, 2017

Luis A. Diaz, MD

Luis A. Diaz, MD

Pembrolizumab (Keytruda) has demonstrated antitumor activity in heavily pretreated patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC). Now, in the phase III KEYNOTE-177 trial, investigators hope to show that frontline treatment with the PD-1 inhibitor can improve progression-free survival (PFS) compared with standard-of-care chemotherapy.

In May, the FDA granted an accelerated approval to pembrolizumab for the treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. The approval also covered adults and children with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options.

The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety patients had CRC and the remaining 59 patients had 1 of 14 other tumor types.

The objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.

In KEYNOTE-177, 270 patients will be randomly assigned to 200 mg of pembrolizumab every 3 weeks or investigator’s choice of 1 of 6 chemotherapy regimens chosen prior to randomization. Treatment is to continue until disease progression, unmanageable toxicity, or the completion of 35 cycles (pembrolizumab only).

“A crossover is allowed for patients who progressed on the standard chemotherapy arm who would prefer anti–PD-1 [treatment],” said lead researcher Luis A. Diaz, MD.

The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS), safety, and tolerability.

In an interview with OncLive conducted at the 2017 ASCO Annual Meeting, Diaz, head of the division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discussed KEYNOTE-177 and the implications of the FDA approval of pembrolizumab for patients with MSI-H or dMMR CRC or other solid tumors.

OncLive: What where you hoping to find when you began studying pembrolizumab?

Diaz: When we started the study, we didn't know if it would be limited to CRC or to other tumors. We thought it would be something that we would see across many different tumor types. What was remarkable was we discovered that not only did colon cancers respond excellently, but also endometrial cancers, gastric cancers, small intestine cancers, pancreatic cancers, brain tumors, prostate cancers, and more, as we kept adding patients who are mismatch deficient across any tumor type and we started seeing responses. The thinking has started to change—perhaps this is a genetic alteration that is a more powerful indicator than where the tumor comes from.

Our initial study, KEYNOTE-16, was a Johns Hopkins–initiated study that was presented 2 years ago at ASCO and published in the New England Journal of Medicine.

What was remarkable about that paper was that we only reported 12 patients with CRC, which achieved breakthrough status by the FDA. The following year, we became accumulated with more patients that were non-CRC and the approach was to begin to look at this across all tumors. We saw that the efficacy was potent across all the different tumor types and was substantiated by KEYNOTE-158, which is the topic of the abstract where it showed response across all tumor types.

Even in the original study that we started in 2012 and reported in 2015, we still have not reached the median OS. These patients are doing extraordinarily well. I think the approval is well warranted and the data is exciting.

As you said, the sample size in CRC was tiny. Why do you think the FDA was so impressed?

The main data here is showing that in CRC and non-CRC, we're seeing response rates with pembrolizumab that are quite impressive. The PFS and OS are quite durable, and it's recapitulated in entirely different studies. I believe that is what led to the FDA approval.

What's impressive about the FDA approval is that it is not only across all tumor types, but it is in adults and children. It’s the first time that we're no longer looking at tumors by the site of origin, but rather by the genetic lesion.

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