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

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.

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

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.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.

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

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.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.

What does that mean for the future of precision medicine?

What is the prevalence of MSI-H in some of the other tumor types?

Should providers test for MSI-H at diagnosis?

What’s the takeaway for community physicians?

This is incredibly exciting and is a historic approval by the FDA. In my opinion, it will knock down the walls of how we think about cancer in the future.I think, historically, we've had some precision medicine. I think imatinib (Gleevec) was incredibly effective and was the poster child. Before that, we had retinoic acid receptor inhibitors, which was another poster child. But until then, targeted therapies had been hit or miss. I think this is a new generation of how we think about precision medicine and targeted therapy.It’s hard to pinpoint but if we look across all metastatic tumors, we think it’s about 4%. In the United States, that's around 30,000 patients. If we look worldwide, it’s probably closer to 500,000 patients. If we move into the earlier stage, the numbers go up.That remains to be seen, but I think right now, anyone with metastatic disease who has progression on standard-of-care therapy, should have their MSI-H status checked because it can have a profound impact. In that initial study, we pulled 2 or 3 patients out of hospice. They are still alive today with no evidence of tumor.I think with this approval, we’re seeing a change in how we think about cancer. It’s going to take some time to reach everyone and to be accepted. The challenge is to get everyone tested and I think that is the first step. Once you find a patient with MSI-H, it's easy to treat them and the tumor goes away.

Diaz LA, Le DT, Yoshino T, et al. Phase 3, open-label, randomized study of first-line pembrolizumab (pembro) vs investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC): KEYNOTE-177. J Clin Oncol 35 2017 (suppl; abstr TPS3618).