Impact of ASCO Results Hold: Pembrolizumab Granted Breakthrough in Advanced CRC

After melanoma and non-small cell lung cancer, the FDA has granted Breakthrough Therapy status to pembrolizumab in advanced colorectal cancer patients with mismatched repair deficiency.

When the results of the KEYNOTE-164 trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) earlier this year, they created quite a fuss. One of the lead authors on the paper, Dung T. Le, MD, assistant professor of oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, showed results that claimed efficacy of pembrolizumab (Keytruda) in colorectal cancer (CRC) patients deficient in mismatch repair (mismatch repair deficiency or MMRD), which leads to microsatellite instability. These results have led to the drug being granted it’s third Breakthrough Therapy designation, this time in advanced colorectal cancer patients with microsatellite instability high. Pembrolizumab already has Breakthrough designation in advanced melanoma and advanced non-small cell lung cancer.

The results presented at ASCO, subsequently published in the New England Journal of Medicine, were from the phase 2 study conducted to evaluate the clinical activity of the anti—PD-1 monoclonal antibody, pembrolizumab, in 41 patients—with and without MMRD—who had previously been treated for progressive metastatic disease. The patients were divided into 3 cohorts: cohort A, CRC patients deficient in mismatch repair; cohort B, CRC patients proficient in mismatch repair; and cohort C, non-CRC patient deficient in mismatch repair. The primary end points, said Dr Le, were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. A majority of the patients enrolled had 2 or more prior therapies.

At 20 weeks, the irORR for cohort A was 62% and the disease control rate (DCR) was 92%; for cohort B, the irORR was 0% and DCR was 16%; for cohort C, the irORR was 60% and DCR was 70%. Durable disease control was achieved in cohort A, with most responses lasting over a year. While progression-free survival (PFS) had not been reached in cohorts A and C, PFS was 2.3 months in cohort B. Adverse events observed were primarily of low grade.

Senior study author Luis A. Diaz, Jr, MD, associate professor of oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said in an interview with The American Journal of Managed Care that he expects pembrolizumab to be standard of care in colon cancer in the near future and that mismatched repair testing will be standard of care for these patients as well. “I suspect that up front, when you get diagnosed with advanced colon cancer, you’re going to get mismatched repair testing,” Dr Diaz said.

“We are committed to understanding the full potential of Keytruda to help patients with a broad range of difficult-to-treat cancers,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a press release. “The data investigating the use of Keytruda in patients with advanced colorectal cancer whose tumors have substantial evidence of mismatch DNA repair defects have been encouraging, and we appreciate the opportunity that this FDA Breakthrough Therapy Designation provides us to accelerate our effort to bring Keytruda to these patients.”

The company is planning a phase 3 study (KEYNOTE-177) in treatment-naïve CRC patients.