Frontline pembrolizumab significantly improved progression-free survival versus chemotherapy in patients with microsatellite instability–high or mismatch repair deficient unresectable or metastatic colorectal cancer.
Roy Baynes, MD, PhD
Pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) versus chemotherapy as a first-line treatment for patients with microsatellite instability—high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer (CRC), meeting 1 of the dual primary endpoints of the phase III KEYNOTE-177 trial.
Based on the recommendation of an independent Data Monitoring Committee, the study is continuing to evaluate the other primary endpoint of overall survival (OS). There were no new safety signals compared with previous pembrolizumab studies, according to Merck (MSD), the developer of pembrolizumab.
“These data in the first-line treatment setting provide further evidence of the benefits of Keytruda monotherapy in patients whose tumors are MSI-H or dMMR. We look forward to sharing these data as quickly as possible with the medical community and regulatory authorities,” added Baynes.
The open-label phase III KEYNOTE-177 trial (NCT02563002) included 308 patients with MSI-H or dMMR advanced colorectal cancer. Patients were randomized to single-agent pembrolizumab or chemotherapy. Beyond the dual primary endpoints of OS and PFS, overall response rate (ORR) was the key secondary endpoint.
Pembrolizumab was administered at a fixed dose of 200 mg every 3 weeks for up to 35 treatment cycles (about 2 years). In the control arm, investigator’s choice of treatment comprised 1 of these regimens: mFOLFOX6; mFOLFOX6 plus bevacizumab (5 mg/kg IV on day 1 of each 2-week cycle); mFOLFOX6 plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle); FOLFIRI; FOLFIRI plus bevacizumab (5 mg/kg IV on day 1 of each 2-week cycle); or FOLFIRI plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each 2-week cycle).
In May 2017, the FDA granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.
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 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.
The pivotal data for the approval included patients from the KEYNOTE-016 (n = 58), KEYNOTE-164 (n = 61), KEYNOTE-012 (n = 6), KEYNOTE-028 (n = 5), and KEYNOTE-158 (n = 19) trials. Pembrolizumab was administered at 200 mg every 3 weeks or 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.
The median age among the 149 patients was 55 years, with 36% of patients aged 65 or older. Across the population, 77% of patients were white, 56% were male, 36% had an ECOG performance status (PS) of 0, and 64% had an ECOG PS of 1.
Two percent of patients had locally advanced, unresectable disease, and 98% of patients had metastatic disease. Among patients with metastatic or unresectable disease, the median number of prior therapies was 2. In patients with metastatic CRC, 84% had received at least 2 prior lines of therapy, compared with 53% in patients with other solid tumors.
Beyond CRC, other tumor types in which patients had responses included endometrial cancer (n = 5), biliary cancer (n = 3), gastric or GE junction cancer (n = 5), pancreatic cancer (n = 5), small intestinal cancer (n = 3), breast cancer (n = 2), prostate cancer (n = 1), esophageal cancer (n = 1), retroperitoneal adenocarcinoma (n = 1), and small cell lung cancer (n = 1).
Among the majority (n = 135) of the 149 patients, MSI-H or dMMR tumor status was determined prospectively with IHC tests for dMMR or laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status. MSI-H status for the remaining 14 patients was determined through a retrospective evaluation of 415 tumor samples using a central laboratory-developed PCR test.
IHC identified dMMR cancer in 47 patients, MSI-H was identified by PCR in 60 patients, and 42 patients were identified with both tests.
Common side effects of pembrolizumab, including fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Immune-mediated side effects associated with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
The accelerated approval for pembrolizumab in this setting is contingent on the results of a confirmatory trial. The approval was preceded by a breakthrough therapy designation the FDA granted to pembrolizumab in November 2015 as a treatment for patients with MSI-H metastatic CRC.
“These head-to-head data with Keytruda are the first time a single-agent, anticancer therapy, and particularly an anti—PD-1 monotherapy, achieved a statistically significant improvement in progression-free survival over chemotherapy, including the current standard of care regimen of mFOLFOX6 plus bevacizumab (Avastin), in patients with MSI-H colorectal cancer,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release.