On June 29, 2020, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda®) for first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.
Approval was based on a multicenter, international, open-label, active-controlled, randomized (1:1) trial (KEYNOTE‑177; NCT02563002) that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer. Investigators determined MSI or MMR tumor status locally using polymerase chain reaction or immunohistochemistry, respectively.
Patients were randomized to receive pembrolizumab 200 mg via IV every three weeks or investigator’s choice of mFOLFOX6/FOLFIRI with or without bevacizumab or cetuximab via IV every two weeks. Patients randomized to chemotherapy were offered pembrolizumab at the time of disease progression.
The main efficacy outcome measures were progression-free survival (PFS) and overall survival (OS). Median PFS was 16.5 months (95% CI = 5.4, 32.4) in the pembrolizumab arm and 8.2 months (95% CI = 6.1, 10.2) in the chemotherapy arm (HR = 0.60; 95% CI = 0.45, 0.80; two-sided p-value = 0.0004). At the time of PFS analysis, OS data were not mature.
The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
The recommended pembrolizumab dose for MSI-H/dMMR colorectal cancer is 200 mg every three weeks or 400 mg every six weeks.
FDA conducted the review under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this application, a modified Project Orbis was undertaken because of the timing of submission to other regulatory agencies. FDA is collaborating with Australia’s Therapeutic Goods Administration, Health Canada, and Swissmedic. The review is ongoing for these three agencies.
The review used the Real Time Oncology Review pilot program; Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment; and Summary Level Review, which relied on qualified data summaries to support approval of a supplemental application. FDA approved the application five months ahead of its goal date.
The application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.
For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.