FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma

Abstract

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4–32.4) versus 8.2 months (95% CI: 6.1–10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45–0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0–30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.

Cost-Effectiveness of First-Line Versus Second-Line Pembrolizumab or Chemotherapy in Patients With Microsatellite-Instability-High/Mismatch Repair-Deficient Advanced Colorectal Cancer

“…Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United State ( Siegel et al, 2020 ). Microsatellite-instability-high (MSI-H)/mismatch repair-deficient (dMMR) represents a subtype that occurs in about 4% of patients with advanced disease ( Casak et al, 2021 ). MSI-H/dMMR tumors are less responsive to chemotherapy, however, chemotherapy remains the standard of care for patients with MSI-H/dMMR advanced colorectal cancer ( Innocenti et al, 2019 ).…”

“…More recently, the landmark KEYNOTE-177 phase 3 trial, investigating pembrolizumab as the first-line therapy for MSI-H/dMMR advanced colorectal cancer, has shown improved outcomes, with a median progression-free survival more than twice as long in patients receiving pembrolizumab compared with chemotherapy (16.5 vs. 8.2 months, respectively) ( André et al, 2020 ). Based on these results, pembrolizumab was approved by the FDA and is a guideline-recommended, first-line treatment option for MSI-H/dMMR advanced colorectal cancer patients and represents the new standard-of-care ( Casak et al, 2021 ; National Comprehensive Cancer Network, 2021 ).…”

The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer

“…In the immunotherapy of CRC, National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines have recommended pembrolizumab as the first-line treatment for dMMR/MSI-H mCRC patients ( 23 ). dMMR/MSI-H is an important predictor biomarker of PD1 inhibitor efficacy, so we analyzed the correlation between HOXC6 expression and dMMR/MSI-H status.…”

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

“…Ipilimumab was the first FDA-approved recombinant humanized anti-CTLA-4 immunoglobulin G1 monoclonal antibody in 2011 for the treatment of advanced melanoma in patients who cannot be surgically cured or have metastasis ( Vaddepally et al, 2020 ). It can also work well with intermediate or poor-risk advanced renal cell carcinoma (RCC), MSI-H/dMMR CRC, metastatic NSCLC, unresectable malignant pleural mesothelioma, and HCC, which have been previously treated with sorafenib, in combination with nivolumab ( Pinto et al, 2019 ; McKay et al, 2020 ; Baas et al, 2021 ; Casak et al, 2021 ; Saung et al, 2021 ). In 2014, nivolumab and pembrolizumab (PD-1 blockade) were approved by the FDA as a humanized IgG antibody for the treatment of unresectable or metastatic melanoma ( Prasad and Kaestner, 2017 ; Finkelmeier et al, 2018 ).…”