General Information

Keytruda (pembrolizumab) is a programmed death receptor-1 (PD 1)-blocking, humanized monoclonal antibody.

Keytruda is specifically indicated for 1) the first line treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS)≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status and 2) for the second line treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Keytruda is supplied as a solution for intravenous injection. The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Clinical Results

FDA Approval

The FDA approval of Keytruda was based on results from the KEYNOTE-052 Phase 2 trial and the KEYNOTE-045 Phase 3 trial.

KEYNOTE-052 included 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for Platinol-containing chemotherapy. All participants received Keytruda once every three weeks for up to 24 weeks, unless they presented signs of treatment-related toxicity. The treatment had an objective response rate (ORR) of 29%, including 7% complete responses and 22% partial responses. The duration of response ranged from 1.4 to 17.8 months. At the time of the analysis, less than half of patients who responded had seen their disease progress again, hence the median duration of response was unattainable.

KEYNOTE-045 was a multicenter, placebo-controlled study in 542 patients with locally advanced or metastatic urothelial carcinoma, whose disease progressed on or after platinum-based chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy. Patients were randomized to receive either Keytruda every three weeks or investigator’s choice chemotherapy. Chemotherapy regimens included Taxol (paclitaxel), Taxotere (docetaxel), or vinflunine. Overall, Keytruda treatment demonstrated a superior overall survival (OS) compared to the other treatment regimens, with a 27% reduction in the risk of death. Keytruda treatment resulted in a median OS of 10.3 months, compared to 7.4 months in the chemotherapy arm. No statistically significant difference in progression-free survival (PFS) was observed between groups, with those receiving Keytruda having a median PFS of 2.1 months, compared to 3.3 months in the chemotherapy arm. Keytruda was also seen to improve objective response rate compared to chemotherapy regimens. The ORR was 21% in the Keytruda-treated group vs. 11% in the chemotherapy group.

Mechanism of Action

Keytruda (pembrolizumab) is a programmed death receptor-1 (PD 1)-blocking, humanized monoclonal IgG4 kappa antibody. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.