General Information

Keytruda (pembrolizumab) is a programmed death receptor-1 (PD-1)-blocking antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.

Keytruda is specifically indicated for use in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Keytruda is supplied as a solution for intravenous administration. The recommended dose of Keytruda for patients with PD-L1 expressing TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks as a 30 minute infusion. Administer Keytruda prior to chemotherapy when given on the same day. The recommended duration of dosing is until disease progression, unacceptable toxicity, or up to 24 months.

Clinical Trials

This indication was approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The accelerated approval was based on data from KEYNOTE-355, a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomized (2:1) to receive either Keytruda (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with the following chemotherapy; all medications were administered via intravenous infusion:

Pac (90 mg/m2 on Days 1, 8 and 15 every 28 days); or

Nab-paclitaxel (100 mg/m2 on Days 1, 8 and 15 every 28 days); or

Gem/carbo (1,000 mg/m2 and AUC 2 mg/mL/min, respectively, on Days 1 and 8 every 21 days).

Randomization was stratified by chemotherapy treatment (pac or nab-paclitaxel vs. gem and carbo), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Assessment of tumor status was performed at Weeks 8, 16 and 24, then every nine weeks for the first year and every 12 weeks thereafter. The main efficacy outcome measure was PFS.

In KEYNOTE-355, efficacy results were in patients who were PD‑L1 positive with a CPS ≥10 (n=323) and randomized to receive Keytruda in combination with pac, nab-paclitaxel or gem/carbo compared with the same chemotherapy regimens alone. Keytruda in combination with pac, nab-paclitaxel or gem/carbo (n=220) reduced the risk of disease progression or death by 35%, with a median PFS of 9.7 months versus 5.6 months with the same chemotherapy regimens alone (n=103). For PFS, 62% (n=136) of patients experienced an event with Keytruda in combination with pac, nab-paclitaxel or gem/carbo versus 77% (n=79) with the same chemotherapy regimens alone. For patients who received Keytruda in combination with pac, nab-paclitaxel or gem/carbo, the ORR was 53%, with a complete response rate of 17% and a partial response rate of 36%. For patients treated with the same chemotherapy regimens alone, the ORR was 40%, with a complete response rate of 13% and a partial response rate of 27%. Median DOR was 19.3 months with Keytruda in combination with pac, nab-paclitaxel or gem/carbo versus 7.3 months with the same chemotherapy regimens alone.

Side Effects

Adverse effects associated with the use of Keytruda in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 may include, but are not limited to, the following:

fatigue/asthenia

nausea

constipation

diarrhea

decreased appetite

rash

vomiting

cough

dyspnea

pyrexia

alopecia

peripheral neuropathy

mucosal inflammation

stomatitis

headache

Mechanism of Action

Keytruda (pembrolizumab) is a programmed death receptor-1 (PD 1)-blocking 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. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.