Earlier this month, the United States Food and Drug Administration (FDA) has granted accelerated approval to pembrolizumab (Keytruda), in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer, whose tumours express PD-L1. Additionally, the FDA has also approved the PD-L1 IHC 22C3 pharmDx test as a companion diagnostic tool to select eligible patients for this treatment.
The approval is based on the recently published results of the KEYNOTE-355 trial, which reported a median progression-free survival (PFS) of 9.7 months and a reduction in the risk of death by 35% (HR[95%CI]: 0.65[0.49-0.86], p= 0.0012) in patients who were given pembrolizumab plus chemotherapy, compared to patients who were given chemotherapy alone, in which the median PFS was found to be 5.6 months.
This multicentre, double-blind, placebo-controlled phase III randomised trial evaluated the use of pembrolizumab in combination with chemotherapy agents in patients with locally recurrent unresectable or metastatic TNBC, who were chemotherapy-naïve. Randomised 2:1, patients received pembrolizumab 200mg on day 1 every 3 weeks, or placebo, in combination with different chemotherapy agents (protein-bound paclitaxel, paclitaxel, gemcitabine plus carboplatin) via intravenous infusion. The primary end point was progression-free survival (PFS0, assessed via blinded independent review according to RECIST 1.1 criteria in the subgroup of patients with a CPS of 10 or higher.
Fatal events occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse events (AEs) occurred in 30% of patients receiving the pembrolizumab combination, of which the most common AEs were pneumonia (2.9%), anaemia (2.2%) and thrombocytopenia (2%). Furthermore, pembrolizumab was discontinued in 11% of patients due to unacceptable toxicity. The most common any-grade adverse events, occurring in 20% of patients or more, included fatigue, nausea, diarrhoea, constipation, vomiting, rash, cough, alopecia, headache and decreased appetite. With an incidence of 20% or over, the most common laboratory findings in patients who received pembrolizumab plus chemotherapy included anaemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia, hyperglycaemia, hypoalbuminemia, increased ALP, ALT and AST, hyponatraemia, hypocalcaemia, hypokalaemia and hypophosphataemia.
The FDA approval includes recommended prescribing guidelines of pembrolizumab 200mg every 3 weeks, or 400mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity or up to 24 months, in patients with locally recurrent and unresectable or metastatic TNBC. When given with pembrolizumab, chemotherapy guidelines includes the administration of protein-bound paclitaxel 100mg/m2 on days 1, 8 and 15 every 28 days, or paclitaxel 90mg/m2 on days 1, 8 and 15 every 28 days, or gemcitabine 1000mg/m2 plus carboplatin AUC 2mg/mL/min on days 1 and 8 every 21 days, to be administered via intravenous infusion.
Although pembrolizumab is not currently licensed by the European Medicines Agency (EMA) for the use in triple-negative breast cancer, it is hoped that the results of this study will be considered by the EMA in the near future.
References
Press release from Merck: https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-in-combination-with-chemotherapy-for-patients-with-locally-recurrent-unresectable-or-metastatic-triple%e2%80%91negative-breast-cancer-whose/
Press release from the FDA: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple?utm_medium=email&utm_source=govdelivery
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