Regulatory Decision Summary for Keytruda

The efficacy and safety of pembrolizumab (Keytruda) in combination with paclitaxel and cisplatin or paclitaxel and carboplatin (with or without bevacizumab) was investigated in Keynote 826 (KN826). KN-826 is a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent.

The primary efficacy outcome measures were overall survival (OS) and progression free survival (PFS) as assessed by investigator according to RECIST v1.1. Secondary efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), according to RECIST v1.1, as assessed by investigator. The median follow-up time was 17.2 months (range: 0.3 to 29.4 months). In terms of OS, there was a 36% risk reduction for death in the pembrolizumab group (PD-L1>1%) when compared with placebo. In terms of PFS, the risk of disease progression was reduced by 38% in the pembrolizumab group (PD-L1>1%) when compared with the placebo group.

There was no apparent risk reduction for death for patients treated with pembrolizumab whose tumor had low or now PD-L1 expressing (<1%). That is why a decision was made to limit the use of pembrolizumab for adult patients whose tumor express a certain level of PD-L1 (>1%). 

In terms of safety, the addition of an additional immunotherapy to chemotherapy +/- bevacizumab adds considerable toxicity; fatal adverse events occurred in 4.6% of patients receiving Keytruda in combination with chemotherapy with or without bevacizumab. The most common treatment-related adverse events (reported in at least 20% of patients) were nausea, anemia, fatigue, vomiting, diarrhea, neutropenia, neuropathy peripheral, peripheral sensory neuropathy and alopecia. Serious adverse events in at least 3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). Keytruda was discontinued for adverse events in 15% of patients.

Despite the added toxicity with Keytruda in combination of chemotherapy +/-bevacizumab, the overall benefit-risk assessment is favorable for patients whose cervical cancer express PD-L1 (CPS≥1), but it was unfavorable for patients whose tumors do not express PD-L1 (CPS<1). The recommended indication and associated efficacy and safety labelling was adjusted accordingly in Product Monograph).