Regulatory Decision Summary for Keytruda

Authorization was based on the results of a Phase 3, randomized, open label, multicenter, controlled trial (Keynote-581) designed to assess the efficacy and safety of lenvatinib in combination with pembrolizumab with sunitinib monotherapy in patients with previously untreated advanced (not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma (RCC). The study randomized 1,069 patients, in which 355 were treated with pembrolizumab (200 mg intravenously every 3 weeks) in combination with lenvatinib (20 mg orally once daily) and 357 were treated with sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off, every cycle.

The study met its primary efficacy endpoint of progression-free survival (PFS). The median PFS was 23.9 months for patients treated with pembrolizumab plus lenvatinib versus 9.2 months in patients treated with sunitinib. The estimated hazard ratio (HR) was 0.39, representing a 61% reduction in the risk of disease progression or death with pembrolizumab plus lenvatinib compared with sunitinib. Results of the secondary endpoint of overall survival were supportive of the benefit of the pembrolizumab and lenvatinib combination.

The most commonly reported adverse events in at least 20% of patients with advanced or metastatic RCC in Keynote-581 who were treated with pembrolizumab in combination lenvatinib were fatigue, diarrhea, stomatitis, nausea, abdominal pain, vomiting, constipation, musculoskeletal pain, hypothyroidism, hypertension, hemorrhagic events, decreased appetite, rash, palmar-plantar erythrodysesthesia syndrome, dysphonia, proteinuria, acute kidney injury, hepatotoxicity, weight decreased and headache. These adverse events were more frequently reported in patients taking the combination therapy when compared to patients treated with sunitinib alone, however, the majority were mild to moderate in severity. No new safety signal was identified. In addition, the safety findings from the Keynote-581 study are consistent with known safety profile observed for this combination therapy for the management of other approved indications. The risks associated with the use of pembrolizumab in combination with lenvatinib for the treatment of adult patients with advanced or metastatic RCC, and risk mitigation strategies have been adequately labelled in the Product Monograph. In addition, each monograph refers to the other for situations in which the drugs are used in combination so that readers are aware of the unique adverse reactions associated with each product. Please refer to the Keytruda Product Monograph for more details.

The recommended dose of pembrolizumab is either 200 mg every 3 weeks or 400 mg every 6 weeks, administered intravenously (up to 2 years), in combination with lenvatinib 20 mg given orally once daily. See the respective Product Monographs for pembrolizumab and lenvatinib for further details.

Overall, the benefit/risk profile of the pembrolizumab and lenvatinib combination therapy is considered positive for adult patients with advanced (not amenable to curative surgery or radiation) or metastatic RCC with no prior systemic therapy for metastatic RCC.