Regulatory Decision Summary for Keytruda

Patients diagnosed with EC have a generally good prognosis due to the fact that most will present with early stage disease. However, there are few available options for patients with advanced, recurrent or metastatic disease that has progressed after prior standard of care systemic treatment. Recently, pembrolizumab monotherapy was authorized for patients with EC who have MSI-H or dMMR disease; however, patients with EC that is not MSI-H or dMMR do not respond well to pembrolizumab monotherapy. Therefore, for patients who are not MSI-H or dMMR, treatment options are limited.

The evidence provided in this submission, to support a combination regimen of pembrolizumab and lenvatinib, was primarily based on a single-arm study that addressed the EC population with disease that is not MSI-H or dMMR and who have had disease progression after prior platinum-based systemic treatment. The trial demonstrated a promising overall response rate and durability of response.

The risks of pembrolizumab and lenvatinib have been established in other disease settings in which they are used as monotherapy. Pembrolizumab treatment can elicit a wide range of immune-related adverse reactions including, but not limited to: pneumonitis, hepatitis, colitis, nephritis and endocrine disorders such as hypothyroidism. These types of adverse reactions are managed through dose interruptions, discontinuations and the use of corticosteroids and/or hormone replacement therapy where appropriate. Lenvatinib treatment can elicit serious reactions and/or life threatening events including, but not limited to, hypertension, cardiac failure, gastrointestinal perforation and hemorrhages. Keytruda combined with lenvatinib increased the incidence of several types of adverse reactions more than would be expected based on the rates observed in response to either drug alone in similar EC populations. Considering the established safety profiles of both pembrolizumab and lenvatinib, there were no new safety signals observed.

The primary tools for risk mitigation are the product monographs for pembrolizumab and lenvatinib. The risks observed in the data submitted are adequately described in the Warning and Precautions and Adverse Reactions sections of the monographs. Each monograph provides detailed directions to prescribers on toxicity management, including recommendations for monitoring, dose interruption, dose reduction or discontinuation as well as directions for the treatment of immune related adverse reactions. As a result of this authorization, each monograph has been updated to refer to the other monograph for specific safety information, toxicity management, and dosage and administration recommendations.

Given the single-arm design of the pivotal clinical study, there remains residual uncertainty regarding the magnitude of the treatment benefit and the potential for this combination treatment to extend overall survival among the target population. As a condition of authorization, the sponsor will be required to file phase 3 trial data to confirm the efficacy of pembrolizumab combined with lenvatinib.

Based on the data submitted, the benefit is considered to outweigh the risk in the proposed indication. However, given the single-arm nature of Study 111/KN146, confirmation of efficacy in a well-controlled, randomized clinical study is necessary to confirm the benefit-risk balance for this combination therapy and is a condition of authorization.