Regulatory Decision Summary for Lenvima

There are few available treatment options for patients with advanced, recurrent, or metastatic Endometrial Carcinoma (EC) that has progressed after prior standard of care systemic therapies. Recently, pembrolizumab monotherapy was authorized for patients with EC who have microsatellite instability - High (MSI-H) or deficient mismatch repair (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 in order to support a combination regimen of lenvatinib and pembrolizumab was primarily based on a single-arm Study 111/KN146, which addressed the EC population who are not MSI-H or dMMR and who have had disease progression after prior platinum-based systemic treatment. Among 94 enrolled patients, an objective response rate (ORR) of 38.3% was observed, with 11% of patients attaining a complete response (CR). The duration of response (DOR) was considered durable, with the median not reached at the time of data cut-off (range: 1.2 -33.1 months) and 69% of responders with a DOR of at least 6 months. Acknowledging the limitations of cross-trial comparisons, the benefits observed in Study 111/KN146, with respect to the ORR, CR and DOR, were favourable compared to the results observed in single-arm monotherapy studies conducted with lenvatinib or pembrolizumab. This provided reasonable assurance that the combined regimen is more efficacious than either drug administered alone. Furthermore, the observed ORR and CR rates from Study 111/ KN146 were in excess of those estimated in a meta-analysis of studies that tested a variety of salvage regimens in patients who had previously been treated for advanced EC. Overall, the benefit observed among EC patients who have disease that is not MSI-H or dMMR and that has progressed after prior platinum-based treatment is considered promising.

The risks of lenvatinib and pembrolizumab have been established in other disease settings in which they are used as monotherapy. Considering the established safety profiles of both lenvatinib and pembrolizumab, there were no new safety signals observed in Study 111/KN-146. Lenvatinib treatment can elicit serious reactions and/or life threatening events, including hypertension, cardiac failure, gastrointestinal perforation and hemorrhages. Pembrolizumab treatment can elicit a wide range of immune-related adverse reactions, including pneumonitis, hepatitis, colitis, nephritis and endocrine disorders such as hypothyroidism. Lenvima combined with pembrolizumab 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, however these were generally of low grade. These events include musculoskeletal pain, hypothyroidism, palmer-plantar erythrodysesthesia, lipase increased, muscular weakness, pancreatitis, adrenal insufficiency, and nephritis events.

The primary tools for risk mitigation are the Product Monographs (PM) for lenvatinib and pembrolizumab. The risks observed in the data submitted are adequately described in the Warning and Precautions and Adverse Reactions sections of each PM. Each PM further provides detailed recommendations on toxicity management, monitoring schedule, dose interruption, dose reduction or discontinuation, and directions for treatment of immune-related adverse reactions. Both PMs have been updated to refer to the other for information regarding safety, toxicity management, and dosage and administration recommendations. Following review, the recommended indication is: Lenvima, in combination with pembrolizumab, is indicated for the treatment of adult patients with advanced EC that that is not MSI-H or dMMR, who have disease progression following platinum-based systemic therapy, and are not candidates for curative surgery or radiation.

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 commit to file phase 3 trial data to confirm the efficacy of lenvatinib combined with pembrolizumab in the indicated population.

Overall, Study 111/KN146 demonstrated a promising and durable overall response rate in a patient population for whom there are few remaining therapeutic options. The safety profile observed in the clinical trial setting is consistent with the known risks associated with either product alone, for which clinical management protocols are well established. Considering these findings, the evidence in support of the efficacy of lenvatinib in combination with pembrolizumab for the indication as specified is promising such that the benefit/risk/uncertainty assessment is favourable. 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.