Recently, the U.S. Food and Drug Administration (FDA) has granted Priority Review to the combination of pembrolizumab and lenvatinib for the treatment of both advanced renal cell carcinoma (RCC) and endometrial carcinoma. The FDA also granted Priority Review to ivosidenib for the treatment of IDH1-mutated cholangiocarcinoma.
Priority Review for Pembrolizumab Plus Lenvatinib in Advanced RCC, Advanced Endometrial Carcinoma
The FDA has accepted and granted Priority Review to applications seeking two new approvals for the combination of pembrolizumab, an anti–PD-1 therapy, plus lenvatinib, an orally available multiple receptor tyrosine kinase inhibitor.
The first set of applications (a supplemental biologics license application for pembrolizumab and a supplemental new drug application for lenvatinib) are for the first-line treatment of patients with advanced RCC, based on progression-free survival, overall survival, and objective response rate data from the pivotal phase III CLEAR study (KEYNOTE-581/Study 307).
The second set of applications are for the treatment of patients with advanced endometrial carcinoma who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, based on progression-free survival, overall survival, and objective response rate data from the pivotal phase III KEYNOTE-775/Study 309 trial.
These are the first applications to be submitted in the United States for this combination therapy based on phase III clinical data. The FDA has set Prescription Drug User Fee Act (PDUFA) dates, or target action dates, of August 25 and 26, 2021, for the advanced RCC applications, respectively, and September 3, 2021, for the advanced endometrial carcinoma applications.
The applications in advanced RCC are based on results from the CLEAR study (KEYNOTE-581/Study 307), in which pembrolizumab/lenvatinib demonstrated statistically significant improvements in progression-free survival, overall survival, and objective response rate vs sunitinib. These data were presented in February at the virtual 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published by Motzer et al in The New England Journal of Medicine.
The applications in advanced endometrial carcinoma are based on results from KEYNOTE-775/Study 309, in which pembrolizumab/lenvatinib demonstrated statistically significant improvements in progression-free survival, overall survival, and objective response rate vs chemotherapy (investigator’s choice of doxorubicin or paclitaxel), regardless of mismatch repair status. These data were presented in March at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer by Makker et al (Abstract 37/ID 11512). KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the 2019 accelerated approval of the combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability–high or mismatch repair–deficient, who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation. This indication was an accelerated approval based on tumor response and durability of response and reviewed under the FDA’s Real-Time Oncology Review pilot program and Project Orbis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
Priority Review for Ivosidenib in IDH1-Mutated Cholangiocarcinoma
The FDA accepted a supplemental new drug application and granted Priority Review for ivosidenib tablets as a potential treatment for patients with previously treated IDH1-mutated cholangiocarcinoma.
Ivosidenib is an isocitrate dehydrogenase-1 inhibitor.
The acceptance is supported by data from the ClarIDHy study, the first and only randomized phase III trial for previously treated IDH1-mutated cholangiocarcinoma. Data from the trial was presented during the 2021 Gastrointestinal Cancers Symposium by Zhu et al (Abstract 266); an encore presentation of the data will be presented at the 2021 ASCO Annual Meeting.
Ivosidenib tablets are currently approved in the United States as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML) and for adults with newly diagnosed IDH1-mutant AML who are aged ≥ 75 years or who have comorbidities that preclude the use of intensive induction chemotherapy.
