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Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US

On September 17, 2019, the Food and Drug Administration granted accelerated approval to the combination of pembrolizumab (KEYTRUDA, Merck) plus lenvatinib (LENVIMA, Eisai) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The FDA, the Australian Therapeutic Goods Administration, and Health Canada collaborated on this review, allowing for simultaneous decisions in all three countries.

Efficacy was investigated in Study 111/KEYNOTE-146 (NCT02501096), a single-arm, multicenter, open-label, multi-cohort trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients were treated with lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg administered intravenously every 3 weeks until unacceptable toxicity or disease progression. Among the 108 patients, 94 had tumors that were not MSI-H or dMMR, 11 had tumors that were MSI-H or dMMR, and in 3 patients the tumor MSI-H or dMMR status was not known. Tumor MSI status was determined using a polymerase chain reaction test. Tumor MMR status was determined using an immunohistochemistry test.

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by independent radiologic review committee using RECIST 1.1. The ORR in the 94 patients whose tumors were not MSI-H or dMMR was 38.3% (95% CI: 29%, 49%) with 10 complete responses (10.6%) and 26 partial responses (27.7%). Median DOR was not reached at the time of data cutoff and 25 patients (69% of responders) had response durations ≥6 months.

In endometrial carcinoma, the most common adverse reactions (incidence ≥20%) for lenvatinib and pembrolizumab were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.

For endometrial carcinoma, the recommended dose is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.

View full prescribing information:
LENVIMA
KEYTRUDA

This review used the OCE’s Real-Time Oncology Review (RTOR) pilot program and its accompanying Assessment Aid, and the combination of pembrolizumab plus lenvatinib was approved three months prior to its FDA goal date.

This indication is approved under FDA’s accelerated approval pathway. FDA granted this application priority review and Breakthrough Therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

Check out recent approvals at the OCE’s podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.)

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

Follow the Oncology Center of Excellence on Twitter @FDAOncology.