FDA Approves Combination of Lenvatinib and Pembrolizumab For Advanced Endometrial Carcinoma Treatment

The FDA has granted accelerated approval to the combination of lenvatinib and pembrolizumab in the treatment of patients with advanced endometrial carcinoma.

The FDA has granted an accelerated approval to the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) 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 ineligible for curative surgery or radiation.1

The approval is based on findings of a study of 94 patients with endometrial carcinoma tumors that were not MSI-H or dMMR. Of these patients, the overall response rate (ORR) was 38.3%, which comprised a 10.6% (n = 10) complete response (CR) rate and a partial response rate of 27.7% (n = 26). Duration of response (DOR) ≥6 months was reported in 69% (n = 25) of patients.

The decision is part of a new initiative of the FDA Oncology Center of Excellence, titled Project Orbis, which is designed to provide a framework for concurrent submission and review of oncology drugs among international partners. Under Project Orbis, the FDA, the Australian Therapeutic Goods Administration (TGA), and Health Canada collaboratively reviewed applications for the two agents and allowed for simultaneous approvals in all 3 countries.

“In addition to the international collaboration with Australia and Canada, this review used the ‘Real-Time Oncology Review’ (RTOR) pilot program, which can streamline the submission of data prior to the completion and submission of the entire clinical application,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “RTOR, and its accompanying Assessment Aid, facilitated discussions among the regulatory agencies, expediting the approval in the three countries. These applications were approved 3 months prior to the FDA goal date.”

Collaboration among international regulators could permit patients with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions, regardless of whether the product has received FDA approval. The agency stated in a press release that, "with a framework for concurrent submission and review of oncology drugs, Project Orbis facilitates a collaborative review to identify any regulatory divergence across review teams."

“We are pleased to be working alongside our Australian and Canadian colleagues to help make potentially life-changing treatments available to patients as quickly as possible while still ensuring the FDA’s high standards of safety and effectiveness,” Acting FDA Commissioner Ned Sharpless, MD, stated in the press release. “As Project Orbis expands, we look forward to welcoming additional international partners to collaborate with us in this important initiative as we work to help further serve the global patient community.”

Regarding safety data in the trial, common adverse events (AEs) were fatigue, high blood pressure, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, and stomatitis. Additional AEs included vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.

In August, the FDA granted a breakthrough therapy designation to the combination of lenvatinib and pembrolizumab for the treatment of patients with advanced and/or metastatic non—MSI-H/proficient mismatch repair endometrial carcinoma who have progressed after ≥1 prior systemic therapy. The designation was based on interim data from the phase Ib/II basket Study 111/KEYNOTE-146 trial. In a 53-patient endometrial cancer cohort, the ORR at week 24 per independent radiology review was 45.3% (95% CI, 31.6-59.6). The overall ORR was 47.2% (n = 25; 95% CI, 33.3-61.4), including 3 CRs and 25 PRs.2

Additional data of the combination in endometrial cancer were recently published in Lancet Oncology. In an open-label, single-arm, multicenter, phase II study (NCT02501096), patients with metastatic endometrial cancer received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients were aged ≥18 years or older, were unselected for microsatellite instability or PD-L1 expression, had an ECOG performance status of 0 or 1, had received ≤2 prior systemic therapies, had measurable disease according to the immune-related RECIST criteria, and had a life expectancy of ≥12 weeks. The primary endpoint was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population.

At the cutoff date of December 15, 2017, the median study follow-up was 13.3 months, and the ORR at week 24 was 39.6% (95% CI, 26.5-54.0). Serious treatment-related AEs (TRAEs) occurred in 16 (30%) patients, and 1 treatment-related death was reported and due to intracranial hemorrhage. The most frequently reported any-grade TRAEs were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%). The most common grade 3 TRAEs were hypertension (34%) and diarrhea (8%), and grade 4 TRAEs were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events.

A version of this article originally appeared on OncLive® as, “FDA Approves Lenvatinib/Pembrolizumab Combo for Advanced Endometrial Cancer


  • FDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma. FDA. Published September 17, 2019. https://bit.ly/2kqmAGq. Accessed September 17, 2019.
  • Makker V, Rasco DW, Vogelzang NJ, et al. Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: updated results. J Clin Oncol. 2018;36 (suppl; abstr 5596).
  • Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncology. 2019;20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8.

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