US approves Keytruda, Lenvima combination for endometrial cancer under new simultaneous review scheme with Canada, Australia

The FDA announced Tuesday that as part of a new initiative that provides a framework for concurrent submission and review of oncology products among international partners, the agency granted accelerated approval to Merck & Co.'s Keytruda (pembrolizumab) in combination with Eisai's Lenvima (lenvatinib) for the treatment of endometrial cancer. Under Project Orbis, the FDA, along with Health Canada and the Australian Therapeutic Goods Administration (TGA), collaboratively reviewed applications for the combination therapy, allowing for simultaneous decisions in all three countries.

Specifically, the US approval was for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) who experienced disease progression following prior systemic therapy, but are not candidates for curative surgery or radiation. The TGA also provisionally approved the combination therapy for the treatment of certain patients with advanced endometrial carcinoma, while Health Canada has not yet officially announced its decision. 

The FDA said partnering with international regulators may give cancer patients earlier access to products in other countries where there may be significant delays in regulatory submissions. "This is partly due to different standards of care around the world that also have an impact on the increasingly international conduct of cancer clinical trials, potentially slowing the development of anticancer products," the FDA said, adding that Project Orbis is expected to "[facilitate] a collaborative review to identify any regulatory divergence across review teams."

Acting FDA Commissioner Ned Sharpless stated "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." He noted that "as Project Orbis expands, we look forward to welcoming additional international partners to collaborate with us."

Approval of the combination therapy was backed by data from the Phase II KEYNOTE-146 trial that included 94 patients whose endometrial carcinoma tumours were neither MSI-H nor dMMR, and whose disease that had progressed following at least one prior systemic therapy in any setting. Participants were treated with Keytruda  intravenously every three weeks in combination with oral Lenvima once daily until unacceptable toxicity or disease progression.

Results showed that the combination regimen led to complete and partial responses in 10.6% and 27.7% of patients, respectively, for an objective response rate of 38.3%. The median duration of response had not been reached at the time of data cut-off, while 25 patients, representing 69% of responders, had a duration of response of at least six months.

Richard Pazdur, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, noted that "in addition to the international collaboration with Australia and Canada, this review used the Real-Time Oncology Review (RTOR) pilot programme, which can streamline the submission of data prior to the completion and submission of the entire clinical application." Other treatments approved under the RTOR programme include Johnson & Johnson and Genmab's Darzalex for certain patients with multiple myeloma, as well as Novartis' Piqray (alpelisib) and Kisqali (ribociclib) for select patients with advanced breast cancer.

Keytruda was initially approved by the FDA in 2014 for the treatment of advanced or unresectable melanoma, becoming the first PD-1 inhibitor to win authorisation in the US, and has since had its label expanded for use in multiple indications. Second-quarter sales of the immunotherapy surged 58% to $2.6 billion.

Meanwhile, Lenvima was first cleared in the US in 2015 for use in certain patients with thyroid cancer and was later expanded to include renal cell carcinoma and hepatocellular carcinoma. Merck gained rights last year to jointly develop the tyrosine kinase inhibitor, both as monotherapy and in combination with Keytruda, for multiple cancer indications. Eisai reported in July that sales of the drug more than doubled to JPY 24.8 billion ($229 million) in the first quarter.

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