FDA Grants Breakthrough Therapy Designation to Lenvima-Keytruda Combo for Advanced Endometrial Carcinoma

FDA Grants Breakthrough Therapy Designation to Lenvima-Keytruda Combo for Advanced Endometrial Carcinoma

The U.S. Food and Drug Administration granted breakthrough therapy designation to an investigational combination of Eisai’s Lenvima (lenvatinib) and Merck‘s Keytruda (pembrolizumab) for the treatment of patients with a subset of advanced endometrial carcinoma.

Specifically, the FDA’s decision covers patients with advanced and/or metastatic non-microsatellite instability high (MSI-H)/proficient mismatch repair (pMMR) endometrial cancer whose disease worsened following at least one systemic therapy.

The FDA awards this designation to therapies that provide significant improvement over currently available options. It is intended to accelerate the development, review, and approval of medications for serious or life-threatening conditions. Benefits include more intensive FDA guidance and potential eligibility for priority review.

The agency’s decision was based on early results in endometrial cancer patients participating in a multicenter, open-label Phase 1b/2 trial (NCT02501096), called Study 111/KEYNOTE-146, which is assessing the effectiveness and safety of the Lenvima-Keytruda combo in adults with selected solid tumors.

Besides endometrial cancer, Study 111 also includes patients with renal cell carcinoma, non-small cell lung cancer, urothelial cancer, squamous cell head and neck cancer, and melanoma.

During the trial, Lenvima is administered orally at a daily 20 mg dose, and Keytruda is injected into the bloodstream at 200 mg every three weeks.

“We designed Study 111 to learn as much as we could about the Lenvima/Keytruda combination as efficiently as possible, driven by a sense of urgency to bring forward a potential new treatment option for patients in need,” Takashi Owa, vice president and chief medicine creation officer of the Oncology Business Group at Eisai, said in a press release.

The primary objective of Phase 1b was to establish the treatment combination’s maximum tolerated dose. In Phase 2, scientists are primarily evaluating the treatment’s objective response rate (ORR) — the proportion of patients with a predefined tumor size reduction over a minimum time period — at 24 weeks.

Other Phase 2 goals are progression-free survival (PFS) — the length of time during and/or after treatment without cancer progression — and how long patients maintain a complete or partial response.

A total of 53 patients with previously treated, metastatic endometrial cancer were included. The Phase 2 portion is ongoing with an endometrial cancer group expansion.

Results showed that, at 24 weeks, 39.6% of patients had experienced a reduction in tumor size, including three patients with a complete response. In addition, 83% of patients had a response duration of six months or more, and 64.5% had a response duration of 12 months or more. Median PFS was 7.4 months.

Severe treatment-related adverse events were observed in 37 patients, but no life-threatening side effects were reported. Five patients (9%) stopped treatment due to adverse events. The most common were hypertension, fatigue, and diarrhea.

Trial results were presented in June at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago.

“We are encouraged by the continued activity seen in patients with endometrial cancer,” Owa said, adding that the FDA’s decision on Lenvima and Keytruda strengthened Eisai’s commitment to providing benefits to these patients as quickly as possible.

“We will continue to work closely with Eisai to build on the robust data for the Lenvima/Keytruda combination in advanced endometrial cancer in an effort to offer a new option for these patients and potentially help address a critical unmet need.” said Roy Baynes, senior vice president and head of global clinical development, and chief medical officer at Merck Research Laboratories.

An international Phase 3 trial — called KEYNOTE-775 — is also testing the combination in recurrent endometrial cancer (NCT03517449). Patient enrollment is ongoing.

Lenvima is a multitarget medication that inhibits the cellular activity of specific intracellular enzymes — known as kinases — associated with blood vessel formation, tumor growth, and progression. The therapy is already approved in combination with Afinitor (everolimus), by Novartis, for patients with advanced renal cell carcinoma who received one prior anti-angiogenic therapy, a type of medication that blocks the formation of new blood vessels.

In March, Eisai and Merck (known as MSD outside the U.S. and Canada) announced a strategic collaboration to develop Lenvima both as a standalone therapy and in combination with Keytruda. In addition to ongoing trials, the companies will start new studies assessing the combination for 11 potential indications in cancer types, including bladder cancer and hepatocellular carcinoma, as well as a trial in six more types of cancer.

In January, the FDA granted the same designation to this combo approach for the treatment of advanced renal cell carcinoma.