Therapy Areas: Autoimmune
FDA Approves Keytruda plus Lenvima Combination Treatment for Patients with Certain Types of Endometrial Carcinoma
20 September 2019 - - The US Food and Drug Administration approved the combination of Keytruda, US-based pharmaceutical company Merck's (NYSE: MRK) anti-PD-1 therapy, plus Lenvima, the orally available kinase inhibitor discovered by Eisai, for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation, Merck said.

This marks the first US approval for the combination of Keytruda plus Lenvima and the first time an anti-PD-1 therapy is approved in combination with a kinase inhibitor for advanced endometrial carcinoma in the US Following submission on June 17, this is an accelerated approval reviewed under the FDA's Real-Time Oncology Review pilot program, which aims to improve the efficiency of the review process for applications to ensure that treatments are available to patients as early as possible.

This approval is based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. According to the FDA, 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 its international partners.

Under this project, the FDA, the Australian Therapeutic Goods Administration and Health Canada collaboratively reviewed applications for two oncology drugs, allowing for simultaneous decisions in all three countries.

The approval was based on data from KEYNOTE-146/Study 111, a Phase 2, multi-cohort, multicenter, open-label, single-arm trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting.

Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with Keytruda 200 mg intravenously every three weeks in combination with Lenvima 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator.

Administration of Keytruda plus Lenvima was permitted beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit.

Keytruda dosing was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months.

Assessment of tumor status was performed at baseline and then every six weeks until week 24, followed by every nine weeks thereafter.

The major efficacy outcome measures were objective response rate and duration of response by independent radiologic review committee using RECIST 1.1.

Among the 108 patients, 87% had tumors that were not MSI-H or dMMR, 10% had tumors that were MSI-H or dMMR, and 3% had tumors that had unknown status.

The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, with 62% age 65 or older; 86% White, 6% Black, 4% Asian, and 3% other races; and Eastern Cooperative Oncology Group performance status of 0 or 1.

All 94 patients had received prior systemic therapy for endometrial carcinoma; 51% had one, 38% had two, and 11% had three or more prior systemic therapies.

In the 94 patients with tumors that were not MSI-H or dMMR, the Keytruda plus LENVIMA combination demonstrated an ORR of 38.3% (95% CI, 29%-49%), with a complete response rate of 10.6% and a partial response rate of 27.7%.

The median follow-up time was 18.7 months. In the patients who had a response as determined by independent review, at the time of data cutoff, the median DOR was not reached (range: 1.2+ to 33.1+ months), and 69% of these patients experienced responses lasting six months or greater.

The median duration of study treatment was seven months (range: 0.03 to 37.8 months), and the median duration of exposure to Keytruda was six months (range: 0.03 to 23.8 months).

Fatal adverse reactions occurred in 3% of patients treated with Keytruda plus Lenvima, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage, and intracranial hemorrhage. Serious adverse reactions occurred in 52% of patients receiving Keytruda plus Lenvima.

The most common serious adverse reactions with the Keytruda plus Lenvima combination were hypertension, abdominal pain, musculoskeletal pain, hemorrhage, fatigue, nausea, confusional state, and pleural effusion (4% each), adrenal insufficiency, colitis, dyspnea, and pyrexia (3% each).

Keytruda was discontinued due to adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with Lenvima.

The most common adverse reactions leading to discontinuation of Keytruda were adrenal insufficiency, colitis, pancreatitis, and muscular weakness (2% each).

Permanent discontinuation due to adverse reactions (Grade 1-4) occurred in 21% of patients who received Keytruda plus Lenvima. The most common adverse reactions resulting in discontinuation of Lenvima were gastrointestinal perforation or fistula, muscular weakness, and pancreatitis (2% each).
Login
Username:

Password: