FDA rejects accelerated approval of Merck & Co., Eisai's Keytruda, Lenvima combination in liver cancer

The FDA issued a complete response letter regarding a filing seeking accelerated approval of the combination of Merck & Co.'s anti-PD-1 therapy Keytruda (pembrolizumab) plus Eisai's multikinase inhibitor Lenvima (lenvatinib) for the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), the companies announced Wednesday. In its letter, the agency said the application does "not provide evidence that [the] combination…represents a meaningful advantage over available therapies" in this patient population.

Merck and Eisai's filing was based on data from the single-arm Phase Ib KEYNOTE-524/Study 116 trial of 100 patients with unresectable HCC who had not received prior systemic therapy. Results showed that the combination of Keytruda plus Lenvima was associated with an objective response rate (ORR) of 36%, with one complete response and 35 partial responses, as well as a median duration of response (DoR) of 12.6 months, using RECIST v1.1 criteria. When assessed using modified RECIST criteria, the combination demonstrated an ORR of 46%, with the number of complete responses jumping to 11, while partial responses stayed at 35. The median DoR was 8.6 months.

Beaten to the finish by Roche

However, Merck and Eisai pointed out that just ahead of the target review date for their filing, the FDA approved the combination of Roche's PD-L1 inhibitor Tecentriq (atezolizumab) with Avastin (bevacizumab) for patients with unresectable or metastatic HCC who have not received prior systemic therapy based on a demonstrated overall survival benefit. Specifically, results from the Phase III IMbrave150 study demonstrated that the combination of Tecentriq and Avastin lowered the risk of death and disease worsening or death by 42% and 41%, respectively, compared to Bayer's Nexavar (sorafenib), meeting the trial's co-primary endpoints.

"Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval," Merck and Eisai stated, "[we] plan to work with the FDA to take appropriate next steps," which include conducting a well-controlled clinical trial that demonstrates "substantial evidence of effectiveness and the clinical benefit." The Phase III LEAP-002 trial evaluating the combination as a first-line treatment for advanced HCC is currently ongoing, with study's main goals being progression-free and overall survival.

Lenvima is already approved in the US for the first-line treatment of patients with unresectable HCC, while Keytruda is authorised in the country for HCC patients previously treated with Bayer's Nexavar (sorafenib). Merck and Eisai are continuing to evaluate the Keytruda plus Lenvima combination across 13 different tumour types in 18 clinical trials, including the LEAP clinical programme. The combination was cleared by US regulators last September for certain patients with advanced endometrial carcinoma. 

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