Merck and Eisai Face Setback in Liver Cancer Treatment as Keytruda-Lenvima Combination Fails to Meet Survival Endpoint

Merck & Co. and Eisai have announced the discontinuation of their phase 3 LEAP-012 study, evaluating the combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib) in patients with unresectable, non-metastatic hepatocellular carcinoma (HCC). The decision comes after the treatment failed to demonstrate a statistically significant improvement in overall survival when added to transarterial chemoembolization (TACE), compared to TACE alone.

Study Termination and Key Findings

The LEAP-012 trial, which had previously shown promising results in progression-free survival, was terminated following a pre-specified interim analysis. According to Merck's October 29 press release, the likelihood of meeting the threshold for statistical significance in overall survival at a future analysis was deemed "low" by the companies.

Dr. Gregory Lubiniecki, Merck's VP of global clinical development, stated, "Although the progression-free survival results from this study are encouraging, unfortunately, the addition of Keytruda plus Lenvima to TACE did not show the overall survival benefit we hoped."

The safety profile of the Keytruda-Lenvima combination remained consistent with previous studies, although the treatment group experienced a higher rate of grade 3 or above treatment-related adverse events (71.3%) compared to the control arm (31.5%).

Implications for Liver Cancer Treatment

This setback represents another challenge in the development of the Keytruda-Lenvima combination for liver cancer. In 2022, a previous study failed to demonstrate improved survival in patients with newly diagnosed metastatic liver cancer compared to Lenvima monotherapy.

Dr. Corina Dutcus, Eisai's head of oncology clinical development, emphasized that the findings provide "important insights" for treating HCC, noting that many patients on standard-of-care TACE experience disease progression.

Despite this disappointment, the combination therapy retains its approval in China for unresectable, non-metastatic HCC, where it was greenlit earlier this year.

Broader Context and Future Directions

The Keytruda-Lenvima pairing has shown mixed results across various indications. While it has faced setbacks in gastroesophageal adenocarcinoma and bladder cancer, the combination has secured approvals in renal cell carcinoma and certain types of advanced endometrial carcinoma.

As Merck prepares for the post-Keytruda patent cliff, the company is focusing on its successor, Welireg. Recent results have shown promise for Welireg in combination with Lenvima in advanced renal cell carcinoma, demonstrating improved progression-free survival, though overall survival data are not yet statistically significant.