Merck and Eisai Halt Global Development of Keytruda-Lenvima Combination with TACE for Unresectable, Non-Metastatic Hepatocellular Carcinoma Following Phase 3 LEAP-012 Trial Failure

On October 29, MSD and Eisai jointly announced that they would terminate the development plan for the combination of PD-1 inhibitor Keytruda and tyrosine kinase inhibitor Lenvima with standard transarterial chemoembolization (TACE) for unresectable, non-metastatic hepatocellular carcinoma (HCC), as the Phase 3 LEAP-012 study did not meet its primary endpoint of overall survival (OS). This decision adds another setback to the turbulent HCC development journey of this combination therapy.

The core purpose of the LEAP-012 study is to evaluate the efficacy and safety of Keytruda + Lenvima in combination with TACE therapy, compared to TACE alone, in patients with unresectable, non-metastatic hepatocellular carcinoma.

Positive signals emerged in the early stages of the research, with the combination therapy showing impressive results in terms of progression-free survival. Data revealed that this combination regimen reduced the risk of disease progression or death by 34% for patients. This outcome was showcased at the "Transformative Clinical Trials" session of the 2024 European Society for Medical Oncology (ESMO) conference, restoring confidence in the combination therapy.

In a pre-specified interim analysis, the research team found that the combination therapy failed to significantly prolong overall patient survival. After evaluation by both parties, it was determined that the likelihood of this endpoint reaching statistical significance in subsequent analyses was extremely low. Therefore, the decision was made to terminate the study, while continuing to advance the in-depth analysis of follow-up data.

In terms of safety, the treatment regimen of Keytruda + Lenvima combined with TACE demonstrated a safety profile consistent with previous similar studies and the early analysis results of LEAP-012, but there were still notable differences in toxicity.

Data shows that the incidence of grade 3 or higher treatment-related adverse events in the combination therapy group reached 71.3%, significantly higher than the 31.5% in the control group. Additionally, the discontinuation rate due to treatment-related side effects was also higher in the combination therapy group. This difference in safety has made the attainment of overall survival a critical consideration for the approval of this therapy.

This is not the first setback for the Keytruda-Lenvima combination therapy in the field of liver cancer. In a 2022 study, this combination regimen failed to demonstrate superior overall survival benefits compared to using Lenvima alone in newly diagnosed metastatic liver cancer patients. The recent failure in a non-metastatic subtype of liver cancer has made the development path for this combination therapy in liver cancer even more challenging.

Despite the termination of the LEAP-012 study, MSD and Eisai's efforts regarding this combination therapy have not completely halted. Earlier this year, the Keytruda + Lenvima combined with TACE therapy was approved in China for unresectable, non-metastatic hepatocellular carcinoma, indicating that this regimen may still see continued application in the Chinese market.

From the perspective of the overall R&D pipeline, the performance of the Keytruda-Lenvima combination therapy has been mixed. In addition to two setbacks in the field of liver cancer, this combination failed to reach the overall survival endpoint in a subtype study of gastric esophageal adenocarcinoma this year and encountered a similar setback in bladder cancer research in 2022. However, the combination therapy has been approved for renal cell carcinoma and certain advanced endometrial cancer indications, demonstrating certain clinical value.

Moreover, MSD is actively planning its R&D pipeline post the Keytruda patent cliff, with its next-generation drug Welireg already achieving phased progress. Research data published on October 27 showed that the combination of Welireg and Lenvima can help some patients with advanced renal cell carcinoma extend their progression-free survival period, although the overall survival results have not yet reached statistical significance.

The termination of the LEAP-012 study provides significant insights into the development of combination therapies for liver cancer. Dr. Corina Dutcus, Head of Oncology Clinical Development at Eisai, stated that the study results will bring "important understanding" to the treatment of this type of cancer. Especially given the context where a large number of patients still face disease progression with standard TACE therapy, more effective treatment strategies need to be explored in the future.