Hope for a complete cure for hepatocellular carcinoma: Combining lenvatinib and pembrolizumab with transarterial chemoembolization improves efficacy in treating hepatocellular carcinoma

An international collaborative research group led by Prof. Masatoshi Kudo, MD (Chair, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine) conducted a multicenter, randomized, double-blind, phase 3 study and demonstrated that the combination of the molecular targeted agent lenvatinib and the immune checkpoint inhibitor pembrolizumab in addition to the conventional treatment of transarterial chemoembolization (TACE) in patients with unresectable non-metastatic hepatocellular carcinoma (HCC) significantly extended progression-free survival and showed a trend toward extending overall survival compared to TACE alone. Based on the results of this study, it is anticipated that lenvatinib plus pembrolizumab, in combination with TACE, will become the standard of care for patients with unresectable non-metastatic HCC and may lead to a complete cure.

A procedure called TACE, in which anti-cancer drugs and an embolic agent are injected via a catheter placed in the hepatic artery to suppress the growth of cancer cells was developed in Japan in 1983 as a treatment for patients with unresectable, non-metastatic HCC with no distant metastasis or vascular invasion. TACE quickly became the standard of care around the world. Meanwhile, several effective drugs have been developed for the systemic therapy of hepatocellular carcinoma, including sorafenib, lenvatinib, atezolizumab plus bevacizumab, and durvalumab plus tremelimumab. Because the efficacy of TACE is limited, various treatments combining systemic therapy have been attempted. Treatment policies would change significantly with each development of a new drug. To date, six clinical trials have been conducted combining systemic therapy and TACE in patients with non-metastatic HCC, but all have failed, except for the investigator-initiated trial, TACTICS, conducted by a research group led by Prof. Kudo at the Kindai University Faculty of Medicine. The research group subsequently developed a treatment combining lenvatinib and TACE (LEN-TACE therapy) and confirmed that LEN-TACE therapy provides favorable therapeutic effects. Although LEN-TACE is highly effective, since 2020, immune checkpoint inhibitors have become the mainstream treatment for HCC, as they are for other cancers, and are becoming the first treatment choice. Combining LEN-TACE therapy with immune checkpoint inhibitors might be more effective than using either alone. However, since the efficacy and safety of the combination were unknown, verification in a large-scale clinical study was to be required.

The research group conducted a multicenter, randomized, double-blind, phase 3 study to evaluate the efficacy and safety of combining the LEN-TACE therapy developed in previous research with the immune checkpoint inhibitor pembrolizumab in patients with unresectable non-metastatic hepatocellular carcinoma. Pembrolizumab received accelerated approval from the FDA in the US based on the results of phase 1 trials. Favorable efficacy has also been observed in combination therapy with lenvatinib and pembrolizumab. It has also demonstrated clinically significant improvement in overall survival.

From sites in 33 countries and regions, among patients with unresectable non-metastatic hepatocellular carcinoma who were eligible for TACE, 480 patients with no physical limitations in activity or who could perform light or seated tasks and had only minor liver damage were randomly assigned to receive TACE plus lenvatinib/pembrolizumab (n = 237) or TACE plus dual placebos (n = 243). Results of progression-free survival and overall survival of the trial were obtained: The median progression-free survival was 10.0 months in the TACE plus dual placebos group and 14.6 months in the TACE plus lenvatinib/pembrolizumab group, demonstrating an extension of progression-free survival. In addition, 69 of 237 patients (29%) in the TACE plus lenvatinib/pembrolizumab group and 82 of 243 patients (34%) in the TACE plus dual placebos group died. The 24.0-month overall survival rate was 75% in the TACE plus lenvatinib/pembrolizumab group and 69% in the TACE plus dual placebos group.

This study concluded that compared with TACE plus dual placebos, the TACE plus lenvatinib/pembrolizumab treatment demonstrated significant and clinically meaningful extension of progression-free survival in patients with unresectable non-metastatic HCC and also showed a trend toward improved overall survival. Based on the findings of this study, it is anticipated that TACE plus lenvatinib/pembrolizumab will become the standard of care for patients with unresectable non-metastatic HCC and may lead to a complete cure.