Lenvatinib/Pembrolizumab/TACE Regimen Improves PFS in Intermediate-Stage HCC

Josep M. Llovet, MD, PhD

Lenvatinib (Lenvima) given with pembrolizumab (Keytruda) and transarterial chemoembolization (TACE) significantly bettered progression-free survival (PFS) vs placebo and TACE when given for the treatment of intermediate-stage hepatocellular carcinoma (HCC), according to findings from the phase 3 LEAP-012 trial (NCT04246177).¹

LEAP-012 is a phase 3, double-blinded, active-controlled, multicenter, randomized trial. A total of 480 patients with intermediate-stage HCC were enrolled and randomly assigned to receive the lenvatinib/pembrolizumab/TACE regimen (n = 237) or the placebo/TACE regimen (n = 243). Of the patients in each arm, 237 and 241 patients were treated.

Data were presented at the 2024 ESMO Congress, showing that at a cutoff date of January 30, 2024, the median PFS per RECIST v1.1 by blinded independent central review (BICR) was 14.6 months (95% CI, 12.6-16.7) in the lenvatinib/pembrolizumab/TACE arm vs 10.0 months (95% CI, 8.1-12.2) in the placebo/TACE arm.

The PFS rates across the arms at 12 months were 62.2% and 43.4%, respectively, and the 18-month PFS rates were 39.1% and 27.9%, respectively (HR, 0.66; 95% CI, 0.51-0.84; P =.0002).

“Lenvatinib/pembrolizumab certainly provides an alternative treatment that we propose as a frontline option for patients with intermediate HCC, which represents 30% of patients and includes those with liver-only disease without dissemination,” Josep M. Llovet, MD, PhD, told Targeted Oncology^TM in an interview.

In the interview, Llovet, director of the Liver Cancer Program and professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai Hospital in New York, New York, discussed the updated data from the LEAP-012 trial.

3D illustration of human liver: © PIC4U - stock.adobe.com

Targeted Oncology: Can you describe the phase 3 LEAP-012 clinical study?

Llovet: At [ESMO 2024], we presented the phase 3 trial, the LEAP-012 trial, comparing lenvatinib plus pembrolizumab plus TACE in patients with intermediate-stage HCC. Intermediate stage represents those patients with liver-only disease without vascular invasion or extroverted spread that account for around 30% of the total population of patients with hepatocellular carcinoma. During the last 20 years, the standard of care has been TACE, and around 15 randomized control trials have been conducted testing combination of systemic therapies with TACE. All of them unfortunately resulted with negative results.

In our study, we randomized 480 patients to receive either the [triplet] treatment of lenvatinib/pembrolizumab/TACE or the dual placebo plus TACE for 2 years. The primary end point was progression-free survival and overall survival, and then secondary end points were objective response rate and duration of response.

Please discuss the findings from the trial.

Regarding the primary end point, we hit the primary end point of progression-free survival. The median progression-free survival for the [triplet] arm was 14.5 months, while for the treatment with placebo, it was 10 months with a hazard ratio of 0.66 and a P value of 0.0002. In the subgroup analysis, we confirmed that these differences were profound and consistent across the groups.

Regarding overall survival, the analysis was immature. The first interim analysis was based on 151 events, and at that time the hazard ratio showed a trend favoring survival for the combo arm, with a hazard ratio of 0.80 and a P value of 0.086. Additional interim analysis and a final analysis are needed to confirm that.

In terms of objective response rate, we measured it by modified RECIST according to international, European, and [US] guidelines. The objective response rate for the combo arm was 72%, including 56% of patients achieving a complete radiological response compared [with] 49% in the placebo arm.

Overall, I think this study provides the rationale for a new combination in the intermediate space after 20 years of treatment with transarterial embolization. Therefore, we are endorsing lenvatinib plus pembrolizumab plus TACE as a potential alternative for patients with intermediate hepatocellular carcinoma.

How might future studies build upon these findings to further improve patient outcomes?

There are other studies in the same space, particularly the studies comparing head-to-head systemic therapy against TACE. Only 1 study resulted in a positive result with a hazard ratio here of 0.77 with a P value of 0.35. Beyond these, there are no other studies coming that can challenge the LEAP-012 data.

First, we need to see if this is adopted by guidelines, and also, we need to follow up on OS. Needless to say, the median survival of these patients will be beyond 36 months, and second treatments or second-line therapies will impact OS as well.

For a community oncologist, what are the key takeaways from the study?

The key takeaways are that TACE has been in the field of intermediate HCC for 20 years. Second, this is the most robust data reported over these years in intermediate HCC, combining systemic therapies with local/regional therapies. Lenvatinib/pembrolizumab certainly provides an alternative treatment that we propose as a frontline option for patients with intermediate HCC, which represents 30% of patients and includes those with liver-only disease without dissemination.

REFERENCE:

Llovet J, Finn R, Ren ZG, et al. LEAP-012: A phase 3 study of lenvatinib plus pembrolizumab plus transarterial chemoembolization for intermediate-stage hepatocellular carcinoma. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA3.