Lenvatinib-pembrolizumab combo fails to spring forward in HCC treatment

In the phase III LEAP*-002 study, a combination regimen comprising lenvatinib and pembrolizumab appeared to have similar efficacy and safety as lenvatinib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC).

“The dual primary endpoints of overall survival (OS) at the final analysis (FA) and progression-free survival (PFS) at the first interim analysis (IA1) did not meet prespecified statistical significance,” said Dr Richard Finn from University of California, Los Angeles, California, US, at ESMO 2022.

The study comprised 794 individuals (median age 66 years, 81 percent male) with confirmed** diagnosis of HCC, who have not had prior systemic therapy for advanced HCC. They were randomized 1:1 to receive daily oral lenvatinib 8 mg (body weight [BW] <60 kg) or 12 mg (BW ≥60 kg) plus either IV pembrolizumab 200 mg or placebo Q3W. [ESMO 2022, abstract LBA34]

At a median follow-up 32.1 months (FA), 534 OS events had occurred, with 60 patients remaining on treatment (n=36 [lenvatinib-pembrolizumab] and 24 [lenvatinib-placebo]). Median OS for the respective arms was 21.2 vs 19.0 months (hazard ratio [HR], 0.84; p=0.023).

Median PFS was similar between the lenvatinib-pembrolizumab and lenvatinib-placebo arms during the IA1*** (8.2 vs 8.0 months; HR, 0.87; p=0.047) and FA (8.2 vs 8.1 months; HR, 0.83).

Compared with lenvatinib-placebo, lenvatinib-pembrolizumab led to higher objective response rates (ORR; 26 percent vs 18 percent) and longer duration of response (median 16.6 vs 10.4 months) at the FA.

There were similar incidences of grade 3–5 treatment-related adverse events (TRAEs) between the lenvatinib-pembrolizumab and lenvatinib-placebo arms (62 percent vs 58 percent), with low incidences of grade 5 TRAEs (1.0 percent vs 0.8 percent). Rates of grade 3‑4 immune-mediated AEs and infusion reactions were low (9 percent vs 2 percent).

“These results are unexpected, as the combination of lenvatinib and pembrolizumab previously showed promising efficacy in a phase I trial,” commented Prof Stephen Chan from the Chinese University of Hong Kong, in a press release. [J Clin Oncol 2020;38:2960-2970] Chan also mentioned the approval of lenvatinib as first-line treatment for HCC based on the REFLECT study findings. [Lancet 2018;391:1163-1173]

Lenvatinib monotherapy prevails

“[LEAP-002 showed that the] lenvatinib-pembrolizumab combination is active but not superior to lenvatinib monotherapy,” noted discussant Dr Katie Kelley from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, US. “[Hence,] lenvatinib monotherapy remains the preferred first-line agent for fit patients with contraindications to ICI^# therapies.”

“In LEAP-002, OS with lenvatinib monotherapy is the longest we have seen with a tyrosine kinase inhibitor, which is much longer than the median OS … in REFLECT (13.6 months),” stressed Chan. “The median OS … with lenvatinib monotherapy supports its role as standard of care in first-line advanced HCC,” said Finn.

“[Overall, in our study,] lenvatinib continued to demonstrate its importance as a treatment option for advanced HCC,” Finn added.

But hope remains for the combo regimen

Although the findings appear to favour lenvatinib monotherapy over the combo regimen, Finn noted that the median OS achieved with lenvatinib-pembrolizumab in LEAP-002 was “the longest ever reported in first-line HCC phase III studies, with no new safety signals observed”.

“[As such,] there may still be a future for this combination,” said Chan. “We await with interest the results from an ongoing phase III LEAP-012 trial of lenvatinib-pembrolizumab in patients with incurable, non-metastatic HCC.”

Kelley added that while the combination does not appear to have a role in first-line treatment algorithms, there may be “future utility in the early/intermediate stages, based on robust ORR and PFS.” She thus suggested longer follow-ups to further evaluate OS and PFS, as well as analyses on quality of life and patient-reported outcomes.

“These are exciting times in advanced HCC, but we need more research to allow us to move towards personalized treatment. We know which genes are dysregulated in HCC, but we are not yet translating or applying these findings to clinical practice,” said Chan.