Nivolumab in combination with lenvatinib in unresectable hepatocellular carcinoma: The IKF-t006/IMMUNIB translational phase-2 study.

BACKGROUND

Combinations of anti-angiogenic agents, including lenvatinib, and PD-1/PD-L1 inhibitors have demonstrated antitumor activity with manageable toxicity in several tumor types, including hepatocellular carcinoma (HCC).

OBJECTIVE

The IMMUNIB trial aimed to evaluate efficacy of nivolumab in combination with lenvatinib as first-line treatment in patients with unresectable HCC.

DESIGN

This investigator-initiated single-arm phase-2 trial enrolled patients with advanced stage HCC for first-line therapy who were treated with lenvatinib plus nivolumab for a maximum of 18 months or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST v1.1. The study was powered to detect an ORR of 43% using a prespecified null hypothesis ORR of 24%Secondary endpoints included time to progression (TTP), progression free survival (PFS), overall survival (OS) and safety.

RESULTS

Out of 50 enrolled patients, 49 received at least one dose of the combination treatment (24 BCLC-B, 18 BCLC-C, 7 not evaluable). The ORR was 32% [95% CI 19.5,46.7]. Median PFS was 9.0 months, and the median OS was 26.6 months. Notably, 17 patients were still alive at the last follow-up, with 2 remaining progression-free. Recurrent (≥5%) treatment related adverse events grade ≥ 3 included colitis, diarrhea, hypertension and elevated bilirubin. Exploratory translational analysis using plasma-based epigenomic and tissue-based transcriptome profiling indicated a correlation between FGFR activation as well as immune- and inflammatory signatures and treatment benefits.

CONCLUSION

Although the study did not meet its prespecified primary endpoint of an ORR ≥ 43%, the combination of lenvatinib and nivolumab demonstrated encouraging clinical activity with durable responses and prolonged overall survival in a subset of patients. Given the single-arm design, these find-ings should be considered exploratory and support further investigation of TKI/ICI combinations and biomarker-driven patient selection strategies in HCC.