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Nivolumab in combination with lenvatinib in unresectable hepatocellular carcinoma: The IKF-t006/IMMUNIB translational
Arndt Vogel1, Najib Ben Khaled2, Javier Ruiz Ramirez3
1Hannover Medical School, Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover, Germany; Princess Margaret Cancer Centre, University of Toronto, Canada.
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.
Insights
The combination of lenvatinib and nivolumab showed promising results for advanced hepatocellular carcinoma (HCC), with durable responses and prolonged survival in some patients, despite not meeting the primary response rate goal.
Area of Science:
- Hepatocellular Carcinoma Research
- Cancer Immunotherapy
- Targeted Cancer Therapy
Background:
- Anti-angiogenic agents and PD-1/PD-L1 inhibitors show efficacy in hepatocellular carcinoma (HCC).
- Lenvatinib and nivolumab combination therapy is being investigated for unresectable HCC.
Purpose of the Study:
- To evaluate the efficacy of lenvatinib plus nivolumab as a first-line treatment for unresectable HCC.
- To assess objective response rate (ORR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety.
Main Methods:
- A single-arm, phase-2 investigator-initiated trial (IMMUNIB) enrolled patients with advanced HCC.
- Patients received lenvatinib plus nivolumab for up to 18 months or until disease progression/toxicity.
- Primary endpoint was ORR by RECIST v1.1; secondary endpoints included PFS, OS, and safety.
Main Results:
- The objective response rate (ORR) was 32% (95% CI 19.5, 46.7).
- Median progression-free survival (PFS) was 9.0 months, and median overall survival (OS) was 26.6 months.
- Grade ≥3 treatment-related adverse events included colitis, diarrhea, hypertension, and elevated bilirubin.
Conclusions:
- The lenvatinib and nivolumab combination did not meet the primary endpoint of 43% ORR but showed encouraging clinical activity.
- Durable responses and prolonged OS were observed in a subset of patients.
- Findings support further investigation of TKI/ICI combinations and biomarker-driven selection in HCC.
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