Biomarker-Guided Therapy May Improve Treatment Selection in Hepatocellular Carcinoma
Clinical Summary:
- Design/Population: The phase 2 IMMUNIB trial evaluated first-line lenvatinib plus nivolumab in patients with unresectable hepatocellular carcinoma. Exploratory plasma-based epigenomic and tissue transcriptomic analyses were performed to identify biomarkers associated with treatment benefit.
- Key Outcomes: Although the primary end point was not met, the combination demonstrated encouraging clinical activity, with a 32% objective response rate and prolonged survival. Exploratory analyses identified FGFR and immune/inflammatory signatures associated with treatment benefit.
- Clinical Relevance: These findings demonstrate encouraging activity for lenvatinib plus nivolumab in a subset of patients and support further investigation of biomarker-driven treatment selection for tyrosine kinase inhibitor/immunotherapy combinations in hepatocellular carcinoma.
Arndt Vogel, MD, University of Toronto, Canada, discusses results from the phase 2 IMMUNIB trial evaluating first-line lenvatinib plus nivolumab in patients with unresectable hepatocellular carcinoma and the potential role of molecular biomarkers in identifying patients most likely to benefit from combination therapy.
Although the study did not achieve its prespecified objective response rate end point, the combination demonstrated encouraging clinical activity, with durable survival observed in a subset of patients. Dr Vogel also reviews exploratory translational analyses showing that FGFR activation and immune- and inflammatory-related gene signatures were associated with long-term treatment benefit, highlighting the potential for biomarker-guided treatment selection in hepatocellular carcinoma.
Transcript:
Hello, my name is Arndt Vogel. I'm a gastroenterologist by training, working as a GI oncologist in Toronto, Canada. I would like to share with you some of our data from the IMMUNIB study, which we conducted as a multicenter study in Germany.
In this study, 50 patients were included and treated with the combination of lenvatinib and nivolumab in the first-line setting of hepatocellular carcinoma. We started this study when no phase 3 data were available for the combination of lenvatinib with a checkpoint inhibitor. We asked the question: can we increase the response rate with the combination over what we have seen with the single drug?
The response rate was 32%, which was actually quite impressive. However, it did not reach the threshold we had defined upfront for clinical efficacy. The median progression-free survival was 9 months, and the median overall survival was 26.6 months. So all the efficacy data, I think, clearly highlight that there is efficacy for this combination, albeit we have to acknowledge that it's a negative study because it did not meet the predefined end point for overall response rate. So what can we do with this study?
I think we've now also seen the LEAP study, which has been published. In the LEAP study, lenvatinib and pembrolizumab were combined, and the combination did not show superior efficacy over lenvatinib alone. So we still have this problem that when we combine drugs, even if we have a scientific rationale, we do not always see additive effects or synergy for the combination in our patients. Therefore, I think it's really important to have biomarkers to select the patients who really benefit from this treatment.
We also have to recognize that there were some long-term survivors. We now have follow-up of more than 60 months for some of these patients, and there were patients with survival of more than 3, 4, and even 5 years. We need to identify these patients upfront. To do that, we included a translational program in the study and performed epigenomic profiling.
Interestingly, we identified two signatures that were associated with long-term benefit. One was FGFR signaling, which makes a lot of sense because we used lenvatinib, an FGFR inhibitor. The other signature was related to inflammation and interferon-gamma signaling, which also makes sense because we used a checkpoint inhibitor. I think these data show that it is feasible, first, to analyze these combinations in investigator-initiated trials and, second, to conduct biomarker research. This is something that we really need in hepatocellular carcinoma.
We now have several interesting combinations that have shown activity in both the first-line and second-line settings, but we still do not have biomarkers that help us select patients for one specific treatment. I think what we have shown is that biomarker research is feasible. Of course, these data from a small investigator-initiated trial need to be confirmed in larger phase 3 studies.
Hopefully, going forward, we will be able to apply all of the omics technologies that we have today, based on both tissue profiling and blood profiling, to identify biomarkers that help us select patients for specific treatments.
Source:
Vogel A, Khaled NB, Ramirez JR, et al. Nivolumab in combination with lenvatinib in unresectable hepatocellular carcinoma: The IKF-t006/IMMUNIB translational phase-2 study. Eur J Cancer. Published online: June 3, 2026. doi: 10.1016/j.ejca.2026.116847
