Patients with unresectable hepatocellular carcinoma often require systemic therapy, particularly when disease is advanced or unsuitable for locoregional treatment. Immune checkpoint inhibitors and anti-angiogenic agents have reshaped first-line treatment in HCC, but reliable biomarkers for treatment selection remain limited. A phase 2 translational study evaluated nivolumab plus lenvatinib as first-line therapy in patients with unresectable hepatocellular carcinoma.
The original article, titled “Nivolumab in combination with lenvatinib in unresectable hepatocellular carcinoma: the IKF-t006/IMMUNIB translational phase-2 study,” was published as an Article in Press in the European Journal of Cancer on June 3, 2026.
Authors: Arndt Vogel, Najib Ben Khaled, Javier Ruiz Ramirez, Silke Marhenke, Gabriele Siegler, Jürgen Siebler, Udo Lindig, Gregory Schwartz, Michael Schultheiss, Tobias Mueller, Henry Simon, Enrico N. De Toni, Daniel Karl, Salah-E. Al-Batran, and Anna Saborowski.
Why This Study Matters
Lenvatinib is an established first-line tyrosine kinase inhibitor for unresectable HCC, based on the REFLECT trial, where lenvatinib was non-inferior to sorafenib for overall survival and showed longer progression-free survival and higher objective response rates. PD-1 blockade has also shown activity in advanced HCC. In CheckMate-040, nivolumab demonstrated durable responses, although the later CheckMate-459 phase 3 trial did not show superiority over sorafenib.
The first-line treatment landscape has continued to evolve with immune-based combinations. IMbrave150 established atezolizumab plus bevacizumab as a standard first-line option, while LEAP-002 did not show superiority for lenvatinib plus pembrolizumab over lenvatinib alone. More recently, LEAP-012 showed improved outcomes with TACE combined with lenvatinib plus pembrolizumab in unresectable, non-metastatic HCC.
IMMUNIB was designed to evaluate whether combining lenvatinib with nivolumab could improve response outcomes in first-line unresectable HCC, while also exploring plasma epigenomic and tissue transcriptomic biomarkers associated with treatment benefit.
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Study Design
IMMUNIB was an investigator-initiated, prospective, non-randomized, open-label, multicenter, single-arm phase 2 study. Eligible patients had histologically confirmed unresectable, multinodular hepatocellular carcinoma, Child-Pugh score ≤6, ECOG performance status ≤1, and adequate hematologic, hepatic, and renal function. The study included patients with BCLC-B disease unsuitable for locoregional therapy and patients with BCLC-C disease.
Patients received oral lenvatinib once daily at 8 mg for body weight below 60 kg or 12 mg for body weight of at least 60 kg, combined with intravenous nivolumab 240 mg every 2 weeks. Treatment was continued for a maximum of 18 months or until disease progression, unacceptable toxicity, death, or patient request.
The primary endpoint was objective response rate according to investigator-assessed 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, progression-free survival, overall survival, and safety.
Patient Population
Between June 2019 and May 2021, 61 patients were assessed for eligibility. A total of 50 patients were enrolled, and 49 received at least one dose of study treatment. The median age was 65 years. Most patients were male, had ECOG performance status 0, and had preserved liver function. Child-Pugh score was 5 in 84% of patients and 6 in 16%. According to BCLC stage, 24 patients had BCLC-B disease, 18 had BCLC-C disease, 7 were not evaluable, and 1 had missing staging information.
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Efficacy Results
The trial did not meet its prespecified primary endpoint. In the intention-to-treat population, the objective response rate was 32% with a 95% confidence interval of 19.5% to 46.7%. Responses included 3 complete responses and 13 partial responses. In the response-evaluable population of 43 patients, the ORR was 37%.
Median follow-up for the entire cohort was 21.3 months. Among surviving patients, median follow-up was 53.5 months. Median time to progression was 9.9 months. Median progression-free survival was 9.0 months, and median overall survival was 26.6 months. At the last follow-up, 17 patients were still alive. At the 48-month landmark, 11 of 50 patients remained alive, including 2 patients without evidence of disease progression.
The authors noted that the ORR was numerically higher than historical results reported with lenvatinib or nivolumab monotherapy, including data from REFLECT and CheckMate-459, and was broadly comparable to response rates reported with lenvatinib plus pembrolizumab in LEAP-002 and atezolizumab plus bevacizumab in IMbrave150. However, because IMMUNIB was a single-arm phase 2 study, these comparisons remain exploratory.
Safety
All 49 patients included in the safety analysis experienced at least one adverse event. Overall, 582 adverse events were reported, including 302 considered treatment-related.
There were 56 serious adverse events, of which 23 were considered treatment-related. Two fatal serious adverse events occurred, one due to bowel perforation and one due to acute kidney injury, but neither was considered treatment-related by the investigators.
The most common adverse events occurring in at least 20% of patients included diarrhea, fatigue, increased blood bilirubin, oral mucositis, nausea, hypothyroidism, and hypertension.
Grade 3 or higher adverse events occurring in at least 10% of patients included diarrhea, hypertension, and increased gamma-glutamyl transferase. Recurrent grade 3 or higher treatment-related adverse events included colitis, diarrhea, hypertension, and elevated bilirubin. No new safety signals were reported, and the toxicity profile was considered consistent with the known safety profiles of lenvatinib and nivolumab.
Translational Findings
IMMUNIB also included exploratory plasma-based epigenomic profiling and tissue-based transcriptomic analysis. The analysis suggested that FGFR pathway activation, including FGF19 and FGFR4-related signals, may be associated with treatment benefit in selected patients.
Plasma epigenomic profiling also identified immune and inflammatory signatures, including interferon-gamma–related pathways, associated with more durable progression-free survival. These findings remain exploratory because tissue and blood samples were available only for a limited number of patients and require validation in larger prospective studies.
Clinical Context
The IMMUNIB results were interpreted within a rapidly evolving HCC treatment landscape. Lenvatinib was established as a first-line option in unresectable HCC based on REFLECT, while nivolumab showed durable activity in CheckMate-040 but did not demonstrate superiority over sorafenib in CheckMate-459.
More recent phase 3 studies have further shaped the field. IMbrave150 established atezolizumab plus bevacizumab as a standard first-line regimen, whereas LEAP-002 did not show superiority for lenvatinib plus pembrolizumab over lenvatinib alone. The original article also discussed ongoing questions around immune-based combinations with local therapy, including LEAP-012 and EMERALD-3, as well as treatment strategies after progression on atezolizumab plus bevacizumab, including IMbrave251.
You can read about IMbrave251 at ASCO 2026 on OncoDaily.
Takeaway
IMMUNIB did not meet its prespecified primary endpoint of achieving an ORR of at least 43%. However, nivolumab plus lenvatinib showed clinically meaningful activity, with an ORR of 32%, median PFS of 9.0 months, and median OS of 26.6 months in patients with unresectable HCC.
The results should be interpreted as exploratory because of the single-arm design, but the study provides a mature clinical and translational dataset supporting further research into biomarker-driven use of TKI–immunotherapy combinations in hepatocellular carcinoma.
The full article is available in the European Journal of Cancer.
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