TOPLINE:

In a single-arm phase 2 trial, lenvatinib combined with nivolumab could not achieve the prespecified objective response rate (ORR) but showed a durable response and enhanced survival outcomes in patients with unresectable advanced hepatocellular carcinoma (HCC).

METHODOLOGY:

• Researchers conducted an investigator-initiated, single-arm phase 2 trial including 50 adult patients with advanced-stage HCC for first-line therapy across multiple centres in Germany between June 2019 and May 2021.
• Patients received lenvatinib orally once daily (8 mg for those with body weight < 60 kg and 12 mg for those with body weight ≥ 60 kg) with intravenous nivolumab every 2 weeks (240 mg) for a maximum of 18 months or until the earliest of disease progression, death, unacceptable toxicity, or termination at the patient's request.
• The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors version 1.1, with the study powered to detect an ORR of 43% using a prespecified null hypothesis ORR of 24%.
• Secondary endpoints were the time to progression, progression-free survival, overall survival, and safety, with tumour assessments performed every 10 weeks during treatment and every 12 weeks during follow-up.
• Exploratory translational analyses utilised plasma-based epigenomic profiling and tissue-based transcriptome profiling to identify molecular markers of treatment response.

TAKEAWAY:

• The overall ORR was 32% (95% CI, 19.5%-46.7%), with three complete responses and 13 partial responses, falling short of the prespecified threshold of 43% but numerically higher than historical monotherapy data.
• The median progression-free survival was 9.0 months (95% CI, 4.99-13.08) based on 36 events, and the median time to progression was 9.9 months (95% CI, 6.87-13.14) based on 27 events.
• The median overall survival reached 26.6 months (95% CI, 16.03-41.59) based on 33 events; 17 patients were still alive at the last follow-up, with two remaining free of progression. The most common adverse events included diarrhoea, fatigue, elevated blood bilirubin levels, oral mucositis, nausea, hypothyroidism, and hypertension.
• Plasma-based epigenomic profiling identified elevated activation of the fibroblast growth factor receptor pathway and inflammatory signals associated with improved and durable treatment benefit.

IN PRACTICE:

"Our study provides a proof of concept for the utility of liquid biopsy-based epigenetic profiling as a minimally invasive method for biomarker discovery, patient selection, and monitoring of response and resistance," the authors wrote, adding that "these insights require validation in ongoing prospective phase-3 trials with larger and more diverse patient populations."

SOURCE:

This study was led by Arndt Vogel, MD, PhD, Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hanover, Germany. It was published online on June 03, 2026, in the European Journal of Cancer.

LIMITATIONS:

The single-arm design of the study and the absence of blinding may have introduced bias. Additionally, tissue and blood samples were available for only a limited number of patients, restricting the translational analyses.

DISCLOSURES:

This study was funded by Eisai GmbH, Bristol Myers Squibb GmbH & Co. KGaA, and the Frankfurt Institute of Clinical Cancer Research IKF GmbH. One author reported receiving honoraria for lectures, presentations, and educational events and participating in advisory boards for multiple pharmaceutical companies, including Eisai, Zymeworks, Biologix, BMS, AbbVie, and others. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.