Unresectable Hepatocellular Carcinoma Care: Investigating a Combination Therapy

The latest phase II clinical study investigating the combination of envafolimab and lenvatinib for unresectable hepatocellular carcinoma (HCC) offers compelling data on efficacy and safety, positioning this regimen as a potential new first-line treatment option. While systemic therapy remains the primary choice for advanced HCC, the combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents continues to garner attention for its therapeutic potential.

How the Study Was Designed

This single-arm, multicenter study enrolled 36 patients. Out of that group, 30 received a combination therapy of the subcutaneous PD-L1 inhibitor envafolimab and the oral kinase inhibitor lenvatinib.

Patients met strict eligibility criteria, including an ECOG performance status of less than or equal to one and Child-Pugh score of less than or equal to seven, ensuring a relatively homogenous cohort. The study’s primary endpoint was overall survival (OS), with secondary assessments including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.

What the Study Found

When it comes to the results, key findings were compared to levatinib monotherapy, a previous first-line treatment examined in the REFLECT trial, and included:

• Median OS of 18.5 months with combination therapy versus 13.6 months with lenvatinib monotherapy.
• Median PFD of 9.4 months with combination therapy versus 7.4 months with lenvatinib monotherapy.
• ORR of 40 percent with combination therapy versus 24.1 percent with lenvatinib monotherapy.
• DCR of 80 percent with combination therapy; DCR of levatinib monotherapy was not specified.

These findings suggest that adding envafolimab enhances the anti-tumor activity of lenvatinib, likely due to the latter’s immunomodulatory properties that may amplify the efficacy of ICIs.

Additionally, safety remains a crucial consideration in systemic therapy for HCC, and while the study reported a treatment-related adverse event (TRAE) incidence of 76.7 percent, the majority were manageable. Grade three or higher TRAEs were observed in 30 percent of patients, with elevated aspartate aminotransferase being the most common at 23.3 percent.

Notably, there were also no treatment-related deaths, and dose adjustments helped mitigate severe toxicities. These findings align with prior studies of envafolimab and lenvatinib, supporting the regimen’s tolerability profile.

What These Results Mean for Clinical Practice

Beyond its efficacy and safety profiles, envafolimab's subcutaneous administration offers a distinct advantage over conventional ICIs, which require intravenous infusion. This method reduces treatment burden, potentially improving patient compliance.

However, while the study presents promising data, certain limitations warrant consideration. Its single-arm design precludes direct comparisons with standard treatments, and the sample size (n=30) is relatively small. Larger, randomized controlled trials are necessary to validate these findings and establish a definitive role for envafolimab-lenvatinib combination therapy in clinical practice. Additionally, biomarker-driven patient selection remains an area of ongoing research, as identifying predictive factors could optimize therapeutic outcomes.

In the evolving landscape of HCC treatment, immune-combination strategies continue to shape the standard of care, and the envafolimab-lenvatinib regimen contributes to this shift. For oncologists and healthcare professionals, these findings represent an exciting development in the pursuit of more effective, tolerable, and accessible treatment options for unresectable HCC.

Reference:

1. Jiang Y, Su K, Li H, et al. Efficacy and safety of the combination of envafolimab and lenvatinib in unresectable hepatocellular carcinoma: a single-arm, multicentre, exploratory phase II clinical study. Investigational New Drugs. Published online December 17, 2024. doi:https://doi.org/10.1007/s10637-024-01468-6