A new retrospective analysis comparing anti-angiogenic agents in hepatocellular carcinoma (HCC) treatment has revealed significant efficacy advantages for lenvatinib-based combinations over bevacizumab regimens when combined with PD-1/L1 inhibitors and hepatic arterial infusion chemotherapy (HAIC).
The multi-center study, conducted across three medical sites in China, analyzed 216 patients with unresectable HCC using propensity score matching to compare lenvatinib plus PD-1/L1 antibodies and HAIC (LenHAP) against bevacizumab plus PD-1/L1 antibodies and HAIC (BevHAP). The patient population was predominantly BCLC stage C (75.5%), with 46.8% having Vp3-4 portal vein tumor thrombosis and 31.5% presenting with metastasis.
Survival and Response Outcomes
The LenHAP group demonstrated significantly longer progression-free survival at 12.6 months compared to 8.1 months for BevHAP (HR 0.64, 95% CI 0.46-0.90, p=0.0085). While overall survival showed a favorable trend for LenHAP at 26.4 months versus 19.6 months for BevHAP, the difference did not reach statistical significance (HR 0.71, 95% CI 0.41-1.1, p=0.091).
Treatment response rates favored the lenvatinib combination, with confirmed objective response rates of 62.0% versus 49.1% per RECIST v1.1 criteria, though this difference approached but did not reach significance (p=0.055). However, using modified RECIST criteria, LenHAP achieved significantly higher response rates at 83.3% compared to 68.5% for BevHAP (p=0.028).
Enhanced Benefits in Potentially Resectable Patients
Patients with potentially resectable features (PotenR) experienced particularly pronounced benefits from lenvatinib therapy. In this subgroup, LenHAP reduced the risk of death by 67% (HR 0.33, 95% CI 0.13-0.85, p=0.018) and disease progression by 55% (HR 0.45, 95% CI 0.23-0.85, p=0.0067) compared to BevHAP.
Critically, the conversion resection rate was significantly higher with LenHAP at 52.6% versus 25.0% for BevHAP (p=0.015) among PotenR patients. This finding has important clinical implications, as conversion to resectable disease can substantially improve long-term outcomes in HCC patients.
Safety Profile Comparison
The safety profiles differed between the two regimens, with LenHAP showing higher rates of hand-foot syndrome (32.4% vs 3.7%, p<0.001) and grade 3-4 hand-foot syndrome (7.4% vs 0%, p=0.007). Conversely, BevHAP was associated with higher rates of upper gastrointestinal bleeding (4.6% vs 0.9%) and anemia (75.9% vs 65.7%). Overall, the incidence of grade 3-4 adverse events was similar between groups (47.2% vs 39.8%, p=0.27), with no treatment-related deaths reported.
Indirect Comparison Validates Findings
A separate matching-adjusted indirect comparison (MAIC) analysis comparing tislelizumab plus lenvatinib against sintilimab plus bevacizumab biosimilar in Chinese patients provided additional support for lenvatinib-based combinations. This analysis of 62 patients from the BGB-A317-211 study compared against 380 patients from the ORIENT-32 trial showed significant advantages for the tislelizumab-lenvatinib combination.
After adjusting for baseline characteristics, tislelizumab plus lenvatinib demonstrated superior objective response rates (39.8% vs 21.0%, OR 2.56, 95% CI 1.40-4.63, p=0.0027) and disease control rates (OR 3.81, 95% CI 1.62-11.20, p=0.0013) compared to sintilimab plus bevacizumab biosimilar.
The survival benefits were equally impressive, with tislelizumab plus lenvatinib showing significantly longer progression-free survival (9.6 vs 4.6 months, HR 0.56, 95% CI 0.37-0.84, p=0.0054) and overall survival (HR 0.43, 95% CI 0.25-0.74, p=0.0023).
Clinical Implications
These findings suggest that lenvatinib-based combinations may offer superior efficacy compared to bevacizumab regimens in unresectable HCC, particularly for patients with potentially resectable features. The higher conversion resection rates observed with lenvatinib therapy could translate into improved long-term outcomes for carefully selected patients.
The mechanistic differences between lenvatinib and bevacizumab may explain the observed efficacy differences. Lenvatinib is a multi-targeted tyrosine kinase inhibitor affecting multiple pathways including VEGF receptors, fibroblast growth factor receptors, and other key signaling cascades, while bevacizumab specifically targets VEGF-A.
However, both studies acknowledge limitations including their retrospective nature, limited follow-up time, and potential confounding factors. The researchers emphasize that prospective randomized controlled trials will be necessary to definitively establish the comparative efficacy of these treatment approaches in unresectable HCC.
