Lenvatinib plus PD-1 inhibitor improves survival versus bevacizumab plus PD-1 inhibitor in unresectable hepatocellular carcinoma

This systematic review and meta-analysis focused on first-line treatment strategies for unresectable hepatocellular carcinoma. The analysis included data from 1659 patients drawn from retrospective cohort studies. The population of interest was specifically East Asian populations. The study design aggregated evidence to compare two distinct therapeutic approaches involving immune checkpoint inhibitors. One arm utilized a lenvatinib-based regimen in combination with PD-1/PD-L1 inhibitors. The comparator arm utilized a bevacizumab-based regimen in combination with PD-1/PD-L1 inhibitors. The primary outcomes assessed were overall survival and progression-free survival. Secondary outcomes included objective response rate, disease control rate, and adverse events. The follow-up duration was not reported in the source data.

The primary outcome analysis revealed a significant difference in overall survival between the two groups. Patients receiving the lenvatinib-based regimen experienced significantly prolonged overall survival compared with those receiving the bevacizumab-based regimen. The hazard ratio for overall survival was 0.69. The 95% confidence interval ranged from 0.5 to 0.95. The p-value was 0.023. This direction of effect was favorable for the lenvatinib-based regimen. Progression-free survival also demonstrated a statistically significant benefit for the lenvatinib-based regimen. The hazard ratio for progression-free survival was 0.73. The 95% confidence interval ranged from 0.59 to 0.9. The p-value was 0.004. This direction of effect was also favorable for the lenvatinib-based regimen.

Secondary outcomes showed no significant differences between the two groups regarding tumor response metrics. There was no significant difference in objective response rate between the lenvatinib-based and bevacizumab-based regimens. The relative risk was 1.09. The 95% confidence interval ranged from 0.91 to 1.31. The p-value was 0.304. Similarly, there was no significant difference in disease control rate. The relative risk was 0.99. The 95% confidence interval ranged from 0.92 to 1.06. The p-value was 0.532. These results indicate that while survival benefits were observed, the rate of tumor shrinkage or stable disease did not differ significantly between the regimens.

Safety and tolerability findings indicated that the overall incidence of adverse events was comparable between the two groups. However, specific adverse event profiles differed. The lenvatinib-based regimen was associated with a higher incidence of hand-foot skin reaction. The lenvatinib-based regimen was also associated with a higher incidence of neutropenia. Conversely, the bevacizumab-based regimen carried a higher risk of gastrointestinal haemorrhage. Serious adverse events were not reported in the source data. Discontinuations were not reported. Tolerability was not reported.

These results must be interpreted within the context of prior landmark studies in hepatocellular carcinoma therapy. Previous trials have established the efficacy of single-agent lenvatinib and bevacizumab in this setting. The addition of PD-1/PD-L1 inhibitors represents a newer standard of care. This meta-analysis suggests that the choice of tyrosine kinase inhibitor may influence survival outcomes when combined with immunotherapy. The findings align with the general understanding that lenvatinib and bevacizumab have different toxicity profiles. The survival advantage observed here supports the potential superiority of lenvatinib in this specific population.

Key methodological limitations include the reliance on retrospective cohort studies. Retrospective designs are prone to selection bias and confounding variables. The findings require confirmation in large-scale, prospective, multinational randomized controlled trials. Such trials are necessary to validate these results in other populations beyond East Asian groups. The lack of reported follow-up duration limits the ability to assess long-term durability of response. Funding sources and conflicts of interest were not reported.

Clinical implications suggest that lenvatinib plus PD-1/PD-L1 inhibitor regimens were associated with superior overall survival and progression-free survival compared with bevacizumab plus PD-1/PD-L1 inhibitor regimens. This observation applies specifically to first-line regimen use for unresectable hepatocellular carcinoma in East Asian populations. Practitioners should consider these data when evaluating treatment options for eligible patients. However, the evidence base remains observational in nature. Questions remain unanswered regarding the applicability of these findings to Western populations. Long-term safety data beyond the reported adverse events are also lacking. Further research is needed to determine if these survival benefits translate into improved quality of life or overall survival in diverse global cohorts.