In a groundbreaking real-world study, researchers have shed light on the comparative efficacy of a dual-drug regimen combining tislelizumab with lenvatinib against tislelizumab monotherapy in treating advanced hepatocellular carcinoma (HCC) patients who have experienced lenvatinib treatment failure. This investigation, carried out at a single center between 2019 and 2023, offers critical insights into optimizing second-line therapies for this aggressive liver cancer subtype, emphasizing the importance of personalized treatment strategies based on liver function status.
Hepatocellular carcinoma, especially at advanced stages, remains a formidable challenge in oncology due to its high mortality rates and often limited therapeutic options. Lenvatinib, a tyrosine kinase inhibitor targeting angiogenesis pathways, has been widely used as a first-line treatment, but resistance or failure commonly develops, necessitating effective second-line interventions. Tislelizumab, a programmed death-1 (PD-1) inhibitor, has surfaced as a promising agent in this therapeutic niche, with prior evidence supporting its antitumor activity through immune checkpoint blockade.
The study retrospectively analyzed 51 patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage C HCC who experienced disease progression after lenvatinib therapy. Patients were divided into two cohorts: those receiving a combination treatment of tislelizumab and lenvatinib (TL group) and those treated with tislelizumab monotherapy (T group). The primary endpoints evaluated were overall survival (OS) and progression-free survival (PFS), with secondary measures focusing on objective tumor responses and safety profiles.
Statistical analysis revealed a meaningful extension in PFS for the TL group, registering a median duration of 6.8 months versus 4.5 months observed in the T group, a difference bearing statistical significance (p=0.003). Similarly, OS was notably prolonged in the combination cohort, with patients surviving a median 14.0 months compared to 10.4 months among those on monotherapy (p=0.012). These findings underscore the potential synergistic effect of continuing lenvatinib alongside PD-1 blockade, even after initial lenvatinib resistance.
While the disease control rate was numerically superior in the TL cohort (64%) relative to monotherapy patients (53.8%), this difference did not achieve statistical significance (p=0.461). Likewise, the objective response rate favored the combination group (20% versus 7.7%), yet the p-value of 0.202 suggests more extensive studies are required to confirm definitive tumor shrinkage benefits. These nuances highlight the complex interplay between tumor biology and immune modulation, indicating the need for further biomarker-driven refinements.
An intriguing aspect of the study was the influence of liver function, assessed through the Child–Pugh classification, on therapy outcomes. Patients exhibiting better hepatic reserve (Child–Pugh A) derived a significant OS advantage from combination therapy, with median survival extending to 14.0 months compared to 12.0 months on monotherapy (p=0.013). Conversely, individuals with compromised hepatic function (Child–Pugh B) did not show statistically significant survival improvements, signaling the critical role of liver health in therapeutic efficacy and tolerability.
In exploring prognostic factors using Cox proportional hazards regression models, the researchers identified Child–Pugh B status and the choice of monotherapy as independent predictors of poor overall survival. Notably, for progression-free survival, only monotherapy was a negative prognostic factor, while impaired liver function did not exert a measurable impact. These findings suggest that immune-kinase inhibitor combination regimens may partially mitigate the deleterious consequences of hepatic insufficiency on disease progression, though survival remains vulnerable.
Safety profiles between the two groups displayed remarkable similarities, alleviating concerns over increased toxicity associated with combination treatment. The most frequently reported treatment-related adverse events (AEs) within the TL ensemble included hand–foot skin reactions (32%), hypertension (28%), diarrhea (32%), and hypothyroidism (20%). Approximately one in four patients experienced grade 3 or higher AEs, predominantly severe hand–foot reactions and diarrhea, yet these were manageable and did not dramatically affect adherence or quality of life.
The tolerability of the dual-agent approach is particularly promising given the delicate clinical balance in advanced HCC, where liver dysfunction often complicates the administration of aggressive therapies. The comparable AE incidence between groups reinforces the feasibility of employing tislelizumab plus lenvatinib as a second-line strategy, potentially reshaping clinical paradigms where monotherapy has traditionally prevailed after first-line failure.
Mechanistically, the continued use of lenvatinib alongside immune checkpoint inhibition may sustain antiangiogenic pressure on the tumor microenvironment, thereby enhancing immune cell infiltration and potentiating T-cell mediated cytotoxicity initiated by PD-1 blockade. This multifactorial mode of action aligns with emerging evidence supporting combined modality treatments to overcome immune resistance in hepatocellular carcinoma landscapes.
Moreover, the real-world nature of this analysis provides invaluable clarity on treatment effectiveness outside the rigid confines of controlled clinical trials, reflecting patient heterogeneity and the complexity of comorbidities typical in daily oncology practice. Although the retrospective design and single-center scope impose intrinsic limitations, the study’s robust statistical associations merit further prospective exploration and validation in diverse populations.
These findings hold significant clinical implications, advocating for a more nuanced approach to HCC management, integrating liver functional status alongside tumor biology to guide therapeutic decisions. For patients maintaining adequate hepatic reserves, the combination of tislelizumab and lenvatinib may offer a lifeline, extending survival and delaying progression with manageable side effects.
Future research should focus on elucidating biomarkers predictive of response to combination therapy to maximize patient selection precision. Additionally, trials investigating optimal dosing, scheduling, and potential integration with locoregional therapies could amplify the benefits observed and potentially transform standards of care in advanced liver cancer management.
In conclusion, the retrospective study compellingly demonstrates that in patients with advanced stage C hepatocellular carcinoma refractory to lenvatinib monotherapy, the addition of tislelizumab to lenvatinib confers significant survival benefits without compromising safety. The stratification by liver function highlights the necessity of personalized medicine in this domain and sets the stage for further innovations aiming to improve outcomes in this challenging patient population.
Subject of Research: Comparative efficacy and safety of tislelizumab plus lenvatinib versus tislelizumab monotherapy in advanced hepatocellular carcinoma after lenvatinib failure
Article Title: Comparative efficacy of tislelizumab plus lenvatinib and tislelizumab alone against advanced hepatocellular carcinoma after lenvatinib failure: a real-world study
Article References:
Yang, J., Xu, Q., Luo, S. et al. Comparative efficacy of tislelizumab plus lenvatinib and tislelizumab alone against advanced hepatocellular carcinoma after lenvatinib failure: a real-world study. BMC Cancer 25, 708 (2025). https://doi.org/10.1186/s12885-025-14092-1
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