Physical Activity Improves Outcomes of Combined Lenvatinib Plus Anti-PD-1 Therapy In Patients With Unresectable Hepatocellular Carcinoma

Abstract Background: Adaptive resistance is one of the major hinderances for unresectable hepatocellular carcinoma (HCC) treated with lenvatinib and anti-programmed cell death protein 1 (anti-PD-1) therapy. Physical activity is known to have anti-cancer effects, including immunomodulatory actions, influencing patients’ outcomes. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC. Methods: The physical activity levels of patients with unresectable HCC treated with combination therapy using lenvatinib plus anti-PD-1 antibodies were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS), analyzed using the Kaplan-Meier method with a log-rank test. Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). Factors associated with survival and ORR were analyzed using regression analyses. A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter. Results: Fifty-nine patients with unresectable HCC were categorized to active (n=28) or sedentary (n=31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI, 0.060-0.799) and PFS (HR = 0.158, 95% CI, 0.044-0.562) and higher ORR (OR = 4.571, 95% CI, 1.482-14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy. Conclusions: Regular physical activity was associated with improved outcomes in patients receiving combined lenvatinib plus anti-PD-1 therapy for unresectable HCC. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.