Comparison of outcomes of second-line durvalumab plus tremelimumab and lenvatinib following first-line atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma

Abstract Background and Aim: The optimal second-line therapy following first-line atezolizumab plus bevacizumab (Atezo/Beva) remains unascertained. This study compared second-line durvalumab plus tremelimumab (Dur/Tre) with lenvatinib (Len) after first-line Atezo/Beva in unresectable hepatocellular carcinoma (uHCC). Methods: This prospectively registered cohort study analyzed patients with uHCC who received Dur/Tre (n = 14) or Len (n = 67) as second-line therapy after first-line Atezo/Beva. Tumor response was assessed by RECIST version 1.1. Progression-free survival (PFS), overall survival (OS), adverse events (AEs), and changes in the albumin–bilirubin (ALBI) score were compared. Results: The objective response rate and disease control rate were 7.7% and 15.4% in the Dur/Tre group, and 23.3% and 76.7% in the Len group, respectively; median PFS was 1.7 vs. 4.2 months ( p < 0.001) and median OS was 5.3 vs. 14.0 months ( p = 0.047) in the Dur/Tre and Len groups, both significantly favoring Len. Multivariable analysis showed that Len treatment and neutrophil-to-lymphocyte ratio ≥3 were independent predictors of longer PFS and worse OS, respectively. Grade ≥3 AEs were more frequent with Len than with Dur/Tre (70.1% vs. 21.4%; p = 0.002). At week 4, the ALBI score did not worsen with Dur/Tre (−2.30 to −2.21; p = 0.318) but worsened with Len (−2.36 to −1.97; p < 0.001). Conclusions: After first-line Atezo/Beva, second-line Len achieved superior disease control and longer survival than Dur/Tre. However, grade ≥ 3 AEs were more frequent with Len than with Dur/Tre, and careful management of AEs is essential when choosing therapy for individual patients.