Immune-mediated adverse events and overall survival with tremelimumab plus durvalumab and durvalumab monotherapy in unresectable hepatocellular carcinoma: HIMALAYA phase 3 randomized clinical trial

Background and Aims: In the global, Phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (HCC), STRIDE significantly improved overall survival (OS) versus sorafenib; durvalumab was noninferior to sorafenib. Immune checkpoint inhibitor studies have shown an association between the occurrence of immune-mediated adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA. Approach and Results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS hazard ratios (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56-0.95) for STRIDE and 1.14 (0.82-1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1-46.7) and 27.7% (22.4-34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation. Conclusions: Participants who experienced imAEs with STRIDE had a numerical improvement in OS versus those who did not, which was not observed for durvalumab. Long-term OS with STRIDE was observed regardless of imAEs. Most imAEs were low grade, manageable, and occurred in the first 3 months after treatment initiation. Results continue to support the benefits of STRIDE in a diverse population that reflects unresectable HCC globally.