Early safety analysis of the phase 3b SIERRA trial

Dr Willem Lybaert spoke at the ESMO GI 2025 congress with Prof Lorenza Rimassa about the SIERRA trial, a phase 3b study evaluating the safety and potential efficacy of the STRIDE regimen in patients with unresectable HCC who present with negative prognostic factors typically excluded from pivotal phase 3 trials such as HIMALAYA.

While the HIMALAYA trial demonstrated significant survival benefits for STRIDE in well-selected patients with preserved liver function, ECOG PS 0–1 and absence of main portal vein thrombosis, the SIERRA trial expands investigation into a broader, more representative patient population. Specifically, it includes patients with ECOG PS 2, Child-Pugh B7–B8, and/or main portal vein thrombosis (Vp4). These criteria reflect real-world scenarios more accurately, acknowledging that such patients are frequently encountered in clinical practice but often excluded from large RCTs.

The SIERRA trial enrolled 111 patients after screening 184, and an early safety analysis was conducted once approximately 60 patients had completed at least six months of follow-up. At ESMO-GI 2025, data from 98 patients were presented. This analysis is non-randomised, with unequal numbers across the three predefined subgroups. Despite the patients’ compromised clinical status, the safety profile of the STRIDE regimen was comparable to that observed in HIMALAYA. The incidence of grade 3–4 TRAEs remained within expected ranges, and discontinuation due to toxicity was not increased. Importantly, only 11% of patients required high-dose steroids to manage immune-related adverse events, reinforcing the tolerability of the regimen even in more fragile populations.

These interim findings are encouraging, particularly as the STRIDE regimen maintained a manageable safety profile despite the inclusion of patients with worse hepatic reserve and performance status. The study’s co-primary endpoints are grade 3–4 treatment-related adverse events and OS, with secondary endpoints including PFS, ORR, duration of response, time to response, and PROs related to quality of life. These forthcoming data will provide critical insights into both the efficacy and broader clinical utility of the STRIDE regimen in patients who more closely resemble those seen in daily oncology practice.

Prof Rimassa emphasised that, although preliminary, the safety results are reassuring and suggest that clinicians may cautiously consider STRIDE in select patients with poorer prognostic features, especially when clinical deterioration occurs between visits. However, definitive changes in clinical practice will depend on the final efficacy and safety outcomes, as well as quality-of-life measures that remain under investigation. The SIERRA trial thus fills a critical gap in HCC research by addressing a real-world population often excluded from conventional trials and could have important implications for future treatment guidelines.