Background and aims Atezolizumab plus bevacizumab (A+B) and STRIDE (tremelimumab plus durvalumab) represent two of the approved first-line immunotherapy strategies for unresectable hepatocellular carcinoma (HCC). As no head-to-head trial exists, we assessed temporal differences in survival benefit using complementary analytic frameworks. Methods Three independent analyses were conducted: (1) anchored indirect comparison using reconstructed survival from IMbrave150 and HIMALAYA; (2) a real-world A+B cohort (n = 883) weighted via MAIC to match STRIDE baseline characteristics; and (3) a propensity-matched population-level dataset from TriNetX (n = 309 per arm). Time-interval hazard ratios (HRs), RMST, and conditional landmark survival were calculated. Proportional hazards were assessed by Schoenfeld testing; pooled interval HRs were synthesized through meta-analysis. Results Across all models, A+B showed a consistent early advantage. In the first 6 months, the pooled HR favored A+B (0.75; 95% CI 0.64–0.88), with absolute survival differences of + 5–7%. From 6–12 months, HRs remained numerically favorable but non-significant. Between 12 and 24 months, pooled HRs approached neutrality (0.93–1.06), with confidence intervals crossing unity and no meaningful absolute survival differences. Beyond 24–36 months, the effect reversed in favor of STRIDE (anchored HR 1.41; RWD HR 2.52; TriNetX HR 1.47). Meta-analysis confirmed a progressive late benefit for STRIDE from 36 to 60 months (pooled HR 1.54–1.75). Schoenfeld tests indicated time-dependent effects in all frameworks (p < 0.05), and ΔRMST trajectories were highly concordant (Pearson r > 0.97). Conclusions A+B is associated with stronger early tumor control, while STRIDE provides more durable long-term survival beyond 2–3 years. These findings support selecting therapy based on temporal treatment objectives and advocate for biomarkers predicting early versus sustained treatment benefit.
Early and late survival dynamics of immunotherapy combinations in advanced HCC: Anchored indirect comparison of atezolizumab plus bevacizumab versus durvalumab + tremelimumab
Scartozzi M.;Persano M.;
2026-01-01
Abstract
Background and aims Atezolizumab plus bevacizumab (A+B) and STRIDE (tremelimumab plus durvalumab) represent two of the approved first-line immunotherapy strategies for unresectable hepatocellular carcinoma (HCC). As no head-to-head trial exists, we assessed temporal differences in survival benefit using complementary analytic frameworks. Methods Three independent analyses were conducted: (1) anchored indirect comparison using reconstructed survival from IMbrave150 and HIMALAYA; (2) a real-world A+B cohort (n = 883) weighted via MAIC to match STRIDE baseline characteristics; and (3) a propensity-matched population-level dataset from TriNetX (n = 309 per arm). Time-interval hazard ratios (HRs), RMST, and conditional landmark survival were calculated. Proportional hazards were assessed by Schoenfeld testing; pooled interval HRs were synthesized through meta-analysis. Results Across all models, A+B showed a consistent early advantage. In the first 6 months, the pooled HR favored A+B (0.75; 95% CI 0.64–0.88), with absolute survival differences of + 5–7%. From 6–12 months, HRs remained numerically favorable but non-significant. Between 12 and 24 months, pooled HRs approached neutrality (0.93–1.06), with confidence intervals crossing unity and no meaningful absolute survival differences. Beyond 24–36 months, the effect reversed in favor of STRIDE (anchored HR 1.41; RWD HR 2.52; TriNetX HR 1.47). Meta-analysis confirmed a progressive late benefit for STRIDE from 36 to 60 months (pooled HR 1.54–1.75). Schoenfeld tests indicated time-dependent effects in all frameworks (p < 0.05), and ΔRMST trajectories were highly concordant (Pearson r > 0.97). Conclusions A+B is associated with stronger early tumor control, while STRIDE provides more durable long-term survival beyond 2–3 years. These findings support selecting therapy based on temporal treatment objectives and advocate for biomarkers predicting early versus sustained treatment benefit.
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