e14544 Background: Preclinical data suggest that β-adrenergic signaling may impair antitumor immunity and modulate responses to immune checkpoint inhibitors (ICIs). Whether beta-blockers influence ICI effectiveness in routine practice remains uncertain. We investigated the association between beta-blocker use at ICI initiation and survival outcomes across advanced solid tumors. Methods: Adults (≥18 years) with advanced solid tumors initiating PD-1/PD-L1/CTLA-4 therapy (2014–2024) were identified from the TriNetX Research Network. Beta-blocker exposure was defined as prescription within −90 to +30 days of first ICI administration. Propensity score matching (1:1) balanced demographics, tumor type, comorbidity, and concomitant medications. Co-primary endpoints were overall survival (OS) at 1 and 5 years; secondary endpoints included time to next systemic therapy or death (TTNTD) and immune-related adverse events (irAEs) based on diagnostic codes. A 30-day landmark excluded early mortality bias. Kaplan–Meier and log-rank tests were used for comparisons. Results: Before matching, 20,612 patients received beta-blockers and 56,578 did not; after matching, 18,217 per group. At 5 years, OS was lower with beta-blockers (30% vs 32%, p < 0.0001; median 17.1 vs 22.3 months) and 1-year OS was similarly reduced (57% vs 63%, p < 0.0001). TTNTD was shorter (15.5 vs 20.2 months). The composite rate of irAEs was modestly higher with beta-blockers (44% vs 42%, p < 0.0001) with earlier onset (median 19.3 vs 21.1 months). In the 30-day landmark analysis, OS differences persisted (5-year: 32% vs 33%, p < 0.0001; median 20.0 vs 24.7 months; 1-year: 61% vs 66%, p < 0.0001). TTNTD remained shorter (18.7 vs 22.6 months, p < 0.0001), and irAE rates were similar (40.5% vs 39.6%, p = 0.061) with no difference in time to irAE. To our knowledge, this represents the largest real-world analysis to date evaluating beta-blocker exposure at ICI initiation across solid tumors. The direction of association contrasts with preclinical expectations and selected small clinical series reporting potential benefit, highlighting the importance of context and prospective validation. Conclusions: Beta-blocker exposure at ICI initiation was associated with inferior survival and reduced treatment durability. This suggests caution when extrapolating preclinical hypotheses regarding β blockade and reinforce the need for prospective subtype-specific evaluation of beta-blockers as immunomodulatory agents. Residual confounding and selection bias cannot be fully excluded given the retrospective real-world design. Key matched clinical outcomes comparing beta-blocker vs no beta-blocker exposure at ICI initiation. Outcome Beta-Blocker No Beta-Blocker p-value 1-yr OS 57% 63% <0.0001 5-yr OS 30% 32% <0.0001 Median OS 17.1 mo 22.3 mo — Median TTNTD 15.5 mo 20.2 mo — irAE composite 44% 42% <0.0001
Syed et al. (Thu,) studied this question.
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