Overall and Line-Specific Impact of Targeted Therapies in Advanced Biliary Tract Cancer After Chemoimmunotherapy Failure.

BACKGROUND & AIMS: The effectiveness and optimal timing of matched targeted therapy after first-line chemoimmunotherapy in biliary tract cancer (BTC) remain uncertain. We evaluated access to matched agents and line-specific outcomes. METHODS: This retrospective study included 1,358 patients with advanced BTC treated with first-line cisplatin, gemcitabine, and durvalumab at 55 centers in 12 countries. Actionable alterations were defined as ESCAT tier I. The principal post-progression analysis excluded patients receiving best supportive care only and compared matched targeted therapy with active non-targeted treatment. Outcomes were assessed using Cox models, multivariable adjustment, inverse probability of treatment weighting, and landmark analyses. RESULTS: Molecular testing was performed in 1,072 patients and identified actionable alterations in 238 (22.2%); 76/238 (32.0%) received matched therapy. Among 125 patients receiving active treatment after first-line progression, matched therapy was associated with longer overall survival (OS) than non-targeted treatment (median 24.8 vs 16.6 months; HR 0.36, 95% CI 0.20-0.63; p=0.0004) and remained independently associated with improved OS (adjusted HR 0.35, 95% CI 0.22-0.56; p<0.0001). In the second-line cohort (n=127), matched therapy improved OS (HR 0.50, 95% CI 0.30-0.84; p=0.0009), progression-free survival (5.9 vs 3.2 months; HR 0.60, 95% CI 0.38-0.95; p=0.028), and objective response rate (27.1% vs 9.1%; p=0.010). No significant benefit was demonstrated in third line. CONCLUSIONS: Matched targeted therapy was associated with improved outcomes after chemoimmunotherapy failure, particularly when delivered in second line. Early molecular profiling and access to matched agents may reduce missed treatment opportunities. IMPACT AND IMPLICATIONS: This study was undertaken to address a clinically relevant gap: whether the benefit of targeted therapies in molecularly selected advanced biliary tract cancer is maintained in real-world practice after chemoimmunotherapy failure, and whether timing of administration matters. The findings are important for clinicians, multidisciplinary teams, and patients because they show that matched targeted therapies were associated with longer survival, particularly when delivered in second line, while fewer than half of eligible patients ultimately received them in routine care. These results support early and systematic molecular profiling, ideally before first-line progression, to improve the likelihood that patients can access matched therapy while still fit for treatment. Given the retrospective design and the limited size of some molecular subgroups, these findings should be viewed as practice-informing and hypothesis-generating, while also highlighting the need for prospective validation and health-system strategies to improve access to precision oncology.