IDH1 R132 mutations or HER2-positivity and benefit from platinum-based therapy for biliary tract cancers

Background & aims: Targeted therapies for biliary tract cancers (BTC) are approved in the second-line setting. We investigated response to first-line platinum-based palliative systemic anti-cancer treatment in patients with the most common druggable alterations to determine the optimal positioning of targeted therapies in the treatment algorithm. Methods: Patients treated at the Beatson West of Scotland centralized BTC clinic who underwent genomic profiling were retrospectively selected; those with the most common actionable alterations who received platinum-based treatment were included in clinical analyses. Observations were supported by tracking IDH1 mutations with digital droplet PCR on longitudinal cell-free DNA samples. Results: Druggable alterations were identified in 39.7% of patients; HER2 overexpression/amplification and IDH1 R132 mutations were the most commonly identified alterations. Compared to patients with HER2-positive tumors (n = 11), patients with IDH1 R132 mutations (n = 6) had longer median time to best response (5.99 vs. 2.5 months; hazard ratio [HR] 0.28; 95% CI 0.09-0.91; p = 0.0033), and median time to progression (17.2 vs. 5.6 months; HR 0.266; 95% CI 0.0955-0.741; p = 0.0075). Compared to a cohort of patients without either alteration, those with IDH1-mutated BTC had longer median overall survival (HR 0.30; 95% CI 0.14-0.67; p = 0.0229); those with HER2-positive BTC showed a worse median time to progression (HR 1.97; 95% CI 0.85-4.58; p = 0.0408) and a trend towards worse median overall survival (HR 1.38; 95% CI 0.61-3.13; p = 0.3884). IDH1 variant allele frequency decreased during first-line treatment, regardless of response; prolonged benefit from ivosidenib in the second line was observed when variant allele frequency was <1 at the start of targeted treatment. Conclusions: These preliminary data suggest that targeted therapies may need to be introduced earlier, including in the first-line setting, with strategies tailored to specific molecular alterations. Access to platinum-based palliative systemic anti-cancer treatment remains particularly important for patients with IDH1-mutated BTC. Impact and implications: We conducted an analysis to determine whether patients with biliary tract cancer harboring the most common actionable alterations (i.e. IDH1 R132 mutations and HER2 overexpression or amplification) had different patterns of response to first-line platinum-based chemo(immuno)therapy. The goal was to determine whether the introduction of targeted therapies in the first-line setting should be tailored based on the alteration detected. In our cohort, patients with IDH1 R132 mutations experienced durable benefit from platinum-based chemotherapy, while those with HER2-positive tumors only experienced a short-lived benefit from it. Although these findings are exploratory and limited by small sample size, they may inform future strategies for earlier integration of targeted therapies and support the design of prospective clinical trials.