Treatment and Survival Outcomes with Systemic Therapy for Patients with BTC with IDH1 Mutations: A Retrospective Study

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes involved in cell metabolism. Missense IDH1 mutations block normal cell differentiation and promote tumorigenesis due to the accumulation of the oncometabolite 2-hydroxygluterate. Based on the results of the phase 3 ClarIDHy trial, ivosidenib was approved in 2021 for patients with IDH1-mutated biliary tract cancer (BTC) who did not respond to prior systemic therapy; however, long-term outcomes for patients with IDH1-mutated BTC treated with chemotherapy, targeted therapy, and immunotherapy remain unclear. Dr Darren Cowzer presented results from a retrospective analysis of patients with BTC aimed at defining clinical outcomes of systemic therapy in patients with IDH1 mutations. Secondary objectives included determining co-occurring alterations.

A total of 1124 patients with BTC underwent genomic sequencing using MSK-IMPACT (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets). Of these patients, 12.7% were found to have IDH1 mutations, almost all of whom had intrahepatic cholangiocarcinoma (97%). Most patients had unresectable/metastatic disease at diagnosis, and the median tumor mutational burden was 2.6 mut/Mb. ARID1A, PBRM1, and BAP1 were the most common co-occurring mutations, seen in 22%, 20%, and 17% of patients, respectively. A total of 103 patients received first-line platinum-based chemotherapy, and the median progression-free survival (PFS) was 8.3 months (95% confidence interval [CI], 6.4-11.2). Eleven patients received immunotherapy, and the median PFS was 2.73 months (95% CI, 2.23-not reached). In addition, 49 patients received an IDH1 inhibitor in any line, and the median PFS was 5.4 months (95% CI, 3.7-10.0). In patients who received an IDH1 inhibitor in the second line, the median PFS was 4.6 months (n = 28; 95% CI, 3.57-10.03) versus 2.57 months (n = 24; 95% CI, 1.8-6.73) in patients who received second-line 5-FU–based chemotherapy (P = .032). The overall survival (OS) in patients who ever received an IDH1 inhibitor was 25.7 months (n = 49; 95% CI, 22.1-45) versus 20.7 months (n = 53; 95% CI, 14.4-29.3) in patients who had never received an IDH1 inhibitor (P = .54). The OS in patients with stage IV disease (n = 107) was 20.7 months (95% CI, 17.6-28).

Overall, outcomes were favorable in patients treated with an IDH1 inhibitor in the second line versus 5-FU–based chemotherapy. PFS for first-line platinum-based chemotherapy was similar to results seen in the original ABC-02 study and was longer than what was observed in ClarIDHy in patients treated with ivosidenib.

Source: Cowzer D, Huq R, Perry M, et al. Clinical outcomes for IDH1 mutant biliary tract cancer treated with contemporary systemic therapy. Poster presented at: ASCO Gastrointestinal Cancers Symposium, January 19-21, 2023; San Francisco, CA. Abstract 513.