Real-world outcomes in circulating tumor DNA-detected isocitrate dehydrogenase 1-mutant cholangiocarcinoma: First-line gemcitabine and cisplatin with versus without immunotherapy.

BACKGROUND

Comprehensive genomic profiling (CGP) is recommended for advanced cholangiocarcinoma (aCCA). Circulating tumor DNA (ctDNA) testing provides a noninvasive alternative with concordance to tissue. Standard first-line (1L) therapy is gemcitabine and cisplatin (GemCis) with or without immune checkpoint inhibitors (ICIs). Data suggest that patients with isocitrate dehydrogenase 1 (IDH1) mutations may derive less benefit from ICIs. This study evaluated outcomes with 1L GemCis versus GemCis + ICI in ctDNA-identified IDH1-mutant (IDH1+) aCCA.

METHODS

Real-world data were analyzed from the InfinityAI Data Library, which links claims data with CGP results from Guardant360. Patients with IDH1+ aCCA identified between April 2019 and February 2025 who received 1L GemCis or GemCis + ICI were included. Outcomes were real-world time to next treatment (rwTTNT), real-world time to treatment discontinuation (rwTTD), and real-world overall survival (rwOS), compared via Kaplan-Meier estimates and log-rank tests.

RESULTS

Among 416 IDH1+ patients, 155 received GemCis and 113 received GemCis + ICI. No significant differences were observed in rwTTNT (hazard ratio [HR], 0.75; p = .13) or rwTTD (HR, 1.12; p = .40); however, rwOS was worse with GemCis + ICI compared with GemCis alone (16.0 months [95% CI, 13.6-19.9 months] vs. 30.0 months [95% CI, 24.1-41.0 months]; HR, 0.40; p < .001). In the GemCis + ICI aCCA cohort (N = 1150), IDH1+ patients (n = 113) had numerically shorter rwOS than non-IDH1+ patients (n = 1037) (HR, 0.75; p = .06).

CONCLUSIONS

In IDH1+ aCCA, addition of immunotherapy to GemCis was associated with inferior rwOS. These findings support obtaining ctDNA-based CGP before initiating 1L therapy, and underscore the need for prospective studies.