Treatment options for cholangiocarcinoma remain limited, particularly once the disease becomes unresectable or metastatic, and advanced disease is associated with poor survival outcomes. Although molecularly targeted therapies have expanded treatment options for selected patients, less is known about how patients with actionable alterations were treated and how they fared before these therapies became routinely available.
The EvIDHence study provides a real-world snapshot of this earlier treatment landscape, comparing treatment patterns and survival outcomes among patients with mutant IDH1 and IDH1 wild-type cholangiocarcinoma before the commercial availability of IDH1 inhibitors.
The article, titled “The EvIDHence study: real-world treatment patterns and safety outcomes in mutant and wild-type IDH1 cholangiocarcinoma before availability of mIDH1 inhibitors,” was published in the September 2026 issue of ESMO Gastrointestinal Oncology.
Authors: V. Sahai, J.W. Valle, N. Fares, M. Javle, I. Ghanem, P. Cerdà, I.G. Rapposelli, I.G. Jimenez, M.A. Gonzalez-Carmona, A. Hollebecque, R. Pazo Cid, D.H. Palmer, R. Vera, A. Casadei-Gardini, D. Melisi, J.-F. Blanc, L. Perkhofer, A. Lamarca, H. Gharbi, V. Manuel-Minguez, R. Robert, and L. Rimassa.
A Real-World Study From the Pre-Ivosidenib Era
EvIDHence was an international, multicenter, retrospective chart-review study conducted across France, Germany, Italy, Spain, the United Kingdom, and the United States.
The study included adults with advanced or metastatic cholangiocarcinoma who had documented IDH1 testing and had initiated second-line systemic therapy after progression on first-line treatment. In France, Germany, Italy, Spain, and the United Kingdom, second-line treatment was initiated between July 1, 2019, and December 31, 2021; in the United States, patients with an index date on or before December 31, 2021, were eligible.
Patients who had received an investigational or commercially available mIDH1 inhibitor at any stage of treatment were excluded. The study aimed to describe treatment sequences, survival outcomes, patient and tumor characteristics, and molecular testing in patients with mutant IDH1 and IDH1 wild-type cholangiocarcinoma before the commercial availability of mIDH1-targeted therapy.
A total of 63 patients from 28 centers were included: 31 had mutant IDH1 cholangiocarcinoma and 32 had IDH1 wild-type disease. Most patients had intrahepatic cholangiocarcinoma, accounting for 83.9% of the mutant IDH1 group and 71.9% of the wild-type group.
The two groups were generally similar in terms of age, sex, disease characteristics, comorbidities, and performance status. Among patients with available ECOG performance status data, 54 of 55 patients, or 98.2%, had an ECOG performance status of 0–1 at first-line treatment, while 44 of 47 patients, or 93.6%, had an ECOG performance status of 0–1 at second-line treatment.
Molecular Testing
Biomarker testing was performed in the context of research or clinical trials in 61.9% of patients, reflecting the limited integration of routine molecular testing during the study period.
Next-generation sequencing was the most frequently used method for identifying IDH1 alterations, accounting for 93.5% of testing in the mutant IDH1 group. The mean time from biological sampling to the availability of results was 34.9 days, with a standard deviation of 63.3 days.
Among patients with mutant IDH1 disease, 75% had the IDH1 R132C variant. Five patients, representing 16.1% of the mutant IDH1 group, also had an FGFR fusion or rearrangement.
These findings show that molecular testing was often carried out in research or clinical trial settings rather than as part of standard medical practice during the study period.
First-Line Treatment
Gemcitabine plus cisplatin was the most frequently used first-line regimen in both groups. It was administered to 64.5% of patients with mutant IDH1 disease and 56.3% of those with IDH1 wild-type cholangiocarcinoma.
A smaller number of patients received other gemcitabine-based combinations, fluoropyrimidine-based regimens, or immunotherapy-containing regimens. Only two patients received gemcitabine plus cisplatin combined with immunotherapy, reflecting the fact that the study eligibility period preceded the introduction of immune checkpoint inhibitors into first-line treatment.
Treatment interruptions during first-line therapy occurred in 25.8% of patients with mutant IDH1 disease and 37.5% of those with wild-type disease. Toxicity was the most frequently documented reason for interruption.
Second-Line Treatment
FOLFOX was the leading second-line treatment, used in 45.2% of patients with mutant IDH1 disease and 43.8% of those with IDH1 wild-type cholangiocarcinoma.
Other second-line approaches varied considerably and included CAPOX, capecitabine, FOLFIRI, FOLFIRINOX, immunotherapy-based regimens, PARP inhibitor-based regimens, targeted FGFR2 therapy, and tazemetostat.
Treatment interruptions during second-line therapy were reported in 22.6% of the mutant IDH1 group and 50% of the wild-type group. Adverse drug reactions were again the most frequent reason for interruption.
Survival Outcomes by IDH1 Status
From the start of first-line treatment, median progression-free survival was 10.3 months in the mutant IDH1 group and 6.3 months in the IDH1 wild-type group.
Median overall survival from first-line treatment initiation was:
- 20.8 months for patients with mutant IDH1 cholangiocarcinoma
- 18.6 months for patients with IDH1 wild-type disease
Following the initiation of second-line therapy, median progression-free survival was 3.5 months in the mutant IDH1 group and 3.3 months in the wild-type group.
Median overall survival from the start of second-line treatment was:
- 9.7 months in the mutant IDH1 group
- 8.5 months in the IDH1 wild-type group
IDH1 mutational status was not significantly associated with overall survival in either the univariate or multivariable analyses. It was also not significantly associated with progression-free survival during first- or second-line treatment.
Among patients who specifically received gemcitabine-platinum chemotherapy in the first-line setting, median overall survival was 23.6 months for the mutant IDH1 group and 19.0 months for the wild-type group.
Among those treated with second-line FOLFOX, median overall survival was 8.0 months and 6.3 months, respectively.
These descriptive differences should not be interpreted as evidence that mutant IDH1 disease has a more favorable prognosis, particularly given the small sample size and the absence of a statistically significant association between IDH1 status and survival.
Tumor Responses
Among patients with evaluable imaging, partial responses to first-line treatment were observed in 21.7% of patients with mutant IDH1 disease and 31.3% of patients with IDH1 wild-type disease.
During second-line treatment, partial responses were observed in 1 of 10 patients with mutant IDH1 disease (10.0%) and 2 of 13 patients with IDH1 wild-type disease (15.4%). No complete responses were reported in either group during first- or second-line treatment.
Reported Adverse Drug Reactions
At least one adverse drug reaction was reported during first-line treatment in 17 patients from each IDH1 group. During second-line therapy, adverse drug reactions were documented in 17 patients with mutant IDH1 disease and 21 patients with wild-type disease.
Anemia and fatigue were among the most frequently reported reactions and were consistent with the labels of the administered regimens. Most reported adverse drug reactions were grade 1.
Because the study relied on retrospective medical records, safety data were limited to adverse drug reactions that had been documented and attributed to treatment.
Study Limitations
The investigators emphasized several limitations when interpreting the findings. The study enrolled only 63 patients, considerably fewer than the originally anticipated sample of 200. Recruitment was restricted because many potentially eligible patients with mutant IDH1 disease had already received an IDH1 inhibitor through clinical trials or compassionate-access programs.
Patients were also required to have survived first-line treatment and remained fit enough to begin second-line therapy. This created a selected population with a relatively young median age and predominantly favorable performance status, potentially contributing to longer survival estimates than would be expected in an unselected real-world population.
The retrospective design and incomplete medical records further limited the analysis. In addition, the small sample size meant that the study was not powered to establish IDH1 mutations as prognostic biomarkers.
In addition, the study period preceded the widespread use of first-line immune checkpoint inhibitors. Its results therefore do not fully represent the current treatment landscape.
Takeaway
EvIDHence offers a useful historical benchmark for understanding cholangiocarcinoma outcomes before the routine availability of mutant IDH1 inhibitors.
In this selected population, treatment patterns were broadly similar between patients with mutant and wild-type IDH1 disease. Gemcitabine plus cisplatin remained the dominant first-line regimen, while FOLFOX was the most frequently used second-line treatment.
Survival outcomes were numerically longer among patients with mutant IDH1 disease, but IDH1 status was not significantly associated with progression-free or overall survival. The study was not sufficiently powered to determine whether IDH1 mutations independently influence prognosis.
The findings provide a real-world description of second-line treatment outcomes during the pretargeted therapy era. The ongoing phase 3b, prospective, real-world ProvIDHe study is expected to provide further information on outcomes among patients with mutant IDH1 cholangiocarcinoma receiving ivosidenib.
The full article is available in ESMO Gastrointestinal Oncology.
