LY3410738 In Combination With CISGEM In Advanced IDH1/2m CCA

Mutations in IDH1 and IDH2 (referred to as IDH1/2) are found in 10-15% of intrahepatic cholangiocarcinoma (CCA) cases. Ivosidenib, a reversible inhibitor of IDH1, is approved for second-line treatment of IDH1-mutant CCA. The primary chemotherapy for advanced CCA is Cisplatin and gemcitabine (CISGEM). Although PD1/PDL1 inhibitors slightly increase overall survival (median 12.8 months), there’s still a significant unmet need for treatment.

LY3410738 is an orally-taken, selective drug that targets both IDH1/2 mutations. This study provided insights from the ongoing phase 1 trial for LY3410738, both alone and combined with CISGEM, in treating advanced IDH1/2-mutated CCA.

During the phase 1 trial, the researchers examined the effects of LY3410738 on patients (pts) with advanced CCA who had returned or not responded to previous treatments. They looked at its effects when combined with CISGEM in CCA pts who hadn’t received prior treatment. The goals were to determine the optimal dose, safety, drug behavior in the body, and its effectiveness against tumors.

In one study model, LY3410738 showed a notable reduction in tumor growth. A combined treatment of LY3410738 with CISGEM over 21 weeks led to an 85% decrease in tumor growth compared to only 47% when using CISGEM alone. As of November 1, 2022, 45 previously treated pts got the LY3410738 treatment alone. The overall response rate was 4.5%. On the other hand, 13 pts who hadn’t been treated before got LY3410738 in tandem with CISGEM. Most pts experienced side effects such as anemia, low platelet count, nausea, and reduced appetite, among others. However, the overall response rate was higher at 46%.

From the phase 1 trial, LY3410738 combined with CISGEM showed promising initial results and safety for newly diagnosed advanced CCA with IDH1/2 mutations. The research to determine the ideal dosage is still underway.

Source: https://www.annalsofoncology.org/article/S0923-7534(23)00615-4/fulltext

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04521686

Harding, J., Ikeda, M., Goyal, L., Rodon, J., Bai, L., Oh, D., Park, J., Chen, L., Ueno, M., Liao, C., Kondo, S., Cosman, R., Yokota, T., Shroff, R., Satoh, T., Palmieri, L., Hollebecque, A., Adeva, J., Bender, M., Liu, H., Macarulla, T. SO-1 A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH1 and IDH2, as monotherapy and in combination with cisplatin and gemcitabine in advanced IDH-mutant cholangiocarcinoma. DOI:https://doi.org/10.1016/j.annonc.2023.04.473