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Published on: July 25, 2020
Final Results from a First-in-Human Phase I Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor,
James J Harding1,2, Do-Youn Oh3, Teresa Macarulla Mercade4
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Isocitrate dehydrogenase (IDH) 1/2-isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance.
Patients And Methods:
This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin-gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed.
Results:
Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma.
Conclusions:
LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.
Insights
LY3410738, a dual IDH1/2 inhibitor, showed promising antitumor activity, especially in combination with cisplatin-gemcitabine for newly diagnosed IDH-mutant cholangiocarcinoma. Further exploration of this combination is warranted.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Isocitrate dehydrogenase (IDH) 1/2 inhibitors offer clinical benefits for IDH-mutated cancers.
- Resistance to IDH inhibitors necessitates the development of novel therapeutic strategies.
- LY3410738 is an oral, brain-penetrant, dual IDH1/2 inhibitor designed to overcome resistance.
Purpose of the Study:
- To evaluate the safety and preliminary antitumor activity of LY3410738 in patients with IDH-mutant solid tumors.
- To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of LY3410738.
- To assess the efficacy of LY3410738 as monotherapy and in combination with cisplatin-gemcitabine or durvalumab.
Main Methods:
- A global, multicenter, open-label, phase I study involving 119 patients with IDH-mutant solid tumors.
- Dose escalation of LY3410738 monotherapy and dose expansion in combination regimens.
- Assessment of safety, pharmacokinetics, D-2-hydroxyglutarate inhibition, and ctDNA.
Main Results:
- No dose-limiting toxicities were observed in monotherapy; MTD was not determined. Common adverse events included nausea, vomiting, and decreased appetite.
- LY3410738 monotherapy showed overall response rates of 5.2% (cholangiocarcinoma) and 11.1% (glioma).
- LY3410738 plus cisplatin-gemcitabine demonstrated a 42.1% response rate, 8.1-month median duration of response, and 10.2-month median progression-free survival in newly diagnosed IDH-mutant cholangiocarcinoma.
Conclusions:
- LY3410738 exhibited largely cytostatic antitumor activity in IDH-mutated cholangiocarcinoma and gliomas.
- The combination of LY3410738 and cisplatin-gemcitabine showed favorable antitumor activity in treatment-naïve IDH-mutant cholangiocarcinoma.
- This combination warrants further investigation as a potential treatment strategy for IDH-mutant cholangiocarcinoma.
