CYP3A4 inhibitors (CYP3A4i) and myelosuppression in patients (Pts) with newly diagnosed mutant isocitrate dehydrogenase 1 (mIDH1) Acute Myeloid Leukemia (AML) in the phase 3 AGILE study

Abstract

Abstract Introduction Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mIDH1 approved for the treatment of pts with mIDH1 AML. In the pivotal AGILE study of IVO in combination with azacitidine (AZA) in newly diagnosed AML (NCT03173248), the most common grade ≥3 adverse events (AEs) were hematologic in both the IVO+AZA and placebo (PBO)+AZA arms (Montesinos, NEJM 2022). Antifungal prophylaxis is recommended for pts with AML who are at risk for prolonged and profound neutropenia (Taplitz, JCO 2018). Azoles are CYP3A4i and can increase exposure to AML therapies that are CYP3A4 substrates. For example, venetoclax requires dose reduction when administered concomitantly with CYP3A4i, yet increased exposure and myelosuppression still occur (Kawedia, AJH 2025). IVO is mainly metabolized by and induces CYP3A4, thereby promoting its own metabolism. It is unknown whether concomitant CYP3A4i administration with IVO therapy may increase the risk of myelosuppression. Herein, we analyze myelosuppression events by CYP3A4i use in the AGILE study, as well as the pharmacokinetic (PK) profile of IVO when coadministered with CYP3A4i. Methods Pts with newly diagnosed mIDH1 AML who were ineligible for intensive chemotherapy were enrolled in AGILE. Pts were randomly assigned (1:1) to receive oral IVO 500 mg daily, on 28-day cycles and AZA or PBO+AZA. Pts taking strong CYP3A4 inducers or sensitive CYP3A4 substrates with narrow therapeutic window were excluded; CYP3A4i were allowed with no IVO dose reductions. Pts were grouped on the basis of CYP3A4i category: strong, moderate, or mild-none. AML- and treatment-related myelosuppression were analyzed from enrollment to the data cutoff in June 2022, within each CYP3A4i category. IVO PK was assessed after a single 500-mg dose on cycle 1 day 1 and cycle 2 day 1 (steady state [SS]). Trough concentration (Ctrough) was measured predose on day 8 and 15 of cycle 1, and on day 1 of cycle 3 and beyond; data were summarized by CYP3A4i category. A prior population PK model was used to assess IVO PK, with strong or moderate CYP3A4i included as covariates. Results Overall, 72 pts received IVO+AZA and 74 pts PBO+AZA. In the IVO+AZA group, concomitant CYP3A4i use was 38% (n=27), 28% (n=20), and 35% (n=25) of pts in the strong, moderate, and mild-none categories, respectively; in the PBO+AZA group, 47% (n=35), 23% (n=17), and 30% (n=22) of pts received strong, moderate, and mild-none CYP3A4i. Myelosuppression events of any grade occurred in 54 (75%) pts in the IVO+AZA group and 52 (70%) pts in the PBO+AZA group. Overall, myelosuppression was not impacted by CYP3A4i (strong/moderate/mild-none), occurring in 21 (78%)/15 (75%)/18 (72%) pts in the IVO+AZA group, and in 26 (74%)/12 (71%)/14 (64%) pts in the PBO+AZA group. Anemia and thrombocytopenia rates were overall comparable across CYP3A4i categories and between IVO+AZA and PBO+AZA groups. The rate of grade ≥3 neutropenia was higher in the IVO+AZA group vs PBO+AZA (22 [31%] vs 16 [22%]), mainly due to a higher frequency among pts receiving mild-none CYP3A4i (IVO+AZA: 11 [44%]; PBO+AZA 2 [9%]). Febrile neutropenia rate was lower among pts receiving mild-none CYP3A4i in the IVO+AZA group (2 [8%] vs 11 [41%] for strong and 7 [35%] for moderate); in the PBO+AZA group, febrile neutropenia rates were comparable across CYP3A4i categories (13 [37%]/6 [35%]/6 [27%]). Population PK modeling predicted the AUC of IVO at SS to increase moderately (<2-fold) when coadministered with voriconazole, fluconazole, and posaconazole—by 48.7%, 60.8%, and 58.8%, respectively—compared with IVO alone. A trend toward increased IVO Ctrough at SS was observed with moderate or strong CYP3A4i, consistent with population PK predictions. Conclusions Overall, IVO+AZA administration with concomitant CYP3A4i resulted in similar rates of myelosuppression compared with PBO+AZA, regardless of strength of the CYP3A4i. Neutropenia was more frequent in the IVO+AZA group, particularly among pts receiving mild-none CYP3A4i, possibly due to longer treatment duration in this category. However, low rates of individual AEs limit the ability to draw firm conclusions. IVO exposure was predicted to increase <2-fold when given in combination with moderate/strong CYP3A4i. As concomitant use of CYP3A4i—particularly antifungal azoles—is frequently necessary in pts with AML, the ability to deliver the full dose of IVO without increased risk of myelosuppression is an added benefit of IVO-based therapy.