Ivosidenib/CPX-351 Shows Early Activity and Is Safe in IDH1-Mutated R/R AML, High-Risk MDS

The combination of the IDH1 inhibitor ivosidenib (Tibsovo) with CPX-351 showed early signals of efficacy and was associated with an acceptable safety profile and in patients with newly diagnosed or relapsed/refractory IDH1-mutated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), according to interim results from a phase 2 trial (NCT04493164) presented at the 2024 ASH Annual Meeting.1

At a data cutoff of July 10, 2024, patients in arm A (newly diagnosed; n = 4) treated with ivosidenib plus CPX-351 achieved an overall response rate (ORR) of 100%; All patients in this arm also achieved undetectable measurable residual disease (uMRD) levels by flow cytometry at a sensitivity of 10–4. Patients in arm B (relapsed/refractory; n = 7) had an ORR of 43% following treatment with ivosidenib plus CPX-351; All 3 responders had uMRD.

“Interim results suggest the acceptable safety and promising efficacy of CPX-351 combined with ivosidenib in newly diagnosed or relapsed/refractory, IDH1-mutated AML,” lead study author Jennifer Croden, MD, and coauthors wrote in the poster presentation of the data. Croden is a clinical fellow in the Leukemia Clinical Fellowship Program at The University of Texas MD Anderson Cancer Center in Houston.

Ivosidenib and CPX-351 Background and Phase 2 Study Design

In May 2022, the potent oral IDH1 inhibitor ivosidenib in combination with azacitidine (Vidaza) was approved by the FDA for the treatment of patients with newly diagnosed AML harboring IDH1 mutations.2 In October 2023, ivosidenib monotherapy was approved by the FDA for the treatment of adult patients with relapsed/refractory MDS with a susceptible IDH1 mutation, as detected by an FDA-approved test.3

A study previously published in The Lancet demonstrated that treatment with CPX-351 led to a superior response rate and superior overall survival (OS) outcomes vs standard 7 + 3 chemotherapy in patients with newly diagnosed secondary AML.4 Of note, CPX-351 is a dual-drug liposomal encapsulation of daunorubicin with cytarabine in a 1:5 synergistic molar ratio.

Based on previous findings regarding ivosidenib and CPX-351, Croden and colleagues designed the phase 2 study to investigate the efficacy of ivosidenib plus CPX-351 in patients with relapsed/refractory IDH1-mutated AML and high-risk MDS.1

Patients enrolled on the study were at least 18 years of age with newly diagnosed or relapsed/refractory AML or high-risk MDS harboring an IDH1 mutation. Eligibility criteria included IDH1-mutated disease status as assessed by local laboratory; treatment-naive or relapsed/refractory AML eligible for intensive chemotherapy or high-risk MDS or myeloproliferative neoplasms; adequate hepatic and renal function; and an ECOG performance status of 0 to 2.5

Patients were treated with CPX-351, consisting of daunorubicin at 44 mg/m2 and cytarabine at 100 mg/m2, which were administered according to the FDA-approved schedules.1 At first induction, CPX-351 was administered on days 1, 3, and 5 of a 28-day cycle; the agent was subsequently administered on days 1 and 3 of a 28-day cycle during the second induction if complete remission was not achieved. At consolidation, CPX-351 was administered on days 1 and 3 of a 28-day cycle for up to 2 cycles. Patients also received oral ivosidenib at 500 mg daily beginning on day 1 of induction and continuing through consolidation. Ivosidenib was then continued as an oral maintenance therapy for up to 2 years.

The primary end point was ORR; key secondary end points included duration of response (DOR), event-free survival (EFS), OS, and safety.

Patient Baseline Characteristics

Among patients in arm A, the median age was 56 years (range, 51-69). Half of all patients were male and/or in the adverse European LeukemiaNet (ELN) risk group. In total, 50% and 25% of patients had DNMT3A or NPM1 comutations, respectively. Best responses were complete remission (CR) (25%); CR with incomplete count recovery (CRi), CR with incomplete platelet recovery (CRp), or CR with partial hematologic recovery (CRh; 50%); and morphologic leukemia-free state (25%) .

Patients in arm B had a median age of 63 years (range, 45-72), and most were male (57%). These patients had received a median of 3 prior lines of therapy (range, 1-4). Median prior lines of therapy included a hypomethylating agent (71%), venetoclax (Venclexta; 100%), and hematopoietic stem cell transplantation (HSCT; 29%). Most patients were in the adverse ELN risk group (71%); and co-mutational profiles included NPM1 mutations (29%), DNMT34 mutations (29%), and TP53 mutations (29%). The best responses from patients in arm B included CR (14%), CRi/CRp/CRh (29%), hematologic response (29%), and no response (29%).

Additional Efficacy Data

In arm A, the median DOR was 16.3 months, the median EFS was 17.5 months, and the median OS was 29.3 months; in arm B, the median EFS and OS were 4.2 months and 12.0 months, respectively.

At a median follow-up of 32.5 months, the IDH1 variant allele frequency (VAF) was measured in 9 of 11 total patients in the study, of whom a decrease in VAF was observed in 89% and undetectable VAF at a sensitivity of 2% was observed in 67%. Of note, 4 responders proceeded to HSCT; among these patients, 3 remained in remission, and 1 experienced relapse at 17.5 months following HSCT.

Safety Findings

Among patients in arm A, the most common treatment-related adverse effects (TRAEs) included rash (any-grade, 50%; grade ≥ 3, 25%) and electrocardiogram (ECG) changes (25%; 0%). In arm B, TRAEs included rash (29%; 29%), thrombocytopenia (29%; 29%), and ECG changes (14%; 0%).

No episodes of differentiation syndrome were reported, and there were no reported deaths due to TRAEs. However, there were 2 dose-limiting toxicities, both of which were grade 4 prolonged thrombocytopenia in marrow remission. These were resolved without dose hold on day 45 in both patients with attainment of CR and CRi. The median count recovery after induction was 39 days (range, 30-55).

References

1. Croden J, Hammond D, Chien KS, et al. Interim results of the phase II study investigating CPX-351 in combination with ivosidenib for patients with IDH1-mutated acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2024;144(suppl 1):4271. doi:10.1182/blood-2024-207476
2. FDA approves ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. FDA. Updated August 1, 2022. Accessed March 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-combination-azacitidine-newly-diagnosed-acute-myeloid-leukemia
3. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed March 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes
4. Lancet JE, Uy GL, Newell LF, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e491. doi:10.1016/S2352-3026(21)00134-4
5. CPX-351 and ivosidenib for the treatment of IDH1 mutated acute myeloid leukemia or high-risk myelodysplastic syndrome. ClinicalTrials.gov. Updated October 24, 2024. Accessed March 3, 2025. https://clinicaltrials.gov/study/NCT04493164