Fewer Infections, Neutropenia Observed With Ivosidenib/Azacitidine Combo vs Placebo in IDH1-Mutant AML

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The combination of ivosidenib and azacitidine revealed a manageable safety profile and quality of life profile in patients with IDH1-mutant acute myeloid leukemia in the phase 3 AGILE study.

The combination of ivosidenib (Tibsovo) and azacitidine (Vidaza) showed clinical benefit compared with placebo plus azacitidine in difficult-to-treat patients with IDH1-mutated acute myeloid leukemia (AML). Investigators observed fewer infections and febrile neutropenia in the ivosidenib plus azacitidine group than in the placebo and azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib plus azacitidine group.1

The intention-to-treat population included 146 patients.At a median follow-up of 12.4 months, event-free survival (EFS) was significantly longer in the ivosidenib plus azacitidine group (n = 72) than in the placebo plus azacitidine group (n = 74; hazard ratio [HR] 0.33; 95% CI, 0.16-0.69; P = .002).

In this phase 3 AGILE trial (NCT03173248), investigators randomly assigned patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive induction chemotherapy to receive oral ivosidenib at 500 mg once daily and subcutaneous or intravenous azacitidine at 75 mg/m2 of body-surface area for 7 days in 28-day cycles, or to receive matched placebo and azacitidine. The primary end point was EFS, defined as the time from randomization until treatment failure relapse from remission or death. Secondary end points included complete remission, complete remission or complete remission with partial hematologic recovery, overall survival (OS), objective response, safety, and health-related quality of life, which used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30).2

Thirty-four patients (47%) experienced complete remission in the ivosidenib plus azacitine group vs 11 patients (15%) in the placebo and azacitidine group. Complete remission or complete remission with partial hematologic recovery occurred in 38 patients (53%; 95% CI, 41%-65%) with ivosidenib and azacitidine and in 13 patients (18%; 95% CI, 10%-28%) with placebo and azacitidine (P < .001). Complete remission in patients with incomplete hematologic or platelet recovery occurred in 5 patients (7%) in the ivosidenib group and in 1 patient (1%) in the placebo group.

There were 74 deaths reported—28 (39%) in the ivosidenib plus azacitidine group and 46 (62%) in the placebo plus azacitidine group. The median OS was 24.0 months (95% CI, 11.3-34.1) and 7.9 months (95% CI, 4.1-11.3), respectively (HR, 0.44; 95% CI, 0.27-0.73; P = .001).

Forty-five patients (62%; 95% CI, 50%-74%) experienced an objective response with ivosidenib and azacitidine compared with 14 patients (19%; 95% CI, 11%-30%) with placebo and azacitidine (P < .001). The median duration of response was 22.1 months (95% CI, 13.0-not estimable) with ivosidenib and azacitidine and 9.2 months (95% CI, 6.6 to 14.1) with placebo and azacitidine. The median duration of treatment was 6.0 months (range, 0.1-33.5) with ivosidenib and azacitidine vs 2.8 months (range, 0.1-19.8) with placebo and azacitidine.

The median age of patients was 76.0 years (range, 58.0–84.0) and 75.5 (range, 45.0–94.0) in the ivosidenib and placebo groups, respectively. Both groups had slightly more male patients (58% and 51%, respectively). The most common IDH1 mutation type was R132C in both groups in 62% of the ivosidenib group and in 69% in the placebo group.

Baseline EORTC QLQ-C30 scores were available for 69 patients (96%) receiving ivosidenib and azacitidine and 66 (89%) receiving placebo and azacitidine. Grade 3 or worse adverse events (AEs) were observed in 66 of 71 patients (93%) receiving ivosidenib and azacitidine and 69 of 73 patients (95%) receiving placebo and azacitidine. Grade 3 or higher AEs occurring in more than 15% of patients within both groups included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine), anemia (25% and 26%, respectively), neutropenia (27% and 16%), thrombocytopenia (24% and 21%), and pneumonia (23% and 29%).

The ivosidenib and azacitidine combination revealed improved EFS, response, and OS compared to the placebo and azacitdine combination. These benefits are further supported by a favorable by manageable safety profile and quality of life profile.

References

1. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344

2. Aaronson NK, Ahmedzai S, Bergman B, et al. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. doi:10.1093/jnci/85.5.365

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