FDA Grants Priority Review to Ivosidenib Combination for Previously Untreated IDH1-mutated AML

The FDA has awarded priority review to a supplemental new drug application (sNDA) for ivosidenib (Tibsovo) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML).¹

The application follows the findings of the phase 3, global AGILE study, which included patients with previously untreated IDH1-mutated AML. The data were presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

The study showed that treatment with ivosidenib in combination with azacitidine significantly improved event-free survival (EFS) (hazard ratio [HR] = 0.33, 95% CI 0.16, 0.69, 1-sided P = 0.0011^1,2). Furthermore, the combination showed a statistically significant improvement in overall survival (OS) (HR = 0.44 [95% CI 0.27, 0.73]; 1-sided P = 0.0005), with a median OS of 24.0 months.

“On the heels of our recent FDA approval of [ivosidenib] in cholangiocarcinoma, we are pleased with this important step forward in the agency’s consideration to expand its current indication to include the treatment of patients with previously untreated IDH1-mutated AML,” said David K. Lee, chief executive officer of Servier, in a press release. “We are thrilled with the positive momentum of this program as we continue to grow our leadership in oncology and deliver more life-changing medicines to patients living with difficult-to-treat cancers.”

The multicenter, double-blind, placebo-controlled, AGILE trial included patients with untreated AML per the World Health Organization criteria, with centrally confirmed IDH1 mutational status and who were not candidates for induction chemotherapy. Patients needed to have an ECOG performance status ranging from 0 to 2.

Between March 19, 2018, and March 18, 2021, 146 participants were randomized 1:1 to receive ivosidenib plus azacitidine (n = 72) or azacitidine plus placebo (n = 74). Patients in the investigative cohort received the IDH1 inhibitor at a once-daily dose of 500 mg plus azacitidine at a dose of 75 mg/m² for 7 days in 28-day cycles.

The trial’s primary end point was EFS, and key secondary end points included complete response (CR) rate, OS, CR plus CR with partial hematological recovery (CRh) rate, and objective response rate (ORR).

When the data were presented at the 2021 ASH Annual Meeting, 27 of 72 patients in the ivosidenib plus azacitidine cohort were still on treatment compared with 12 of 74 patients in the azacitidine-alone cohort.

Other data found that the ivosidenib combination produced an ORR of 62.5% (95% CI, 50.3%-73.6%) compared with 18.9% (95% CI, 10.7%-29.7%) in the azacitidine alone group (P < .0001).

Further, the median time to CR was 4.3 months in the investigative cohort compared with 3.8 months in the control group. The study also showed that CR + CRh rates in the ivosidenib/azacitidine and azacitidine-alone cohorts were 52.8% (95% CI, 40.7%-64.7%) and 17.6% (95% CI, 9.7%-28.2%), respectively (P < .0001). At 24 weeks, the CR rate in the investigative cohort was 37.5% compared with 10.8% in the control arm.

The most common all-grade adverse effects (AEs) reported in more than 20% of patients in the investigative and control cohorts, respectively, included nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%).

Additionally, 93.0% and 94.5% of those administered ivosidenib/azacitidine and azacitidine/placebo, respectively, reported grade 3 or higher toxicities, the most common of which were febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%).

“Tibsovo is the first therapy targeting cancer metabolism to demonstrate improved EFS and OS in combination with azacitidine in patients with previously untreated IDH1-mutated AML,” said Susan Pandya, MD, vice president of Clinical Development and head of Cancer Metabolism Global Development Oncology and Immuno-Oncology, in the press release. “With this FDA acceptance for priority review, we are closer to offering this critical treatment option to patients in the United States and we look forward to engaging with regulatory agencies around the world.”