FDA Grants Priority Review to Ivosidenib Plus Azacitidine for Previously Untreated IDH1-Mutated AML

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

The sNDA is supported by findings from the phase 3 AGILE study (NCT03173248), which showed that the combination resulted in a significant improvement in event-free survival (EFS) vs azacitidine alone (HR, 0.33; 95% CI, 0.16-0.69; P = .0011).² Moreover, the addition of ivosidenib to azacitidine also significantly improved overall survival (OS) vs azacitidine alone, at a median of 24.0 months vs 7.9 months, respectively (HR, 0.44; 95% CI, 0.27-0.73; P = .0005).

Although the decision date was not shared in the press release issued by Servier Pharmaceuticals, priority review accelerates the review and shortens the review time goal from 10 months to 6 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,” David K. Lee, chief executive officer of Servier, stated in the 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, phase 3 AGILE trial enrolled patients with untreated AML per the World Health Organization criteria, who had centrally confirmed IDH1 mutational status and 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, a total of 146 participants were randomized 1:1 to receive ivosidenib plus azacitidine (n = 72) or azacitidine plus placebo (n = 74). Those in the investigative arm 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.

Study participants were stratified by region and de novo vs secondary AML.

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

The median age of those in the investigative arm was 76.0 years (interquartile range [IQR], 70.5-79.5) vs 75.5 years (IQR, 70.0-80.0) in the control arm. Seventy-five percent of those in the ivosidenib/azacitidine arm had de novo AML vs 25.0% who had secondary AML. Moreover, 22.2% of patients in the investigative arm were noted to have poor-risk genetics per European LeukemiaNet guidelines, compared with 27.0% of those in the control arm.

At the time of presentation during the 2021 ASH Annual Meeting, 27 of the 72 patients in the ivosidenib/azacitidine arm were still on treatment vs 12 of the 74 patients in the azacitidine-alone arm.

Additional data showed that the ivosidenib combination elicited an ORR of 62.5% (95% CI, 50.3%-73.6%) vs 18.9% (95% CI, 10.7%-29.7%) with azacitidine alone (P < .0001).

Moreover, the median time to CR was 4.3 months in the investigative arm vs 3.8 months in the control arm. Moreover, the CR + CRh rates in the ivosidenib/azacitidine and azacitidine-alone arms were 52.8% (95% CI, 40.7%-64.7%) and 17.6% (95% CI, 9.7%-28.2%), respectively (P < .0001). By 24 weeks, the CR rate in the investigative arm was 37.5% vs 10.8% in the control arm.

Regarding safety, the most common all-grade adverse effects (AEs) to be experienced in more than 20% of patients in the investigative and control arms, 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%).

Moreover, 93.0% and 94.5% of those who received ivosidenib/azacitidine and azacitidine/placebo, respectively, experienced 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%).

All-grade differentiation syndrome (DS) per investigator assessment occurred in 14.1% of those who received the ivosidenib combination vs 8.2% of those given azacitidine alone; grade 3 or higher DS was experienced by 4.2% and 4.1% of patients, respectively.

“[Ivosidenib] 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,” Susan Pandya, MD, vice president of Clinical Development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, added 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.”

References

1. Servier announces FDA filing acceptance and priority review for TIBSOVO (ivosidenib tablets) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia. News release. Servier Pharmaceuticals; March 7, 2022. Accessed March 7, 2022. https://prn.to/3CtMlJy
2. Montesinos P, Recher C, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. Blood. 2021;138(suppl 1):697. doi:10.1182/blood-2021-147805