Frontline Ivosidenib/Azacitidine Combo Shows Early Promising Efficacy in IDH1+ AML

Courtney D. DiNardo, MD, MSCE

Courtney D. DiNardo, MD, MSCE

Ivosidenib in combination with azacitidine (Vidaza) demonstrated promising efficacy in addition to being well tolerated in patients with newly diagnosedIDH1-mutant acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy.

The combination demonstrated an objective response rate (ORR) of 78.3% (95% CI, 56.3%-92.5%) with complete responses (CRs) achieved in 60.9% (95% CI, 38.5%-80.3%) of patients, according to results from a phase Ib trial presented at the 2019 SOHO Annual Meeting.

Previous in vitro studies of mutantIDH1erythroleukemia cell lines that were treated with the IDH1 inhibitor plus hypomethylating agent showed enhanced cell differentiation and potentiation of apoptosis with the doublet compared with either agent alone.

As such, the phase Ib study was created to explore the safety and early efficacy of the combination. Twenty-three patients with newly diagnosedIDH1-mutant AML were enrolled between the dose-finding portion of the study (n = 7) and the expansion portion (n = 16). Patients with prior hematologic disorders were allowed in the study as long as they had not received prior hypomethylating agents.

Patients received 500 mg daily ivosidenib with 75 mg/m²/day subcutaneous azacitidine on days 1 through 7 of each 28-day cycle.

Primary end points were the recommended dose for the combination, safety, and tolerability. Key secondary endpoints were ORR and CR/CR with partial hematologic recovery (CRh) rate, with an exploratory endpoint of mutantIDH1variant allele frequency.

Of the 23 patients, the median age was 76 years (range, 61-88) with 52% being ≥75 years. A majority of the patients had an ECOG performance status of 1 (61%),de novoAML (65%), and intermediate cytogenetic risk (65%).

The rate of CR/CRh was 69.6% (95% CI, 47.1%-86.8%). A best response of morphologic leukemia-free state was reached in 8.7% of patients and CR with incomplete hematologic or platelet recovery was observed in 8.7%. The median duration of response was not reached as of the data cutoff.

After a median follow-up of 16.1 months (range, 1.3-31.7), the 1-year overall survival rate was 82.0% (95% CI, 58.8%-92.8%).

The most frequency all-grade adverse events (AEs) included thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (44%), pyrexia (44%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), neutropenia (35%), insomnia (35%), and back pain (30%).

Grade 3/4 AEs occurred in 96% of patients, with thrombocytopenia (61%), anemia (44%), febrile neutropenia (44%), neutropenia (30%), and sepsis (22%) being the most common.

Six deaths occurred, 3 during treatment and 3 during follow-up, but none were considered related to treatment. The 60-day mortality rate was 4%.

“The ivosidenib and azacitidine combination was well tolerated in patients with mutantIDH1newly diagnosed AML who were ineligible for intensive chemotherapy,” Courtney D. DiNardo, MD, MSCE, said when presenting the findings. “The safety profile was consistent with those of ivosidenib and azacitidine alone in this patient population.”

DiNardo, an associate professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, added that the rate of cytopenia was “in line with those seen for azacitidine alone, and was favorable compared with other emerging hypomethylating agent combinations.”

Four cases of IDH differentiation syndrome were observed, with 3 being serious, although all 4 eventually resolved. Three patients required treatment for differentiation syndrome and the combination treatment was held for 1 patient. Of the patients with differentiation syndrome, 2 achieved a CR and 1 had stable disease.

MutantIDH1variant allele frequency in both bone marrow mononuclear cells (BMMCs) and peripheral blood mononuclear cells (PBMC) was available for 21 of the 23 patients, including all of the patients who responded to the combination regimen.IDH1mutation clearance was observed in 10 of the 16 patients who achieved a CR/CRh by BMMC and in 12 of 16 by PBMC. No mutation clearance was observed in nonresponders.

“The majority of patients with complete responses also hadIDH1mutation clearance, suggesting a direct impact on the biology of mutantIDH1AML,” DiNardo commented.

She noted that based on the results of the phase Ib trial, the combination is now being investigated in the double-blind, randomized, placebo-controlled phase III AGILE trial in patients with newly diagnosedIDH1-mutant AML who are ineligible for intensive chemotherapy (NCT03173248). The combination will be compared with the use of azacitidine alone, with a primary end point of overall survival.

Reference:

DiNardo CD, Stein AS, Stein EM, et al. Mutant IDH1 inhibitor ivosidenib (AG-120) in combination with azacitidine for newly diagnosed acute myeloid leukemia. Presented at: 2019 SOHO Annual Meeting; September 11-14; Houston, TX. Abstract AML-197.