Ivosidenib/Azacitidine Combo Elicits Survival Benefit Over Placebo in IDH1-Mutated AML

Ivosidenib (Tibsovo) plus azacitidine (Vidaza) displayed benefits in event-free survival (EFS), overall survival (OS), and clinical responses vs placebo plus azacitidine in patients with newly diagnosed, IDH1-mutated acute myeloid leukemia (AML), according to findings from the phase 3 AGILE study (NCT03173248).¹

The results, presented by Courtney D. DiNardo, MD, MSCE, during the 10th Annual Meeting of the Society of Hematologic Oncology, also showed that the combination had a favorable safety profile with manageable treatment-emergent adverse events (TEAEs). Moreover, patients treated with ivosidenib plus azacitidine reported better health-related quality of life (HRQOL) outcomes in comparison with patients in the placebo plus azacitidine arm.

AGILE is a global, randomized, double-blind study in which 200 patients from 20 countries were randomized 1:1 to receive either ivosidenib 500 mg by mouth once daily plus azacitidine 75 mg/m² subcutaneous or intravenously (n = 72) or matching placebo in combination with azacitidine (n = 74). The primary end point evaluated in these patients was EFS, and the secondary end points were complete response (CR) rate, OS, CR plus CR with hematologic recovery (CRh), and objective response rate.

Patients enrolled in the study were over 18 years of age with a centrally confirmed diagnosis of previously untreated AML with IDH1 mutation. Patients could not have received previous treatment with IDH1 inhibitors or hypomethylating agents for myelodysplastic syndrome. Patients were also required to have an ECOG performance status of 0 to 2, adequate liver and kidney function, and be eligible for intensive chemotherapy.

The median age was 76 years (range, 58-84 years) in the experimental arm and 75.5 years (range, 45-94 years) in the control arm. Male patients were the majority in both treatment arms. Most patients in the study had an ECOG performance score of 1 at baseline.

Disease history was assessed by investigator at baseline and showed that 75.0% of patients in the experimental arm and 71.6% in the comparator arm had de novo AML. Twenty-five percent of the ivosidenib/azacitidine arm and 28.4% of the placebo/azacitidine arm has secondary AML. The median IDH1 mutation variant allele frequency in the baseline bone marrow analysis was 36.7% (range, 3.1%-50.5%) in the experimental arm vs 35.5% (range, 3.0%-48.6%) in the control arm.

Most patients in the study had intermediate-risk disease, and the median percent of bone marrow blasts at baseline was 54% (range, 20%-95%) in the ivosidenib/azacitidine group and 48.0% (range, 17%-100%) in the placebo/azacitidine group.

Results showed that at a median follow-up of 12.4 months, the EFS improvement with ivosidenib/azacitidine compared with placebo/azacitidine was significant (HR, 0.33; 95% CI 0.16-0.69; 2-sided P = .0023). Notably, patients who did not achieve a CR by week 24 were considered to have an EFS event at day 1 of randomization. In the experimental arm, the median EFS in those who did not achieve a CR by week 24 was not evaluable (NE; 95% CI, 14.8-NE). In comparison, those in the control arm who did not achieve a CR by week 24 had a median EFS of 17.8 months (95% CI, 9.3-NE).

The EFS benefit observed with ivosidenib/azacitidine was consistent across the subgroups in the study.

The median OS observed with ivosidenib plus azacitidine was 24.0 months vs 7.9 months in the placebo arm (HR, 0.44; 95% CI, 0.27-0.73; 2-sided P = 0.001).

The ORR shown with ivosidenib/azacitidine was 62.5% with a CRh rate of 52.8% and a CR rate of 47.2%. The placebo/azacitidine arm, in comparison, demonstrated an ORR of 18.9% with a 17.6% CRh rate and 14.9% CR rate.

In the experimental arm, 98.6% of patients experienced any-grade TEAEs, and 93% experienced grade 3 or higher TEAEs. Hematologic TEAEs of any grade were observed in 77.5% of patients, and these events were grade 3 or higher in 70.4%. In the control arm, any-grade TEAEs were seen in 100% of patients, with 94.5% of patients having experienced grade 3 or higher TEAEs. Any-grade hematologic TEAEs occurred in 65.8% of the control arm, and these events were grade 3 or higher in 64.4%.

The most common any-grade hematologic TEAEs observed in the ivosidenib/azacitidine group vs the placebo/azacitidine group, respectively, were anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), neutropenia (28.2% vs 16.4%), and thrombocytopenia (28.2% vs 20.5%).

TEAEs that occurred most commonly in the experimental arm vs the control arm were nausea 42.3% vs 38.4%, respectively), vomiting (40.8% vs 26.0%), diarrhea (35.3% vs 35.6%), pyrexia 33.8% vs 39.7%), constipation (26.8% vs 52.1%), and pneumonia (23.5% vs 31.5%).

The TEAEs of special interest were grade 2 or higher differentiation syndrome and grade 3 or higher QT prolongation.

During the presentation, DiNardo, a clinical researcher in the Department of Leukemia within the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, explained the TEAEs of special interest. “I think it's important to show here, when you're looking at [ivosidenib/azacitidine], you're not adding a lot in terms of cytopenias,” she said.

“In terms of infections and in terms of neutropenic complications, it's overlapping with what you're seeing with azacitidine and placebo. So, in terms of its impact on cytopenias and infections, it is minimal. If anything, there are adverse events to be aware of. There is differentiation syndrome, as you would expect with differentiating agent therapy. And there is QT prolongation with ivosedenib that you need to be aware of, especially if you have a patient on fluoroquinolones and ondansetron for antiemetic therapy, etc. You have to be mindful of all the different QT-prolonging agents you have your patients on.”

Compared with what was observed at baseline, treatment with the combination of ivosidenib and azacitidine improved absolute neutrophil count compared with the control arm. Moreover, a larger percentage of patients in the ivosidenib/azacitidine arm achieved transfusion independence vs the control arm.

In terms of HRQOL, there was a clinically meaningful improvement with ivosidenib plus azacitidine over time, but there were few clinically meaningful improvements observed in the placebo/azacitidine arm.

“We don't see a lot of quality-of-life data presented in our AML studies. But I think more and more this is becoming a very important thing,” DiNardo explained, adding that a HRQOL score of 0.2 was observed at baseline.

“And what you can see is for the first 2 or 3 months, quality of life in our AML patients decreases, even in patients who are responding, you see this kind of slow decline. [It’s probably because] they're in and out of the hospital getting labs checked. And then it takes about 3 to 4 cycles for that to kind of get back to where they started at diagnosis. And then you can see patients on the combination are improving quality of life above and beyond where they were at diagnosis at the start of therapy.”

Reference

Dohner H, Montesinos P, Polo 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. . Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.