AGILE: 'Exciting' Survival Results for
IDH1-mutated AML

Neil Osterweil

December 13, 2021

ATLANTA — Patients with acute myeloid leukemia (AML) bearing mutations in isocitrate dehydrogenase 1 (IDH1) who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza) compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitadine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm University Hospital in Ulm, Germany.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

"The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life," he said.

Döhner was speaking at a press briefing here prior to the presentation of the trial results at the American Society of Hematology annual meeting.

"I'm really excited by the results from the AGILE trial," commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami's Sylvester Comprehensive Cancer Center, Miami, Florida, who moderated the briefing.

The results show "survival that's three times longer for a combination of ivosidenib plus azacitidine vs azacitidine alone in a very distinct population of patients who have an IDH1  mutation," he said.

"The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don't receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly non-intensive therapy, and it's probably on a spectrum between non-intensive and intensive therapy, and probably closer to 7+3 than a lot of people recognize," Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML — particularly those with comorbidities — who may not be able to tolerate venetoclax plus azacitidine, he added.

AGILE Results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2 delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial due to significant improvements in outcomes among patients assigned to the combination, and those data are reported here.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention-to-treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events — defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio 4.8; P < .0001), and respective overall response rates of 45% vs 14% (odds ratio 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA vs 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% vs 4.1%.

Infections (any grade) were less common with IVO-AZA, however, at 28.2% vs 49.3% with AZA alone. At the briefing, Medscape Medical News asked co-investigator Stephane de Botton, MD, Gustave Roussy cancer center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Döhner disclosed consultancy and other relationships with various companies. Sekeres has disclosed consulting/advising for Novartis, Takea/Millennium, and BMS.

63rd American Society of Hematology Annual Meeting: Abstract 697. Presented December 11 and 13, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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