IVO-AZA combo therapy boosts OS in IDH1-mutated AML

The combination of ivosidenib and azacitidine (IVO-AZA) improves event-free and overall survival (OS) vs AZA alone in patients with acute myeloid leukaemia (AML) bearing somatic mutations in isocitrate dehydrogenase 1 (IDH1), the AGILE trial has shown.

IVO-AZA was associated with a 67-percent reduction in the risk of treatment failure, relapse, or death, and a 56-percent improvement in OS, reported Dr Hartmut Döhner from Ulm University Hospital in Ulm, Germany at ASH 2021.

Median OS was 24 months with IVO-AZA vs 7.9 months for AZA-placebo. “This translated into a hazard ratio of 0.44 (p=0.0005) for death with IVO-AZA,” added Döhner.

The IVO-AZA combination was safe and well-tolerated and resulted in fewer infections vs AZA-placebo. “To top it all, the clinical benefit of IVO-AZA was supported by favourable health-related quality of life in these patients,” Döhner said in a press briefing prior to his presentation.

A better choice

Briefing moderator Dr Mikkael Sekeres from the Sylvester Comprehensive Cancer Center, the University of Miami in Miami, Florida highlighted that survival was three times longer with IVO-AZA.

“If the standard of care is to give azacitidine and venetoclax to patients who do not receive intensive chemotherapy in the inpatient setting, where does this trial end? I would say the combination of azacitidine is not truly a nonintensive therapy, it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to 7+3 than a lot of people recognize,” Sekeres commented.

He said IVO-AZA may be “a better choice” in older patients with IDH1-mutated AML, particularly those with comorbidities who may not be able to tolerate venetoclax plus azacytidine.

IVO is US FDA-approved as a solo agent in previously treated IDH1-mutated AML and for certain newly diagnosed patients who are ineligible for intensive chemotherapy. Researchers sought to find out if adding AZA to IVO could improve outcomes in this difficult-to-treat population.  

AGILE population

AGILE enrolled 146 patients with IDH1 mutations who were randomly assigned to oral IVO 500 mg daily plus AZA 75 mg/m² delivered subcutaneously or intravenously, or AZA-placebo. [ASH 2021, abstract 697]

The median age of the patients was 76 years; 75 percent of patients in each arm had de novo AML, 25 percent had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. Many of them had intermediate cytogenetic risk disease.

The trial was stopped after an interim analysis due to significant improvements in patient outcomes in those assigned to IVO-AZA.

By week 24, there were significantly fewer treatment failures, relapse from remission, or death from any cause in the IVO-ASA group (hazard ratio [HR], 0.33; p=0.0011). Event-free survival and OS were consistent across subgroups, including in patients with de novo disease, demographics, baseline cytogenetic risk status, WHO classification of AML, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favoured IVO-AZA, with a complete response rate of 34 percent vs 11 percent for AZA alone (odds ratio [OR], 4.8; p<0.0001).  Overall response rates were 45 percent vs 14 percent (OR, 7.2; p<0 .0001), respectively.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome (14.1 percent with IVO-AZA vs 8.2 percent with AZA alone). Grade 3 or higher QT interval prolongation was also more frequent with IVO-AZA (9.9 percent vs 4.1 percent).

However, infections of any grade were less common with IVO-AZA. “This was likely because the combination regimen results in greater production of neutrophils and therefore, better protection against infections vs AZA alone,” commented AGILE co-investigator Dr Stephane de Botton from Gustave Roussy Cancer Center in Villejuif, France.