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Tibsovo, Azacitidine Combo Shows Improved Survival, Response in Newly Diagnosed IDH1-Mutant AML

NEW YORK – Results from a Phase III randomized trial of ivosidenib (Servier Pharmaceuticals' Tibsovo) plus azacitidine chemotherapy showed the combination is effective in newly diagnosed acute myeloid leukemia patients with an IDH1 mutation who are ineligible for intensive induction chemotherapy.

Single-agent ivosidenib is already approved in the US for relapsed or refractory AML patients with IDH1 mutations and for newly diagnosed AML patients with these mutations who are 75 years or older or cannot tolerate intensive induction chemotherapy due to comorbidities.

The randomized Phase III AGILE trial compared ivosidenib plus azacitidine against placebo plus azacitidine in newly diagnosed IDH1-mutant patients who are ineligible for intensive induction chemotherapy. The AGILE study builds on results from a single-arm Phase Ib trial in the same population, which showed that the combination of ivosidenib and azacitidine resulted in a 78 percent overall response rate and a nearly 61 percent complete remission rate.

"In this specific subtype of AML, genetically defined by mutant IDH1, the results were strongly improved by [ivosidenib] therapy," Stephane de Botton, an investigator in AGILE, said at a press briefing during the ASH annual meeting. "Based on these results and the tolerance in this older population, [ivosidenib and azacitidine] should be the preferred treatment in this subgroup of patients."

As of the data cutoff on March 18, 146 patients had been randomized. The median age in the AGILE trial was 76 years. Based on results from these patients, treatment with ivosidenib and azacitidine showed improved event-free survival and overall survival compared to azacitidine alone.

The median overall survival in the ivosidenib-azacitidine arm was 24 months compared to 7.9 months in the azacitidine-placebo arm. The complete remission rate was more than three times higher in the ivosidenib-azacitidine arm, 47.2 percent compared to 14.9 percent on azacitidine-placebo. The median time to complete remission was also slightly higher, 4.2 months on ivosidenib-azacitidine and 3.8 months on azacitidine-placebo.

Because the researchers were evaluating the ivosidenib-azacitidine combination in older patients and patients who had comorbidities, they also explored the combination's effect on health-related quality of life. Across all metrics, including symptoms like fatigue, appetite loss, and diarrhea, patients in the ivosidenib-azacitidine arm reported high quality-of-life improvements. The researchers noted that this metric was important for this subset of patients who may be in more fragile health.

The standard-of-care in AML patients who are ineligible for chemo is venetoclax (AbbVie/Genentech's Venclexta) in combination with azacitidine. However, the researchers said it is difficult to compare the results from the AGILE trial with separate studies of venetoclax. De Botton suggested that ivosidenib and venetoclax should be studied head-to-head to produce definitive answers.

Mikkael Sekeres, chief of the division of hematology at Sylvester Comprehensive Cancer Center, who was not involved with the AGILE study, noted at the press briefing that ivosidenib-azacitidine could be an option for patients who need even less intensive therapy than venetoclax-azacitidine.

"The combo of azacitidine and venetoclax is not truly non-intensive therapy," Sekeres explained. "It's probably on a spectrum between non-intensive and intensive therapy and is probably closer to 7+3 [chemotherapy] than a lot of people recognize." 7+3 chemotherapy comprises seven days of cytarabine and three days of an anthracycline antibiotic or an anthracenedione.

"For an older population, particularly those with comorbidities who might not be able to tolerate the combination of azacitidine and venetoclax, the combination of azacitidine and ivosidenib represents a very real option," Sekeres continued.

Though cross-study comparisons are challenging, Hartmut Döhner, a professor at the University Hospital Ulm who presented the AGILE results at ASH on Monday, cited pooled results from patients with IDH1- or IDH2-mutated AML in two studies of venetoclax-azacitidine. Based on that pooled analysis, median overall survival on venetoclax-azacitidine was 17 months, Döhner said, compared to 24 months on ivosidenib-azacitidine in the AGILE study. This, he said, suggested that ivosidenib-azacitidine had a better safety profile and efficacy than venetoclax-azacitidine.

"The combination of azacitidine and venetoclax is quite myelosuppressive and the frequency of neutropenia, fever, and infections is increased with [this regimen]," he continued. "That appears not to be the case [in AGILE], and there are less frequent infections with ivosidenib-azacitidine." Although AML patients with IDH1 and IDH2 mutations in the pooled analysis of venetoclax-azacitidine had similar clinical responses, there were differences in terms of these subgroups' sensitivity to BCL2 inhibition by venetoclax, Döhner added.

Ivosidenib was first approved in the US as a monotherapy for relapsed and refractory AML patients with an IDH1 mutation in 2018. The drug was again approved the following year for newly diagnosed IDH1-mutated AML patients who are 75 years or older or who can't receive intensive induction chemo.

Earlier this year Agios Pharmaceuticals, which recently sold ivosidenib and its entire oncology portfolio to Servier, pulled its European marketing submission for ivosidenib monotherapy in IDH1-mutated relapsed and refractory AML after the European Medicines Agency's Committee for Medicinal Products for Human Use found insufficient evidence demonstrating ivosidenib's benefit in this indication. The company had submitted data from a single-arm, Phase I trial involving 174 patients, of which roughly 33 percent achieved either complete remission or complete remission with partial hematological recovery.

In a statement about the AGILE data, Claude Bertrand, executive VP of R&D at Servier, said the company planned to share the results of the ivosidenib-azacitidine combination in newly diagnosed IDH1-mutant AML patients who cannot tolerate chemo with regulatory authorities.