Ivosidenib regimen extends OS, EFS for acute myeloid leukemia subset
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The addition of ivosidenib to azacitidine improved outcomes for certain patients with acute myeloid leukemia, according to study results presented at ASH Annual Meeting and Exposition.
The regimen appeared associated with a threefold increase in OS compared with azacitidine alone for newly diagnosed, induction chemotherapy-ineligible patients with isocitrate dehydrogenase 1 (IDH1) mutations, results of the randomized phase 3 AGILE study showed.
The combination also extended EFS and induced a higher complete response rate.
In addition, results showed a significant improvement in quality of life with the combination, according to researcher Stephane de Botton, MD, PhD, head of the hematology department at Institut Gustave Roussy in France.
“This is the first randomized trial in [this] specific subset of AML demonstrating a strong benefit over [azacytidine] alone,” de Botton told Healio. “The combination is a true nonintensive treatment for a frail population with no increased toxicity relative to the safety profile of [azacitidine alone] and [a] lower incidence of infections. ... The study shows that targeted therapy can be efficient and safe."
Approximately 10% of patients with AML harbor somatic mutations in IDH1.
Ivosidenib (Tibsovo, Agios) — an oral IDH1 inhibitor — is approved in the United States for treatment of adults with relapsed or refractory IDH1 mutation-positive AML, as well as for adults with newly diagnosed IDH1 mutation-positive AML who are aged 75 years or older or who are ineligible for intensive induction chemotherapy due to comorbidities.
Results of a phase 1B study that included 23 patients with newly diagnosed IDH1 mutation-positive AML showed the combination of ivosidenib and azacitidine had encouraging clinical activity and exhibited a favorable safety profile.
The global, double-blind AGILE trial included 146 patients from more than 20 countries with newly diagnosed, IDH1 mutation-positive AML ineligible for induction chemotherapy. All patients had ECOG performance status of 0 to 2.
Researchers randomly assigned 72 patients (median age, 76 years; interquartile range, 70.5-79.5) to 500 mg ivosidenib once daily plus azacitidine dosed at 75 mg/m2 subcutaneously or via IV for 7 days of each 28-day cycle. The majority (75%) of these patients had de novo AML, and 25% had secondary AML.
The other 74 patients (median age, 75.5 years; interquartile range, 70-80) received placebo plus azacitidine.
EFS served as the primary endpoint. Key secondary endpoints included OS, complete response rate, complete response plus complete response with partial hematologic recovery, and objective response rate.
A comparable percentage of patients in the ivosidenib and placebo groups had poor-risk genetics by European LeukemiaNet criteria (22.2% vs. 27%).
At data cutoff, 27 patients (37.5%) assigned ivosidenib and 12 patients (16.2%) assigned placebo remained on treatment.
Results showed a statistically significant improvement in EFS among ivosidenib-treated patients (HR = 0.33; 95% CI, 0.16-0.69).
The ivosidenib regimen also appeared associated with improvements in OS (median, 24 months vs. 7.9 months; HR = 0.44; 95% CI, 0.27-0.73), complete response rate (47.2% vs. 14.9%), the composite of complete response and complete response with partial hematologic recovery (52.8% vs. 17.6%), complete response rate by 24 weeks (37.5% vs. 10.8%) and ORR (62.5% vs. 18.9%).
Researchers reported comparable rates of adverse events in the combination and azacitidine monotherapy groups.
All-grade adverse events that occurred among at least 20% of patients assigned ivosidenib included nausea (42.3% with ivosidenib vs. 38.4% with placebo), vomiting (40.8% vs. 26%), diarrhea (35.2% vs. 35.6%), pyrexia (33.8% vs. 39.7%), anemia (31% vs. 28.8%), febrile neutropenia (28.2% vs. 34.2%), thrombocytopenia (28.2% vs. 20.5%), constipation (26.8% vs. 52.1%) and pneumonia (23.9% vs. 31.5%).
Nearly all patients experienced grade 3 or higher adverse events (93% with ivosidenib vs. 94.5% with placebo). Grade 3 or higher adverse events that occurred among at least 20% of patients assigned ivosidenib included febrile neutropenia (28.2% with ivosidenib vs. 34.2% with placebo), anemia (25.4% vs. 26%), thrombocytopenia (23.9% vs. 20.5%) and pneumonia (22.5% vs. 28.8%).
Researchers reported higher rates of investigator-assessed differentiation syndrome in the ivosidenib group (all grade, 14.1% vs. 8.2%; grade 3 or higher, 4.2% vs. 4.1%).
The independent data monitoring committee recommended study enrollment be discontinued prematurely due to the efficacy observed.
After researchers designed the AGILE trial, the FDA approved the BCL-2 inhibitor venetoclax (Venclexta; AbbVie, Genentech) as first-line treatment for this patient population. The combination of venetoclax plus azacitidine now is the current standard in much of the world for patients with AML ineligible for intensive chemotherapy.
Although there is no direct comparison of the ivosidenib-azacitidine and venetoclax-azacitidine combinations, researchers contend the results of AGILE show ivosidenib-azacitidine can be a viable treatment option that may be beneficial for patients with IDH1 mutations, a traditionally difficult-to-treat subgroup.
“This high-risk population still needs improved strategies to prevent relapse or improve the response to front-line treatment,” de Botton said in a press release. “Because of this drug’s mechanism of action, we were able to show a significant increase in the rate of complete response and improvement in symptoms without any increase in complications related to immunosuppression and infection.”
Perspective
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Douglas Tremblay, MD
This is a potentially practice-changing study for patients with IDH1-mutated AML ineligible for induction chemotherapy. As a phase 3 study, the added value of ivosidenib is clearly demonstrated with improvements in response rates and survival.
It is clear that ivosidenib plus azacitidine is an effective option for untreated patients with AML who harbor an IDH1 mutation and are unfit for intensive chemotherapy. However, the implications of this study remain unclear, given the role of hypomethylating agents with venetoclax in the upfront treatment of AML. Prior studies have identified favorable response to this combination among patients with IDH1 mutations, so it is unclear if venetoclax or ivosidenib should be given with azacitidine in this setting. Next steps include evaluating the triplet combination (ivosidenib, azacitidine and venetoclax) in a randomized setting to see if this improves response rates, duration of response and survival.
Perspective
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Mikkael A. Sekeres, MD
I’m really excited by the results from the AGILE trial. They show a survival that is three times longer for the combination of ivosidenib and azacitidine vs. azacitidine alone in a very distinct population of patients who have an IDH1 mutation. This is a small percentage of older adults, but it is a real percentage. The question that will arise is: If the standard is to give azacitidine and venetoclax for patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial fit in? The combination of azacitidine and venetoclax is not truly nonintensive therapy. It’s probably on a spectrum between nonintensive and intensive therapy, and it’s probably closer to 7+3 than a lot of people recognize. I would think 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. Of course, ivosidenib is not approved yet for this indication upfront in the United States.
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Montesinos P, et al. Abstract 697. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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