Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia

N Engl J Med · 2022146 patients (72 ivosidenib + azacitidine, 74 placebo + azacitidine)

Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. N Engl J Med. 2022. 386:1519-1531

Study type: Clinical trial
Study name: AGILE
Phase: Phase 3
Design: Randomised trial controlled with a matching placebo (ivosidenib or placebo, both with azacitidine)
Sample size: 146 patients (72 ivosidenib + azacitidine, 74 placebo + azacitidine)
Source: N Engl J Med · 2022
Trial registration: NCT03173248

In plain words

In some people with acute myeloid leukaemia, the cancer cells have a genetic change called an IDH1 mutation. This study looked at patients who were not fit for intensive chemotherapy. Adding a daily ivosidenib tablet to azacitidine injections raised the median survival from about 8 months to 24 months and increased the chance of staying free of relapse or treatment failure. Infections were less common in this group, but low white blood cell counts and bleeding were seen more often. A side effect called "differentiation syndrome" may also occur, so any new symptom during treatment should be reported to the care team quickly.

Key results

HR 0.33

Event-free survival

95% CI 0.16–0.69; P=0.002; median follow-up 12.4 months

37% vs 12%

Probability of event-free survival at 12 months

Estimate

24.0 vs 7.9 months

Median overall survival

HR for death 0.44 (95% CI 0.27–0.73); P=0.001

28% vs 34%

Grade 3 or higher febrile neutropenia

27% vs 16%

Grade 3 or higher neutropenia

41% vs 29%

Bleeding (any grade)

28% vs 49%

Infection (any grade)

14% vs 8%

Differentiation syndrome (any grade)

Drugs in this study:Azacitidine (Vidaza)

Dose and schedule cards

Ivosidenib + azacitidine (AGILE)

Newly diagnosed IDH1-mutated AML at age 75 or over or with comorbidities that preclude intensive treatmentEach drug’s schedule in the tableOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Newly diagnosed IDH1-mutated AML at age 75 or over or with comorbidities that preclude intensive treatment

Drug	Dose	Route	Schedule
All cycles
Ivosidenib	500 mg once a day (without a high-fat meal)	Oral	Continuously from day 1 of cycle 1
Azacitidine	75 mg/m² a day	Subcutaneous or IV	Days 1 to 7 (or days 1 to 5 and 8 to 9)

Cycle schedule: Every 28 days
Duration: Until progression or toxicity; at least 6 months to allow time for response

Boxed warning for differentiation syndrome. ECG before starting, weekly for the first 3 weeks and then at least monthly; QTc above 480 to 500: hold and resume at 500 mg after it falls to ≤480; above 500: hold and resume at 250 mg. Non-infectious leucocytosis (above 25×10⁹/L): hydroxyurea. With a strong CYP3A4 inhibitor, 250 mg.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ivosidenib + azacitidine

Ivosidenib 500 mg orally once daily, with azacitidine 75 mg/m² body surface area, subcutaneously or IV, for 7 days in each 28-day cycle. Treatment duration in the trial: further details in the full text of the paper.

According to the FDA label (Tibsovo): ivosidenib 500 mg orally once daily with azacitidine 75 mg/m² subcutaneously or IV daily on days 1 to 7 (or days 1 to 5 and 8 to 9) of each 28-day cycle; continue for at least 6 months to allow time for a response; ivosidenib should not be taken with a high-fat meal.

2Placebo + azacitidine (control group)

Placebo matching ivosidenib with azacitidine 75 mg/m² subcutaneously or IV for 7 days in each 28-day cycle.

Source of the regimen details: Abstract of the paper (N Engl J Med 2022) and the FDA label for ivosidenib (Tibsovo; DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with newly diagnosed IDH1-mutated acute myeloid leukaemia (AML) who were not eligible for intensive induction chemotherapy. Other inclusion criteria are not stated in the abstract.

Endpoints

Primary endpoint: event-free survival (EFS), defined as the time from randomisation to treatment failure (failure to achieve complete remission by week 24), relapse after remission or death from any cause, whichever occurred first.

Other outcomes reported in the abstract: overall survival and safety.

Safety and side effects

Common grade 3 or higher adverse events (ivosidenib + azacitidine versus placebo + azacitidine): febrile neutropenia 28% versus 34% and neutropenia 27% versus 16%. Bleeding of any grade 41% versus 29% and infection of any grade 28% versus 49%. Differentiation syndrome of any grade occurred in 14% versus 8% of patients.

Clinical significance and place in guidelines

According to the FDA label, ivosidenib (Tibsovo), in combination with azacitidine or as monotherapy, is indicated for newly diagnosed IDH1-mutated AML in adults aged 75 years or older or in adults whose comorbidities preclude the use of intensive induction chemotherapy. AGILE showed that in these patients, adding ivosidenib to azacitidine improves both event-free survival and overall survival compared with azacitidine plus placebo. This option applies only to patients with an IDH1 mutation, so the mutation status must be known at diagnosis.

Limitations

The study population was relatively small (146 patients) and the median follow-up in this report was 12.4 months. Only patients with an IDH1 mutation who were not eligible for intensive chemotherapy were enrolled. The comparator was azacitidine plus placebo, and no direct comparison was made with other azacitidine-based combinations (such as venetoclax + azacitidine). Neutropenia, bleeding and differentiation syndrome were more frequent in the ivosidenib group. The study was funded by the manufacturers.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.