Combination of ivosidenib and azacitidine in patients with newly diagnosed IDH1-mutated AML

Elderly patients with acute myeloid leukemia (AML) who are unsuitable for high dose chemotherapy have limited treatment options and a poor prognosis. Approval of hypomethylating agents, like azacitidine, as monotherapy in elderly patients, was based on results from a phase III trial (NCT01074047). The study demonstrated a one-year survival rate of 46.5% with an overall response rate (ORR) of 27.8% and a complete remission (CR) rate of 19.5%.¹ Recently, azacitidine in combination with venetoclax was also approved by the US Food and Drug Administration (FDA) based on two open-label studies (NCT02203773, NCT02287233). This combination in 145 patients achieved an ORR of 67%, a CR rate of 37%, and a 1-year OS rate of 59%.² This combination has become a current standard of care for newly diagnosed (ND) patients with AML in the US who cannot tolerate intensive treatment.

With the introduction of ivosidenib (AG-120), a first-in-class inhibitor of mutated IDH1 gene (mIDH1) targeting somatic mutations in the gene that are present in around 10% of patients with AML, became available. When used as a monotherapy in patients with mIDH1 ND AML, ivosidenib has shown to result in 54.4% overall response and 42.4% CR.³ In order to further improve outcome in these difficult to treat patients and based on encouraging in vitro results⁴, Courtney DiNardo from the University of Texas MD Anderson Cancer Center, Houston, US, and colleagues investigated the safety and efficacy of ivosidenib and azacitidine combination. The data from a phase Ib clinical trial (NCT02677922) investigating the combination in patients with ND AML was presented at the 2019 meeting of the Society of Hematologic Oncology (SOHO).⁵

Methods

• In total 23 adult patients with mIDH1 ND AML (Table 1) ineligible for intensive chemotherapy were recruited (seven in the dose-finding phase and 16 in the expansion phase)

• Treatment consisted of ivosidenib 500mg once a day in continuous 28-day cycles and azacitidine 75mg/m²/day subcutaneously on Days 1-7 in each 28-day cycle

Table 1. Baseline characteristics of all 27 patients.

BMMCs, bone marrow mononuclear cells; ECOG PS, Eastern Cooperative Oncology Group performance status; VAF, variant allele fraction; * quantified by digital PCR

Median age (range), years

76 (61-88)

Age ≥ 75 years, n (%)

12 (52%)

Number of females

12

mIDH1 VAF in BMMCs, median (range)*

35 (16-76)

ECOG PS, n (%)

    0

    1

    2

 

5 (22%)

14 (61%)

4 (17%)

Disease history, n

    De novo AML

    Secondary AML

 

15 (65%)

8 (35%)

Cytogenetic risk status, n

    Intermediate

    Poor

 

15 (65%)

5 (22%)

Main findings

• At the time of data cut off, the median follow-up was 16.1 months

• The range of number of treatment cycles was 1 – 30, with a median of 15 cycles

• Ten patients (43.5%) remained on the treatment

• Main reasons for discontinuation were a progressive disease, physician decision, and withdrawal by patient

• Overall survival at 12-month was 82% (95% CI, 58.8 – 92.8)

• The overall response rate was 78.3% (95% CI, 56.3 – 92.5) with the median time to response 1.8 months (95% CI, 0.7 – 3.8)

• CR rate was 60.9% (95% CI, 38.5 – 80.3) with the median time to CR of 3.7 months (95% CI, 0.8 – 15.7)

• The median duration of response was not reached at the time of data cut-off

• There was good concordance between IDH mutation clearance and CR

Safety

• Thrombocytopenia, followed by nausea, and diarrhea were the most common adverse events AEs regardless of cause (Table 2)

• Six deaths were recorded; none were considered to be treatment-related (three were on-treatment due to sepsis and three in follow-up due to disease progression)

• Thrombocytopenia, anemia and febrile neutropenia were main occurring grade ¾ AEs

Table 2. Adverse events (AEs) observed in ≥ 30% of patients regardless of cause.

All-grade AEs

Patients N=23 (%)

Thrombocytopenia

65

Nausea

61

Diarrhea

57

Anemia

52

Constipation

52

Febrile neutropenia

44

Pyrexia

44

Vomiting

35

Fatigue

35

Hypokalemia

35

Dizziness

35

Neutropenia

35

Insomnia

35

Back pain

30

Conclusion

The efficacy data, of the ivosidenib and azacitidine combination in patients with AML with mIDH1 look encouraging. The reported safety profile is consistent with ivosidenib and azacitidine monotherapies. The combination is currently investigated in phase III clinical trial AGILE (NCT03173248) in patients with mIDH1 ND AML ineligible for intensive therapy.