SOHO 2022: Ivosidenib combined with azacitidine has a better survival benefit than placebo in IDH1-mutant AML

According to the results of the Phase III AGILE study (NCT03173248), ivosidenib (Tibsovo) + azacitidine (Vidaza) showed benefits
in event-free survival (EFS), overall survival (OS), and clinical response compared with placebo + azacitidine in newly diagnosed IDH1-mutated acute myeloid leukemia (AML).
Previous Phase 3 results were published in NEJM: NEJM: Phase 3 study results of ivosidenib combined with azacitidine for the treatment of IDH1-mutated AML were announced, and patients benefited significantly

The results presented by principal investigator Courtney D.
DiNardo, Ph.
D.
, MD Anderson Cancer Center, at the 10th Annual Meeting of the American Society of Hematology-Oncology (SOHO), also showed that combination therapy has a favorable safety profile and that adverse reactions (TEAEs) after treatment can be controlled
.
In addition, patients treated with ivosidenib + azacitidine reported better health-related quality of life (HRQOL) outcomes
compared to patients in the placebo + azacitidine group.

AGILE is a global, randomized, double-blind study in which 200 patients from 20 countries randomized to receive ivosidenib 500 mg orally plus azacitidine 75 mg/m2 subcutaneously or intravenously once daily (n = 72) or matched placebo in combination with azacitidine (n = 74).

。 The primary endpoint evaluated in these patients was EFS, with secondary endpoints of complete response (CR) rate, OS, CR plus CR and hematologic recovery (CRh), and objective response rate
.

Patients enrolled in the study were aged > 18 years and had a centrally confirmed diagnosis of previously untreated AML
with IDH1 mutation.
Patients have not previously received IDH1 inhibitors or hypomethylation for myelodysplastic syndromes
.
Patients also need to have an ECOG performance status of 0 to 2, adequate liver and kidney function, and be eligible for intensive chemotherapy
.

The median age was 76 years (58-84 years) in the experimental group and 75.
5 years (45-94 years)
in the control group.
Male patients make up the majority
in both treatment groups.
Most patients in the study had an ECOG performance score of 1
at baseline.

The researchers assessed disease history at baseline and showed that 75.
0% of patients in the experimental group and 71.
6% of patients in the comparison group had new-onset AML
.
Secondary AML
occurred in 25% of ivosidenib/azacitidine and 28.
4% of placebo/azacitidine groups.
The median frequency of IDH1 mutation alleles in baseline bone marrow analysis was 36.
7% (range, 3.
1%-50.
5%) in the experimental group and 35.
5% (range, 3.
0%-48.
6%)
in the control group.

Most patients in the study had moderate-risk disease, with a median percentage of bone marrow blasts at baseline in the ivosidenib/azacitidine group and 48.
0% (17% to 100%)
in the placebo/azacitidine group.

Results showed a significant improvement in EFS compared with placebo/azacitidine at a median follow-up of 12.
4 months (HR, 0.
33; 95% CI 0.
16 to 0.
69; bilateral P = 0.
0023) compared with placebo/azacitidine.

Of note, patients who did not achieve CR before week 24 were thought to have developed an EFS event
on day 1 of randomization.
In the experimental group, median EFS for patients who did not reach CR by week 24 could not be assessed (NE; 95% CI，14.
8-NE）
。 In contrast, the control group that did not achieve CR at week 24 had a median EFS of 17.
8 months (95% CI, 9.
3-NE).

The EFS benefit observed with ivosidenib/azacitidine was consistent
across the subgroups studied.

The median OS observed with ivosidenib plus azacitidine was 24.
0 months compared with 7.
9 months in the placebo group (HR, 0.
44; 95% CI, 0.
27-0.
73; bilateral P = 0.
001).

Ivonib/azacitidine showed an ORR of 62.
5%, a CRh rate of 52.
8%, and a CR rate of 47.
2%.

In contrast, the placebo/azacitidine group had an ORR of 18.
9%, a CRh rate of 17.
6%, and a CR rate of 14.
9%.

In the experimental group, 98.
6% of patients developed any grade of TEAE and 93% developed ≥ grade 3 TEAE
.
Any level of hematological TEAE was observed in 77.
5% of patients, and these events were grade 3 or above
in 70.
4% of patients.
In the control group, 100% of patients developed any grade of TEAE and 94.
5% of patients developed grade 3 TEAE
≥.
The incidence of any grade of hematological TEAE was 65.
8% in the control group and 64.
4%
≥ grade 3 of these events.

The most common hematological TEAE of any grade observed in the ivosidenib/azacitidine versus placebo/azacitidine groups were anemia (31.
0 versus 28.
8 percent), febrile neutropenia (28.
2 versus 34.
2 percent), neutropenia (28.
2 versus 16.
4 percent), and thrombocytopenia (28.
2 versus 20.
5 percent).

The most common TEAE in the experimental versus control group was nausea (42.
3 versus 38.
4 percent), vomiting (40.
8 versus 26.
0 percent), diarrhea (35.
3 versus 35.
6 percent), fever (33.
8 versus 39.
7 percent), constipation (26.
8 versus 52.
1 percent), and pneumonia (23.
5 versus 31.
5 percent).

Of particular interest to TEAE are ≥ Grade 2 differentiation syndrome and ≥ Grade 3 QT prolongation
.

In the report, DiNardo, a clinical investigator in the Department of Leukemia in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, explains TEAE
of particular interest.
"I think it's important to show here that when you look at ivosidenib/azacitidine, you're not adding a lot in terms of cytopenia," she said
.

"In terms of infection and neutropenia complications, it overlaps
with what you see with azacitidine and placebo.
Therefore, in terms of its impact on cytopenia and infection, it is minimal
.
There are some adverse events to be aware of
, if any.
As you would expect from a differentiator treatment, there is a differentiation syndrome
.
You need to be aware of QT prolongation of evosenib, especially if you have patients taking fluoroquinolones and ondansetron for antiemetic therapy, etc
.
You must pay attention to all the different QT prolonging medications
your patients use.
”

Combination therapy with ivosidenib and azacitidine improved absolute neutrophil count
compared to what was observed at baseline.
In addition, a larger proportion of patients in the ivosidenib/azacitidine group achieved transfusion independence
compared with the control group.

In terms of HRQOL, ivosidenib plus azacitidine showed clinically meaningful improvement over time, but little clinically significant improvement
was observed in the placebo/azacitidine group.

"We didn't see a lot of quality of life data
in the AML study.
But I think it's increasingly becoming a very important thing, observing an HRQOL score of 0.
2
at baseline.
DiNardo added,

"What you can see is that in the first 2 or 3 months, our AML patients have a decline in quality of life, and even in patients who have remission, you see this slow decline
.
" This may be because they are in and out of the hospital for laboratory tests
.
Then it takes about 3-4 cycles to return to where it started at the time of
diagnosis.
You can then see an improvement in the quality of life of patients who received the combination therapy beyond where they were diagnosed at the beginning of
treatment.
”

Resources:

Dohner H, Montesinos P, Polo S, et al.
AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an idh1 mutation.
.
Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.