Safety and efficacy of olutasidenib in patients with IDH1-mutated relapsed/refractory AML

Olutasidenib is a selective, oral, small molecule inhibitor of isocitrate dehydrogenase 1 (IDH1) that has been granted approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory (R/R) IDH1-mutated acute myeloid leukemia (AML).

Olutasidenib was assessed for safety and efficacy in the phase I/II 2102-HEM-101 trial (NCT02719574), topline results from which have been previously covered by the AML Hub. Following positive results from the phase I portion of this trial, Cortes¹ presented phase II results at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, which we are pleased to summarize below.

Study design and patients

In this open-label, multicenter study, 153 patients with R/R AML and a median age of 71.0 years received ≥1 dose of olutasidenib monotherapy (phase I identified a dose of 150 mg, twice daily, in continuous 28-day cycles). Of these patients, 66% had de novo AML and 34% had secondary AML. The majority (73%) of patients had intermediate cytogenetics, with 17% and 4% having poor and favorable cytogenetics, respectively. The primary endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh) rate (CR+CRh). Secondary endpoints included overall response rate, duration of CR+CRh, duration of overall response, rate of transfusion independence, and overall survival (OS).

Results

Response rates

Of the 147 patients evaluable for response, the:

• CR+CRh rate was 35% (Table 1);
• median time to CR+CRh response was 1.9 months (range, 0.9–5.6); and
• median duration of CR+CRh response was 25.9 months (95% CI, 13.5–not evaluable).

Table 1. Response rates in patients who received olutasidenib monotherapy*

CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete recovery; MLFS, morphologic leukemia-free state; ORR, overall response rate; PR, partial remission. *Adapted from Cortes.1
Response, %	Patients (n = 147)
CR	32
CRh	3
CR+CRh	35
CRi	10
PR	2
MLFS	1
ORR	48
Non-responders	35

Survival outcomes

The median OS was 11.6 months (95% confidence interval [CI], 8.9–15.5; n = 153) and the estimated 18-month survival among patients who achieved CR+CRh was 78%. Within the different response categories, the median OS was:

• not reached (95% CI, 22.8–not reached) among patients who achieved CR+CRh;
• 13.7 months (95% CI, 6.0–not reached) among other responders; and
• 4.0 months (95% CI, 3.2–5.8) among non-responders.

Transfusion independence

At baseline, 86 patients were platelet and/or red blood cell transfusion dependent. Among these patients, 34% became transfusion-independent by 56 days, across all response groups. Transfusion-independence rates were higher among patients who achieved CR+CRh than among other responders.

Safety

Of the 153 patients, 14% experienced differentiation syndrome (Table 2), which led to one death. Overall, 31% of patients died, mostly due to the progression of AML (14%). Treatment was discontinued due to treatment-emergent adverse events in 31% of patients, the majority due to disease progression (14%).

Table 2. Treatment-emergent adverse events in patients who received olutasidenib*

ALT, alanine transaminase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase. *Adapted from Cortes.1
Adverse events, %	All grades (>5%)	Grade 3 or 4 (>2%)
Any adverse event	73	39
Nausea	23	0
Differentiation syndrome	14	8
Leukocytosis	13	5
Increased ALT	8	3
Constipation	8	0
Fatigue	7	1
Vomiting	7	0
Anemia	6	5
Increased AST	6	2
Thrombocytopenia	5	4
Neutropenia	5	5
GGT increased	5	5
Hepatic enzyme increased	4	3

Conclusion

Olutasidenib demonstrated clinical efficacy with a manageable safety profile in this population of patients with R/R IDH1-mutated AML. Clinical responses were durable and transfusion independence was achieved across all response groups.