Updated guidelines recommend olutasidenib as a targeted therapy for patients with relapsed/refractory acute myeloid leukemia with an IDH1 mutation.
Olutasidenib (Rezlidhia) has been added by the National Comprehensive Cancer Network (NCCN) to the latest NCCN Clinical Practice Guidelines in Oncology for the treatment of adult patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) who harbor the isocitrate dehydrogenase-1 (IDH1) mutation.1
This addition follows the FDA approval of olutasidenib for the treatment of adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test.
Olutasidenib is an oral, small molecule, inhibitor of mutated IDH1 which works by binding and inhibiting mIDH1 to reduce 2-hydroxyglutarate levels and restore normal cellular differentiation of myeloid cells.
"We are pleased that [olutasidenib] was quickly added to the NCCN Guidelines® for AML, receiving important recognition as an appropriate treatment option for adult R/R AML patients with an IDH1 mutation," said Raul Rodriguez, president and chief executive officer of Rigel Pharmaceuticals, Inc. "Inclusion in the NCCN Guidelines for AML reinforces the strength of the data, which supports the safety and efficacy of [olutasidenib]."
The FDA granted olutasidenib approval based on the positive findings from the Study 2102-HEM-101 (NCT02719574). In the phase 2 cohort of the open-label, multicenter trial, treatment with olutasidenib led to high complete response rates in patients with R/R AML and the agent also had manageable toxicity.
Within the safety population, 153 patients with IDH1-mutant were enrolled, all of whom received at least 1 dose of olutasidenib. In the efficacy evaluable population, 147 patients with centrally confirmed IDH1 mutations who received the first dose of olutasidenib at least 6 months before the data cutoff date were included. Additionally, there were 6 patients without centrally confirmed IDH1 mutations who were excluded from the trial.
The primary end point of the trial was complete response (CR)+CR with partial hematologic recovery (CRh) rate, per modified 2003 International Working Group criteria, and secondary end points included overall response rate (ORR), duration of CR+CRh, duration of response (DOR), transfusion independence rate including red blood cells (RBCs) and/or platelets, and overall survival (OS).
Findings presented during the American Society of Hematology (ASH) Annual Meeting revealed that the CR rate observed with olutasidenib was 32% (95% CI, 24.5%-40.2%), and the CRh rate was 3%. The median time to CR was 2.8 months (range, 0.9-7.4) and the median time to CRh was not assessed. The combined CR+CRh rate was 35% (95% CI, 27.0%-43.0%), and the combined median time to response was 1.9 months (range, 0.9-5.6).
Ten percent of patients had a CR with incomplete recovery (CRi), while 2% had a partial response, 1% had a morphologic leukemia-free state, and 35% did not respond.2
For the secondary end points, the ORR was 48%, and the median time to response of 1.9 months (range, 0.9-10.2). The median OS was 11.6 months (95% CI, 8.9-15.5). Then for the CR+CRh responders, other responders, and non-responders, the median OS was not reached (NR; 95% CI, 22.8-NR), 13.7 months (95% CI, 6.0-NR), and 4.0 months (95% CI, 3.2-5.8), respectively. For patients with a CR+CRh, the estimated 18-month survival rate was 78%.
Among the 86 patients who were red blood cell and/or platelet transfusion dependent at baseline, 34% achieved 56-day transfusion independence. Higher transfusion independence rates were also seen in baseline transfusion-dependent patients who achieved CR+CRh compared with other responders.
Further, 11% of patients were eligible for hematopoietic stem cell transplantation (HSCT) after they received olutasidenib. One patient discontinued olutasidenib due to an adverse event (AE) prior to HSCT. Another 15 patients discontinued olutasidenib for HSCT and of them, 11 had a CR+CRh, 3 achieved a CRi, and 1 had stable disease.
Regarding safety, 73% of patients experienced any-grade AE while 39% had a grade 3 or 4 AE. Treatment-related AEs which were the most common included nausea (23%), differentiation syndrome (14%) leukocytosis (13%) alanine aminotransaminase increases (8%), constipation (8%), and fatigue (7%).
Based on these data, olutasidenib is now included as a recommended targeted therapy for adult patients with R/R AML with an IDH1 mutation.