Olutasidenib outcomes by prior number of regimens in the phase 2 pivotal cohort of patients with R/R AML
Introduction/Background/Significance: A subset of patients (7%-14%) with acute myeloid leukemia (AML) have mutations in the isocitrate dehydrogenase 1 gene (mIDH1). Olutasidenib, a selective, potent, oral inhibitor of mIDH1, is approved for treatment of relapsed/refractory (R/R) mIDH1 AML. Results from the phase 2 pivotal cohort (NCT02719574) demonstrated clinical efficacy and tolerability of olutasidenib, with a complete remission/complete remission with partial hematological recovery (CR/CRh) rate of 35% for a median duration of 25.3 months. Here we evaluated the efficacy and safety of olutasidenib in patients with R/R mIDH1-AML grouped by the number of prior treatment regimens.
Materials and Methods/Case Presentation/Objective: The pivotal cohort of the phase 2 study assessed olutasidenib 150 mg BID in adult patients and included efficacy endpoints of CR/CRh, overall response rate (ORR), duration of response, and overall survival (OS). This post hoc analysis evaluated outcomes based on when patients received olutasidenib: after 1-2 or ≥3 prior treatment regimens. Univariate and multivariate analyses were performed using logistic regression.
Results/Description/Main Outcome Measures: Among 147 efficacy-evaluable patients, 48 had received 1 prior regimen, 45 had 2 prior regimens, and 54 had ≥3 prior regimens. Median age was 72 years in patients with 1-2 prior regimens and 66.5 years in those with ≥3 prior regimens. Forty-three percent and 33% of patients had prior treatment with a hypomethylating agent, and 11% and 4% received prior venetoclax therapy (1-2 and ≥3 prior regimens groups, respectively). All 17 patients who had prior hematopoietic stem cell transplant were in the ≥3 prior regimens group (31%). Patients with 1-2 prior regimens had higher ORR (54% versus 39%), CR/CRh rate (41% versus 24%), CR rate (38% versus 22%), and longer median OS (13.0 months vs 8.9 months), compared to those with ≥3 prior regimens. Median time to CR/CRh was 1.9 months in both subgroups; 47% of patients with 1-2 prior therapies and 38% with ≥3 prior therapies required ≥2 months of treatment to achieve CR/CRh, and 11% and 15%, respectively, required >4 months. Univariate analysis identified several significant predictors of CR/CRh, including number of prior regimens (P=0.0393). In multivariate analysis, only bone marrow blast percentage (P< 0.0001) and transfusion independence at study entry (P=0.0019) remained significant; number of prior regimens was not significant (P=0.0526). The most common treatment-emergent adverse events (TEAEs) included nausea, decreased red blood cell count, and fatigue. Serious TEAEs were reported in 73% (68/93) and 78% (42/54) of patients in the 1-2 and ≥3 prior regimens groups, respectively, and TEAEs ≥grade 3 occurred in 89% (83/93) and 91% (49/54). No new safety signals were identified.
Conclusions: Olutasidenib demonstrated higher response rates (including CR and CRh) and improved survival when administered after 1-2 prior regimens versus ≥3, supporting earlier use in the R/R mIDH1-AML treatment paradigm. A substantial portion of patients in each group required more than 2 months to achieve a CR/CRh, supporting continuation of treatment in the absence of disease progression or unacceptable toxicity to allow adequate time for observation of clinical benefit.
