(S-075) Exposure-Overall Survival Analysis for Quizartinib in Newly Diagnosed Patients with FLT3-Internal-Tandem-Duplication-Positive Acute Myeloid Leukemia

Giovanni Smania – Pharmetheus AB, Sweden; Anais Glatard – Pharmetheus AB, Sweden; Pavan Vaddady – formerly Daiichi Sankyo, Inc., USA, currently Merck & Co., Inc., USA; Shintaro Nakayama – Quantitative Clinical Pharmacology – Daiichi Sankyo Co, Ltd., Japan; Hiroyuki Inoue – Quantitative Clinical Pharmacology – Daiichi Sankyo Co, Ltd., Japan; Enrica Mezzalana – Pharmetheus AB, Sweden; Ulrika Simonsson – Pharmetheus AB, Sweden; Malaz Abutarif – Quantitative Clinical Pharmacology – Daiichi Sankyo, Inc., USA; Ming Zheng – Quantitative Clinical Pharmacology – Daiichi Sankyo, Inc., USA

Objectives: Quizartinib, a highly potent type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor, was evaluated in newly diagnosed FLT3-ITD-positive acute myeloid leukemia (AML) patients in the phase 3 QuANTUM-First trial [1]. It was administered in combination with standard induction and consolidation chemotherapy at 40 mg and as monotherapy during continuation treatment at 30 mg for 15 days followed by a QT-guided dose escalation to 60 mg. Vaddady et al. provided model-informed drug development (MIDD) evidence supporting the adequacy of this dosing regimen in terms of QT prolongation [2]. The aim of the present analysis was to provide supportive MIDD evidence for its effectiveness.

Methods: The analysis data set consisted of 527 patients with 282 overall survival (OS) events (placebo: 268 patients, 156 events; quizartinib: 259 patients, 126 events) across all treatment phases. A parametric time-to-event (TTE) analysis including covariate search was conducted using NONMEM 7.5. The original analysis included data from all treatment phases. Following a request from the US Food and Drug Administration, an additional TTE analysis was conducted using data from the continuation phase only, with the aim of better understanding the benefits of the dose escalation to 60 mg.

Results: Kaplan-Meier (KM) curves for OS, stratified by quartiles of the daily average area under the curve (AUC) up to death/date of last dose, whichever is earlier, showed that most patients in the highest exposure quartile had longer survival times. However, this relationship was confounded by (i) quizartinib accumulation over time, (ii) escalation to 60 mg in the continuation phase and (iii) the treatment phase effect on quizartinib PK [3]. The predicted steady-state daily AUC following 40 mg/day in the induction phase (AUCss,ind) independent of these confounding factors and was selected as exposure metric for the model-based analysis.

Age was a statistically significant risk factor, with older patients being at higher risk. A linear positive ER relationship with AUCss,ind was found, but was associated with relatively large uncertainty (RSE 37.2 %). Univariate forest plots predicted a median (95% CI) HR of 0.790 (0.690-0.933) at the median AUCss,ind compared to placebo. Empirical forest plots of the HR showed that the drug effect was comparable across various patient subgroups.

In the analysis based on continuation phase only, quizartinib daily average concentration from the first continuation treatment dose up to death/date of last dose, whichever is earlier, (Cav,cont) was not found to be statistically significant. However, visual predictive checks showed underprediction of the ER relationship at higher exposure levels. A model assuming an ER relationship with Cav,cont better described the observed data, suggesting there was a trend of longer survival with higher quizartinib exposure.

Conclusions: OS was found to be related to quizartinib steady-state exposure in the induction phase. A modest positive trend was shown when evaluating OS from the start of the continuation phase alone. This supported the benefit of achieving higher quizartinib exposure while properly mitigating the risk of QT interval prolongation.

Citations: [1] Erba HP, Montesinos P, Kim HJ, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6
[2] Vaddady P, Smania G, Nakayama S, et al. Concentration‐QTcF analysis of quizartinib in patients with newly diagnosed FLT3‐internal‐tandem‐duplication‐positive acute myeloid leukemia. Clin Transl Sci. 2024;17(11):e70065. doi:10.1111/cts.70065
[3] Vaddady P, Glatard A, Smania G, et al. Population Pharmacokinetic Analysis of Quizartinib in Patients with Newly Diagnosed FLT3-internal-tandem-duplication-positive Acute Myeloid Leukemia. Clin Transl Sci. 2024;17(12). doi:10.1111/cts.70074

Keywords: AML, OS, exposure metrics