Quality-Adjusted Time without Symptoms or Toxicity (Q-TWiST) Analysis of Quizartinib Vs Salvage Chemotherapy in Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Introduction: R/R FLT3-ITD AML is an aggressive hematologic malignancy with a generally poor prognosis and high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). QuANTUM-R (NCT02039726), a large, global, phase 3, randomized, controlled trial, showed that single-agent quizartinib significantly prolonged overall survival (OS) vs salvage chemotherapy (SC) in patients with R/R FLT3-ITD AML after first-line treatment with or without HSCT (Cortes et al, Lancet Oncol 2019). To evaluate both quality and quantity of life for patients with R/R FLT3-ITD AML, we conducted a Q-TWiST analysis of QuANTUM-R data to compare survival between patients receiving quizartinib and SC adjusted for quality of life (QOL).

Methods: The primary analysis cohort was the intent-to-treat (ITT) QuANTUM-R population, which included 367 patients (245 patients receiving quizartinib; 122 patients receiving SC). The secondary analysis cohort was the per-protocol analysis set (PPS), which excluded patients randomized but not treated and patients with major protocol violations who would affect assessment of efficacy endpoints (231 patients receiving quizartinib; 88 patients receiving SC).

Each patient's OS was partitioned into 3 health states: time with any grade 3/4 treatment-emergent adverse events (TEAEs) before relapse (TOX), time without relapse or grade 3/4 toxicity (TWiST), and time after relapse (REL). Q-TWiST was assessed at 104 weeks (approximate median follow-up of QuANTUM-R) as the mean time spent in each state weighted by its respective QOL, represented by health utility (u; 0.0-1.0). Q-TWiST was calculated as follows:

Q-TWiST = u(TWiST) × TWiST + u(TOX) × TOX + u(REL) × REL

for which u(TWiST), u(TOX), and u(REL) represent the utilities applied to the restricted mean time in TWiST, TOX, and REL, respectively.

Relative Q-TWiST gain (ie, Q-TWIST gain divided by mean OS of salvage chemotherapy) of ≥ 15% was considered clinically important, based on published minimally important difference norms (Revicki et al, Qual Life Res 2006).

The base case that assessed the Q-TWiST difference between quizartinib and SC for the ITT population included any grade 3/4 TEAEs and set utilities at commonly assumed values: u(REL) = u(TOX) = 0.5, relative to u(TWiST) = 1.0. A sensitivity analysis was conducted for which u(TOX) and u(REL) were varied from 0.0 to 1.0. The following additional scenarios analyses were conducted: (1) including only treatment-related (TR) grade 3/4 TEAEs, (2) assessing Q-TWiST difference between quizartinib and SC for the PPS cohort, and (3) including only TR grade 3/4 TEAEs for the PPS cohort. 95% CIs were estimated via nonparametric bootstrap.

Results: For the ITT population, quizartinib was associated with a mean OS gain of 8.5 weeks vs SC at 104 weeks from randomization (Table). In base case, the mean (95% CI) Q-TWiST gain at 104 weeks for quizartinib vs SC was 6.7 weeks (1.7-12.3; relative gain, 20.3%), which was statistically significant and clinically meaningful (Table). For the sensitivity analysis for which u(TOX) and u(REL) were varied from 0.0 to 1.0, Q-TWiST gains for quizartinib ranged from 5.0 (u[REL] = u[TOX] = 0.0) to 8.5 weeks (u[REL] = u[TOX] = 1.0). The relative Q-TWiST gains for quizartinib vs SC remained clinically important, irrespective of the values for u(TOX) and u(REL) and ranged from 15.2% to 25.5% (Figure). In the scenario analyses (Table), (1) when only TR grade 3/4 TEAEs were included, the Q-TWiST gain for quizartinib was 7.4 weeks (2.2-13.0; relative gain, 22.5%), (2) in the PPS cohort, the mean (95 % CI) Q-TWiST gain for quizartinib was 6.9 weeks (0.8-13.5; relative gain, 20.7%), and (3) when including only TR grade 3/4 TEAEs in the PPS, the Q-TWiST gain for quizartinib was 7.5 weeks (1.5-14.2; relative gain, 22.5%).

Conclusions: Quizartinib significantly prolonged quality-adjusted survival vs SC in patients with R/R FLT3-ITD AML after disease control, safety, and QOL were accounted for, providing evidence of meaningful clinical benefit in a patient population with few treatment options. To put these results in perspective, the relative Q-TWiST gains for quizartinib reported herein are larger than nearly 90% of the relative Q-TWiST gains reported in a recent systematic review of 81 Q-TWiST comparisons across 13 cancers (Solem et al, Exp Rev Pharmacoecon Outcomes Res 2018).

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