NCRI AML18 trial: Quizartinib + intensive chemotherapy in newly diagnosed AML

The prospective, randomized UK National Cancer Research Institute (NCRI) AML18 trial (NCT02272478) evaluated the addition of the FLT3 inhibitor quizartinib following intensive chemotherapy (IC) and as maintenance therapy in 463 patients aged >60 years with newly diagnosed (ND) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), regardless of FLT3 mutation status. The primary endpoint was overall survival (OS). Results were published in Blood by Knapper et al.

Key data: At a median follow-up of 76 months, 5-year OS in patients not selected for FLT3 status was not significantly different between the quizartinib (n = 232) and no quizartinib (n = 231) groups (35% vs 33%; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.79–1.24; p = 0.937). Non-relapse mortality (NRM) was increased with quizartinib vs without (HR, 1.64; 95% CI, 1.04–2.59; p = 0.032). In a pre-planned subgroup analysis, patients with FLT3-mutated (FLT3m) disease who received quizartinib demonstrated significantly improved 5-year OS (47% vs 25%; HR, 0.59; 95% CI, 0.37–0.93; p = 0.024) and a significant reduction in relapse risk (HR, 0.57; 95% CI, 0.35–0.90; p = 0.017) vs those not treated with quizartinib. No survival benefit or reduction in relapse risk was observed with vs without quizartinib in patients with FLT3-wild-type AML. The most common Grade 3/4 adverse event was febrile neutropenia.

Key learning: In the NCRI AML18 trial, the addition of quizartinib following IC did not demonstrate a significant benefit in a non-FLT3-selected population of patients aged >60 years with AML. Adding quizartinib significantly improved OS in patients with FLT3m AML, primarily through reduced relapse risk; however, it conferred no survival benefit in patients with FLT3-wild-type AML. These findings differ from the results of the recent phase II QUIWI trial (NCT04107727), which showed improved event-free survival (EFS) and OS with quizartinib vs placebo plus IC in patients with ND FLT3-internal tandem duplication (ITD)-negative AML. This could potentially be attributed to the different quizartinib doses administered (40 mg in AML18; 60 mg in QUIWI), the older patient population, and the later introduction of quizartinib (from chemotherapy course 2 vs from course 1) in NCRI AML18 vs QUIWI.