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FLT3 Inhibitor Doubles Overall Survival in Acute Myeloid Leukemia

— Median OS improved from 15 months to nearly 32 months with quizartinib

MedpageToday
A photo of a mature man receiving chemotherapy.

Incorporating quizartinib into standard treatment for newly diagnosed acute myeloid leukemia (AML) followed by maintenance therapy with the investigational FLT3 inhibitor improved survival for patients with internal-tandem-duplication (ITD) mutations of FLT3, a placebo-controlled randomized trial showed.

In the phase III study of over 500 patients undergoing standard induction and consolidation therapy, median overall survival (OS) increased from 15.1 months with placebo to 31.9 months with quizartinib (HR 0.78, 95% CI 0.62-0.98, P=0.032), reported Harry P. Erba, MD, of Duke Cancer Institute in Durham, North Carolina, and colleagues.

"Quizartinib provides a new, effective, and generally well-tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML," the researchers wrote in .

Patients in both arms of the so-called could receive chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both as consolidation, and went on to receive 3 years of maintenance therapy with either placebo or quizartinib.

"The significant improvement in overall survival is clinically relevant because of the high risk of relapse and poor prognosis of the study population," Erba and co-authors explained, adding that the improvement was observed across most prespecified subgroups.

A post-hoc OS analysis by age suggested that younger patients benefited more from the FLT3 inhibitor:

  • <60 years: HR 0.68 (95% CI 0.49-0.95)
  • ≥60 years: HR 0.91 (95% CI 0.66-1.26)

Quizartinib is currently under review at the FDA as a treatment for FLT3-ITD-positive AML, with a , according to drugmaker Daiichi Sankyo.

In a , Amanda C. Przespolewski, DO, and Elizabeth A. Griffiths, MD, both of Roswell Park Comprehensive Cancer Center in Buffalo, New York, noted that based on the , FLT3 inhibition plus chemotherapy for newly diagnosed FLT3-positive AML is the standard of care for adults 60 or younger, but since the median age of AML onset is 68, "most patients might be excluded from this effective additional therapy."

Thus, the inclusion criteria in QuANTUM-First "reflect a more realistic patient population and might have selected those with worse survival," Przespolewski and Griffiths said. "However, responses consistently favored quizartinib."

QuANTUM-First was conducted at 193 hospitals and clinics in 26 countries in Europe, North American, Asia, Australia, and South American. It included 539 patients (ages 18-75) with newly diagnosed FLT3-ITD-positive AML (55% male, median age 56 years).

From 2016 to 2019, patients were randomized 1:1 to receive quizartinib or placebo combined with anthracycline- and cytarabine-based regimens. Eligible patients, including those who underwent allo-HCT, continued with single-agent quizartinib or placebo for up to 36 cycles.

Regarding secondary endpoints, an event-free survival (EFS) analysis (with induction treatment failure defined as not achieving complete remission by day 42 of the last induction cycle) showed no difference between study arms (HR 0.92, 95% CI 0.75-1.11, P=0.24).

However, Erba's team noted that an EFS benefit favoring quizartinib was seen with the original protocol definition of not having composite complete remission by the end of induction up to day 56 (HR 0.73, 95% CI 0.59-0.90, P=0.0031), or not having complete remission by the end of induction up to day 56 (HR 0.82, 95% CI 0.67-1.00, P=0.032). The authors suggested this was probably due to the fact that the period up to day 56 allowed patients to recover from quizartinib's myelosuppressive effects.

Other secondary endpoints -- including rates of complete remission, composite complete remission, complete remission with incomplete neutrophil or platelet recovery, complete remission with minimal residual disease (MRD) negativity, and composite complete remission with MRD negativity at the end of induction -- were similar between treatment groups. However, the median duration of complete remission was significantly longer with quizartinib than placebo (38.6 months vs 12.4 months).

As for safety, almost every patient in each group had at least one adverse event, while 92% of patients in the quizartinib group and 90% in the placebo group had a grade ≥3 event. The most common grade 3/4 adverse events were febrile neutropenia, hypokalemia, and pneumonia in both groups and neutropenia in the quizartinib group.

Erba and colleagues acknowledged that the use of a placebo comparator group was a major limitation of the study, considering midostaurin (Rydapt) has been included in standard treatment since 2017.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by Daiichi Sankyo.

Erba reported financial relationships with AbbVie, Agios, ALX Oncology, Amgen, Ascentage, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Forma, Forty Seven, Genentech, Gilead, GlycoMimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, Kura, MacroGenics, Novartis, Pfizer, PTC Therapeutics, Servier, Sumitomo Dainippon, Syros, Takeda, and Trillium; co-authors also reported multiple relationships with industry.

Przespolewski reported research grants from Jazz Pharmaceuticals; Griffiths reported financial relationships with AbbVie, Alexion, Apellis, Astex, AstraZeneca, Blueprint Medicines, Celgene-Bristol Myers Squibb, CTI Biopharma, Genentech, NextCure, Novartis, Picnic Health, Takeda, and Taiho, as well as honoraria from the American Society of Hematology, the Aplastic Anemia & MDS Foundation, the Dresner Foundation, the MDS Foundation, and MediCom Worldwide.

Primary Source

The Lancet

Erba HP, 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" Lancet 2023; DOI:10.1016/S0140-6736(23)00617-7.

Secondary Source

The Lancet

Przespolewski A, Griffiths E "FLT3-mutated leukaemia: a new opportunity" Lancet 2023; DOI:10.1016/S0140-6736(23)00464-6.