Quizartinib regimen extends survival vs. chemotherapy in acute myeloid leukemia subgroup
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Adding quizartinib to standard chemotherapy and up to 3 years of continuation therapy extended OS among a subset of older adults with newly diagnosed acute myeloid leukemia, according to results of the phase 3 QuANTUM-First trial.
The findings, presented during the European Hematology Association Hybrid 2022 Congress, additionally showed quizartinib (Daiichi Sankyo) had a favorable safety profile, suggesting the agent is safe and effective for patients aged up to 75 years with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia.
Rationale and methods
“The prognosis of patients with AML with FLT3-ITD is poor due to high rates of relapse,” Harry P. Erba, MD, PhD, instructor in the department of medicine and member of Duke Cancer Institute, told Healio. “The RATIFY trial demonstrated an improvement in OS among patients with AML with both FLT3-ITD and FLT-TKD [tyrosine kinase domain] mutations when midostaurin (Rydapt, Novartis) was added to standard intensive AML therapy. However, the prognostic significance of the FLT3-TKD mutation is unclear. Furthermore, the RATIFY trial only enrolled patients up to and including age 59 years. The QuANTUM-First trial evaluated a more potent and more selective type 2 FLT3 inhibitor, quizartinib, only in the poor-prognosis group with a FLT3-ITD mutation and included patients up to age 75 years.”
QuANTUM-First included 539 adults (median age, 56 years) with newly diagnosed FLT3-ITD-positive AML.
Researchers randomly assigned patients 1:1 to quizartinib (n = 268) or placebo (n = 271) in combination with standard anthracycline- and cytarabine-based induction and consolidation regimens.
Eligible patients, including those who underwent allogeneic hematopoietic stem cell transplantation, continued to receive single-agent quizartinib or placebo for up to 36 cycles.
OS served as the primary endpoint. Secondary endpoints included EFS, post-induction rates of complete remission and composite complete remission, and the percentage of patients who achieved complete remission or composite complete remission with FLT3-ITD minimal residual disease negativity.
Median follow-up was 39.2 months.
Key findings
At the time of data cutoff in August 2021, 58 patients remained on continuation therapy.
Results showed improvement in OS in the quizartinib group compared with placebo (HR = 0.77; 95% CI, 0.61-0.97).
Researchers reported median OS of 31.9 months with quizartinib vs. 15.1 months with placebo.
Patients in the quizartinib group had a higher rate of complete remission or complete remission with incomplete hematologic recovery (71.6% vs. 64.9%).
Overall, 31% of patients assigned quizartinib and 27% assigned placebo underwent allogeneic HSCT in first complete remission. Researchers observed longer OS with quizartinib compared with placebo among patients who underwent allogeneic HSCT (HR = 0.75; 95% CI, 0.56-1) and longer RFS (HR = 0.73; 95% CI, 0.55-0.96).
“The improvement in OS was observed in patients who underwent allogeneic HSCT in first complete remission, as well as those who did not undergo allogeneic HSCT in first complete remission,” Erba said. “This improvement appeared to be due to an improvement in RFS, a lower cumulative incidence of relapse and a longer complete remission duration with quizartinib compared with placebo.”
Grade 3 or higher neutropenia occurred more frequently with quizartinib (18.1% vs. 8.6%) and more patients discontinued quizartinib due to adverse events (20.4% vs. 8.6%). Researchers reported mortality-associated treatment-emergent adverse event rates of 11.3% with quizartinib vs. 9.7% with placebo.
Looking ahead
“Quizartinib in combination with intensive chemotherapy with 3 years of continuation therapy should be the treatment of choice for patients with FLT3-ITD-mutated AML who are eligible for intensive curative therapy,” Erba said. “We will next analyze the benefit and toxicity of quizartinib vs. placebo during the 3-year continuation phase. At this point, we know that the median number of cycles of quizartinib compared with placebo were similar in the two arms during continuation treatment.”
References:
Erba HP, et al. Abstract S100. Presented at: European Hematology Association Hybrid 2022 Congress; June 9-12, 2022; Vienna.
Larson RA, et al. Leukemia. 2021;doi:10.1038/s41375-021-01179-4.
For more information:
Harry P. Erba, MD, PhD, can be reached at harry.erba@duke.edu.
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Erba HP, et al. Abstract S100. Presented at: European Hematology Association Hybrid 2022 Congress; June 9-12, 2022; Vienna.
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