Results from QuANTUM-R trial of quizartinib versus salvage chemotherapy in FLT3-ITD mutated acute myeloid leukemia (AML)

In patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), the presence of a FLT3 internal tandem duplication (FLT3-ITD) is prognostic of a poor outcome. Patients with this feature are highly likely to relapse, not respond to salvage therapy and have a shorter overall survival (OS) compared to patients with FLT3-wild type (FLT3-wt). The FLT3-ITD is present in approximately 25% of patients with newly diagnosed AML. When patients relapse with FLT3-ITD AML there is a high unmet need for effective therapies.¹

Quizartinib is an oral type II next-generation FLT3 inhibitor; other examples of which include gilteritinib and crenolanib. In phase I and II studies, these FLT3 inhibitors have shown promising efficacy in patients with FLT3-ITD and are beginning to demonstrate the same in phase III trials. Results from the phase III ADMIRAL trial, investigating gilteritinib in patients with FLT3-ITD R/R AML, were recently presented at the American Society of Clinical Oncology (ASCO) meeting, and showed gilteritinib prolonged OS compared to salvage chemotherapy.²

Jorge E Cortes, University of Texas MD Anderson Cancer Center, Houston, US, and colleagues, conducted the phase III QuANTUM-R study (NCT02039726) to evaluate quizartinib monotherapy, compared to salvage chemotherapy, in patients with R/R AML.¹ During the American Society of Hematology (ASH) meeting, 2018, Doctor Cortes presented the phase III safety and efficacy data, showing that quizartinib was well tolerated and prolonged OS compared to salvage chemotherapy.³ The final results have now been published in Lancet Oncology and are summarized here.¹

Study design and patient characteristics¹

This phase III, randomized, open-label, multicenter trial aimed to investigate whether quizartinib as monotherapy could improve OS when compared to standard-of-care salvage chemotherapy. The study enrolled patients with R/R AML with FLT3­-ITD who were refractory or relapsed after ≥one cycle of a standard anthracycline-containing or mitoxantrone-containing AML therapy with a duration of response (DOR) ≤six months, with or without prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Patients also had an Eastern cooperative oncology group (ECOG) score of 0–2. The median follow-up was 23.5 months (interquartile range [IQR]: 15.4–32.3). The primary endpoint of the study was OS in the intention-to-treat (ITT) population and the secondary endpoint was event-free survival (EFS) in the ITT population.

Patients (N= 367) were randomized 2:1 to either:

• Quizartinib (n= 245): 60mg administered orally, once daily with a lead-in dose of 30mg
  • Lead-in dose: 30mg
• Investigators choice of chemotherapy (n= 122), either:
  • LoDAC (n= 29): subcutaneous (SC) low-dose cytarabine (LoDAC): 20mg twice daily on days 1–10 of a 28-day cycle
  • MEC (n= 40): intravenous (IV) infusions of:
    • Mitoxantrone (8mg/m² per day)
    • Etoposide (100mg/m² per day)
    • Cytarabine (1000mg/m² per day on days 1–5 of up to two 28-day cycles)
  • FLAG-IDA (n= 53): IV infusions of:
    • Granulocyte colony-stimulating factor (G-CSF, 300µg/m² per day or 5µg/kg per day SC on days 1–5)
    • Fludarabine (30mg/m² per day on days 2–6)
    • Cytarabine (2000mg/m² per day on days 2–6)
    • Idarubicin (10mg/m² per day on days 2–4 in up to two 28-day cycles
• Patients were stratified by response to prior therapy (relapsed with no prior allo-HSCT or refractory) and choice of chemotherapy (MEC/FLAG-IDA or LoDAC)
• Quizartinib or LoDAC was administered until lack of benefit, discontinuation for allo-HSCT or unacceptable toxicity and MEC or FLAG-IDA were given for up to two cycles
• Patients on quizartinib who stopped treatment to undergo allo-HSCT were allowed to resume treatment after transplantation

Adherence to treatment

Given as quizartinib versus salvage chemotherapy unless otherwise stated

Of the 367 patients randomly allocated, 245 were assigned to the quizartinib arm, and 122 to the chemotherapy arm. Of these, 241 and 94, respectively, received treatment. In the quizartinib arm the median drug exposure was 97 days, compared to 28 days for the salvage chemotherapy arm. In the quizartinib arm, 235 discontinued treatment and 70 patients in the salvage chemotherapy arm discontinued. The reasons for this are shown in Table 2.

Table 2. Reasons for discontinuation of study treatment, by arm

Of the patients who received allo-HSCT in the quizartinib arm, 49 resumed treatment post-allo-HSCT and of those, 34 subsequently discontinued. No patients in the salvage chemotherapy arm who received allo-HSCT resumed treatment.

Efficacy

• Efficacy result are shown in Table 3
• Median OS was longer for quizartinib compared to salvage chemotherapy
• HR: 0.76, 95% CI, 0.58–0.98, p= 0.02
• In a prespecified exploratory analysis, the most frequent response in both study groups was complete remission (CR) with incomplete hematological recovery

Table 3. Efficacy of quizartinib versus salvage chemotherapy

Safety

• The most frequent grade 3–5 adverse events (AEs) were hematological events, electrolyte abnormalities, infections and dyspnea
• Grade 3 QT prolongation was uncommon in the quizartinib arm; n= 8 (3%) by central reading and 10 (4%) by investigator report, with no grade 4 events
• Most common treatment-emergent (TE) grade 3-5 adverse events in both arms were sepsis, pneumonia and hypokalemia
• TE related deaths were higher in the quizartinib arm (33%) compared to the salvage chemotherapy arm (17%). See Table 4 for details.

Table 4. Safety analysis of quizartinib versus salvage chemotherapy

Study limitations

• Open-label: some patients may have withdrawn consent prior to treatment in the chemotherapy arm
• Transplant procedures and post-transplant therapy with quizartinib were uncontrolled
• The small sample size of the chemotherapy arm limits the interpretation of the subgroup analysis

Conclusion

The use of quizartinib as monotherapy for patients with FLT3-ITD R/R AML conferred a survival benefit compared to salvage chemotherapy, with a manageable safety profile. As a single-agent, quizartinib can be administered in the outpatient setting and represents a potential new treatment for patients who have very poor prognoses.

In this study, three-times more patients received subsequent allo-HSCT in the quizartinib arm, indicating quizartinib may stabilize the disease for a sufficient time to allow patients to receive allo-HSCT. However, transplant decisions in this study were investigator-led and therefore no definitive benefit can be concluded.

These results highlight the importance of FLT3-ITD mutation targeting. A phase III trial (QuANTUM-First, NCT02668653) is currently ongoing to investigate whether quizartinib with standard chemotherapy, followed by quizartinib monotherapy, will benefit patients with newly diagnosed AML.

FDA approval status

In August 2018, the US FDA granted quizartinib breakthrough therapy designation for R/R FLT3-ITD AML⁴ and in November 2018 the new drug application was accepted, with a priority review granted.⁵

However, in June 2019, the Oncolytic Drug Advisory Committee (ODAC) of the FDA voted against approving quizartinib, with concerns raised about the generalizability and credibility of the data. However. the final decision is with the FDA, who are expected to make a decide by 25^th August 2019.⁶