The important ADMIRAL trial, reported by Perl et al in The New England Journal of Medicine¹ and reviewed in this issue of The ASCO Post, shows the efficacy of a specific FLT3 inhibitor in patients with advanced acute myeloid leukemia (AML) and enhances the era of personalized medicine in leukemia.

Richard M. Stone, MD

AML is an intrinsically chemotherapy-resistant disease; despite a relatively high remission rate, newly diagnosed patients who receive standard chemotherapy with agents such as daunorubicin/cytarabine commonly experience relapse. The relapse rate is particularly high in patients whose blasts harbor an activating mutation encoding the FLT3 transmembrane tyrosine kinase.

Of the two types of FLT3 mutations, the more common length or internal tandem duplication (ITD) mutation—representing a duplication (from 3–100 amino acids) in the juxtamembrane region promoting spontaneous ligand-independent dimerization and mitogenesis—has an adverse prognostic impact. Midostaurin, a relatively nonspecific FLT3 inhibitor that inhibits both the aforementioned ITD mutation as well as the less common but also activating point mutation in the tyrosine kinase domain, is approved for use along with chemotherapy in the upfront treatment of patients with FLT3-mutant AML.² Although midostaurin was the first mutationally targeted agent to be approved in AML, the drug is relatively highly protein bound, nonspecific, and less potent than newer FLT3 inhibitors.

ADMIRAL Trial: Gilteritinib vs Standard Salvage Chemotherapy

One important new FLT3 inhibitor, gilteritinib, is a well-tolerated oral agent given once daily that inhibits both types of FLT3 mutations. Based on the results of a single-agent phase I trial of gilteritinib, in which responses occurred in about 40% of patients with advanced FLT3-mutant AML,³ the pharmaceutical company–sponsored ADMIRAL trial pitted gilteritinib as a single agent vs “dealer’s choice” standard salvage chemotherapy in patients with relapsed or refractory FLT3-mutant AML.

Would it really be possible for a single oral agent to “beat” standard chemotherapy in a complicated disease such as relapsed or refractory AML? Patients aged 18 years and older, whose blasts had one of the two types of FLT3 mutations, were eligible if their disease was refractory to one or two cycles of conventional anthracycline-containing induction therapy or if they had hematologic relapse after a previously achieved complete remission. There was a random assignment on a 2:1 basis in favor of the oral experimental agent vs salvage chemotherapy.

“The results [of the ADMIRAL trial] indicate that patients with relapsed or refractory FLT3-mutant AML should not receive standard chemotherapy alone.”

— Richard M. Stone, MD

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Those randomized to the control arm received a preselected salvage chemotherapy regimen. The choices included mitoxantrone/etoposide/cytarabine (MEC), fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA), low-dose cytarabine, or azacitidine. The dose of gilteritinib was 120 mg/d, although dose escalation to 200 mg was possible. The primary endpoints of the trial were overall survival and percentage of patients who had complete remission with full or partial hematologic recovery.

Survival, Transplantation Eligibility, and Response

A total of 625 patients were screened to find the 371 eligible patients who underwent randomization. Overall, 61% of the patients had relapsed AML, and the others had primary refractory disease. Of note, just 6% had received midostaurin during induction therapy. In the control arm, well over half of the patients received one of the two “high-intensity” therapies (MEC or FLAG-IDA). The primary endpoint of the trial was met: patients randomly assigned to gilteritinib survived significantly longer than patients in the chemotherapy group (median = 9.3 months vs 5.6 months, hazard ratio = 0.64, 95% confidence interval [CI] = 0.49–0.83). Patients were more than twice as likely to be alive at 1 year if they received gilteritinib compared with chemotherapy. Patients who had primary refractory AML lived longer if they received gilteritinib, but this difference did not reach statistical significance.

Insofar as the primary goal for many patients with refractory or relapsed disease is to have an allogeneic stem cell transplantation after a suitable response, it was encouraging that about one-fourth of the gilteritinib-treated patients were able to have transplantation, compared with just 15% in the chemotherapy group. However, the increased likelihood of transplantation in the gilteritinib group was not the sole reason for improved survival; censoring survival follow-up at the time of transplantation yielded a statistically significant hazard ratio in favor of gilteritinib (0.58, 95% CI = 0.43–0.76). The complete remission rate (with or without hematologic recovery) was superior in the gilteritinib group (34% vs 15%). Gilteritinib worked equally well in patients with a FLT3 tyrosine kinase domain or ITD mutation.

The drug was reported to be well tolerated. Grade 3 or greater nonhematologic events due to gilteritinib were rare except for mild to moderate increases in liver enzymes.

Clinical Implications

This trial shows the potential benefit of using a potent and specific inhibitor of an activated enzyme in advanced AML. Even though FLT3 mutations are commonly regarded as a progression or “late-hit” mutation, potent inhibition has a disease reduction benefit compared with more toxic and nonspecific chemotherapy.

The ADMIRAL trial is highly encouraging for several reasons (despite uncommonly long-term survival even in the gilteritinib group). First, the results indicate that patients with relapsed or refractory FLT3-mutant AML should not receive standard chemotherapy alone. Second, this trial will form the basis of subsequent trials. To improve long-term results, gilteritinib should be added to chemotherapy or other therapies, such as the BCL2 inhibitor venetoclax (ClinicalTrials.gov identifier NCT03625505), in the setting of well-designed clinical trials. The results of the ADMIRAL trial were encouraging, mainly due to the suggestion that gilteritinib might be a key first step. Indeed, investigator-initiated trials with gilteritinib plus chemotherapy are underway. Such studies include a comparison of gilteritinib and midostaurin plus chemotherapy in the upfront treatment of FLT3-mutant AML (NCT03836209) and gilteritinib vs placebo after allogeneic transplantation in this AML subtype (NCT03730012). 

DISCLOSURE: Dr. Stone has received honoraria from Dava Pharmaceuticals, Medscape, Prime Oncology, and Research to Practice; has served as a consultant or advisor for AbbVie, Actinium Pharmaceuticals, Agios, Amgen, Argenx, Arog, Astellas Pharma, AstraZeneca, BioLineRx, Celgene, Celgene/Jazz, Cornerstone Pharmaceuticals, Daiichi Sankyo, MacroGenics, Novartis, Otsuka, Pfizer, Roche/Genentech, Stemline Therapeutics, Takeda, and Trovagene; and has received institutional research funding from AbbVie/Genentech, Agios, and Novartis.

REFERENCES

1. Perl AE, Martinelli G, Cortes JE, et al: Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381:1728-1740, 2019.

2. Stone RM, Mandrekar SJ, Sanford BL, et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454-464, 2017.

3. Perl AE, Altman JK, Cortes J, et al: Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: A multicentre, first-in-human, open-label, phase I-II study. Lancet Oncol 18:1061-1075, 2017.