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Gilteritinib represents ‘major change’ for treatment of relapsed, refractory acute myeloid leukemia
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ATLANTA – The FLT3 inhibitor gilteritinib significantly prolonged survival compared with standard salvage chemotherapy in patients with FLT3-mutated relapsed or refractory acute myeloid leukemia, according to final results of the randomized, phase 3 ADMIRAL trial presented at American Association for Cancer Research Annual Meeting.
Gilteritinib (Xospata, Astellas) — which received FDA approval in November for treatment of adults with relapsed or refractory AML and an FLT3 mutation as detected by an FDA-approved test — also appeared associated with a higher rate of complete responses than salvage chemotherapy and less toxicity during the first 30 days of treatment.
“AML is an extremely chemotherapy-sensitive disease at initial diagnosis, and a number of patients are cured with that approach, or with chemotherapy followed by bone marrow transplant,” Alexander E. Perl, MD, associate professor in the division of hematology oncology at Perelman School of Medicine at University of Pennsylvania, and member of the leukemia program at Abramson Cancer Center, said during a press conference. “However, if patients relapse after primary therapy, or they fail to enter complete remission after frontline therapy, their outcome is dismal. One of the predictors of which patients are more likely to fail frontline therapy or relapse is mutation in FLT3.”
Perl and colleagues evaluated 371 patients (median age, 62 years; range, 19-85; 54% women) with AML and known FLT3 mutations (FLT3-internal tandem duplication [ITD], 88.4%; FLT3-tyrosine kinase domain [TKD], 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%). Eligible participants had disease that was refractory to induction chemotherapy or were in an untreated initial relapse. More than half of patients (60.6%) had relapsed AML, whereas 39.4% had refractory disease.
The researchers excluded patients who had previously received FLT3 inhibitors other than midostaurin (Rydapt, Novartis) or sorafenib (Nexavar; Bayer, Onyx Pharmaceuticals).
The researchers randomly assigned participants 2:1 to uninterrupted, 28-day cycles of 120 mg/day gilteritinib (n = 247) or salvage chemotherapy chosen before random assignment (n = 124).
Salvage chemotherapy regimens included low-dose cytarabine or azacytidine until disease progression or intolerance, or high-intensity (one to two cycles) of mitoxantrone, etoposide and cytarabine, known as MEC; or fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin, known as FLAG IDA.
OS and the combined rate of complete remission and complete remission with partial hematologic recovery (CR/CRh) served as co-primary endpoints.
EFS and complete response rate served as secondary endpoints. The researchers also assessed the safety and tolerability of single-agent gilteritinib.
Patients assigned gilteritinib attained significantly longer OS than those assigned salvage chemotherapy (9.3 months vs. 5.6 months; HR = 0.63; 95% CI, 0.49-0.83). Survival rates at 1 year were 37.1% with gilteritinib vs. 16.7% in the salvage chemotherapy group.
Gilteritinib-treated patients had a combined CR/CRh rate of 34% vs. 15.3% for patients treated with salvage chemotherapy (P = .0001). Rates of complete response were 21.1% (n = 52) with gilteritinib vs. 10.5% (n = 13) for salvage chemotherapy (2-sided P = .0106).
Gilteritinib yielded median EFS of 2.8 months vs. 0.7 months for salvage chemotherapy (HR = 0.79).
The most prevalent adverse events among all patients were febrile neutropenia (43.7%); anemia (43.4%) and pyrexia (38.6%). The most common grade 3 or higher adverse events associated with gilteritinib included anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%) and reduced platelet count (12.2%).
Perl noted that although incidence of adverse events was similar in both groups, the duration of treatment with gilteritinib was considerably longer than with chemotherapy (median duration of exposure, 4.1 months vs. 0.9 months). An analysis adjusted for duration of exposure revealed that gilteritinib was associated with a lower rate of serious treatment-emergent adverse events per patient-year than salvage chemotherapy (7.1% vs. 9.2%).
According to Perl, these findings could represent a new treatment paradigm for AML.
“This is a major change in how we approach patients in the relapsed/refractory setting, because now we are using molecularly targeted therapy to select patients who may benefit from this approach,” Perl said. “We’ve shown that a toxicity agent can outperform the general fallback of using standard toxicity chemotherapy that requires an inpatient hospital stay. This is a practice-changing result that we think establishes a new standard of care for this population.” – by Jennifer Byrne
Reference:
Perl AE, et al. Abstract CT184. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: This study was funded by Astellas. Perl reports honoraria from AbbVie, Actinium Pharmaceuticals, Agios, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, Novarits, New Link Genetics and Takeda; consultant fees from AbbVie, Arog, Astellas and Daiichi Sankyo; and research funding to his institution from Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, Daiichi Sankyo, FujiFilm and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Michael Caligiuri, MD
What is important about this study is that it evaluates a very potent molecule that has powerful on-target effects and limited off-target effects, such that it is eradicating more of the disease with less untoward side effects. The study is an example of how once we have a lead molecule — a breakthrough molecule in a disease, as we did with the first generation of FLT3 inhibitors — the pharmaceutical industry is very quick to build off that molecule and develop a better one.
Five to 7 years ago, we had the first FLT3 inhibitor, which had significant activity for ITD mutations but did not have significant activity against FLT point mutations. Gilteritinib appears to have activity against both FLT3-ITD and FLT3 point mutations with seemingly limited toxicity. When it was given to a really tough group of patients — those with refractory and relapsed AML with either FLT3 mutation — it likely decreased tumor burden and was then shown to extend survival when followed by a bone marrow transplant.
I believe we will see more and more of this; that is, once a new target is discovered that contributes to the malignant phenotype, a drug is developed that inhibits the target. This is then followed by modifications to the structure of the drug so that it either inhibits the target better or causes fewer off-target side effects, or both.
We’re seeing it in this study — played out in better OS for a group of patients who normally do poorly. The clinical research community will then take this drug and move it up earlier and earlier in the treatment regimen until it’s in the very first line of treatment for this disease, which has traditionally had a poor prognosis. Very exciting developments in this field are on the horizon.
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