Gilteritinib Improves OS in Relapsed/Refractory FLT3+ AML

Alexander E Perl, MD

Alexander E Perl, MD

Gilteritinib (Xospata) was found to significantly improve overall survival (OS) in patients with relapsed/refractory FLT3 mutation—positive acute myeloid leukemia (AML), according to updated findings of the phase III ADMIRAL trial that were presented at the 2019 AACR Annual Meeting.

The median OS in patients who were treated with the FLT3 inhibitor was 9.3 months (95% CI, 7.7-10.7) compared with 5.6 months in those who received salvage chemotherapy (95% CI, 4.7-7.3), leading to a 36% reduction in the risk of death (HR, 0.637; 95% CI, 0.490-0.830; P = .007).

Additionally, results showed that the complete response (CR)/CR with hematologic recovery (CRh) rate more than doubled with gilteritinib versus chemotherapy at 34% and 15%, respectively. Patients on gilteritinib also had higher rates of undergoing allogeneic hematopoietic stem cell transplant (HSCT) than those on salvage therapy, at 26% versus 15%, respectively.

“Single-agent, oral gilteritinib, a targeted inhibitor of FLT3, improves both response and survival in patients with FLT3-mutated relapsed/refractory AML. This is a major change in how we approach patients in the relapsed/refractory setting, because now we’re using molecularly targeted therapies to select patients who can benefit from this approach,” said lead study author Alexander E. Perl, MD, associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania, and member of the Abramson Cancer Center, in a press conference during the meeting. “We have shown that a lower toxicity agent, more or less comparable to the low-intensity approaches, can outperform the general fallback of using standard toxic chemotherapy that requires patient hospital stays. This is a practice-changing result and we think establishes a new standard of care for this patient population.”

Forty percent to 70% of patients with AML relapse following remission with induction chemotherapy, and up to 40% of patients are refractory to induction therapy and do not achieve CR, Perl explained. FLT3 mutations are detected in approximately 30% of patients with AML; moreover, FLT3-internal tandem duplication (ITD) mutations confer an increased risk for early relapse and poor survival.

“For a long time, there has been interest in developing a FLT3 inhibitor that would effectively do everything,” said Perl. “It would inhibit the target, it would do so potently, it would have single-agent activity, and it would be active against both FLT3-ITD and FLT3-TKD D835 mutations.”

Gilteritinib is an oral, potent type I FLT3 inhibitor that is designed to elicit activity against patients with FLT3-ITD and FLT3-tyrosine kinase domain D835 mutations. The agent was initially approved by the FDA in November 2018 for the treatment of adult patients with FLT3 mutation—positive relapsed/refractory AML, based on encouraging response rates observed in the ADMIRAL trial.

The prior ADMIRAL data showed that in 138 adult patients with FLT3 mutation—positive relapsed/refractory AML who received gilteritinib, the CR/CRh rate was 21% (n = 29; 95% CI, 14.5-28.8) at a median follow-up of 4.6 months.²

In the international, phase III ADMIRAL study, 371 adult patients with FLT3-mutant relapsed/refractory AML were randomized 2:1 to receive gilteritinib at 120 mg daily (n = 247) or salvage chemotherapy (n = 124). Patients in both arms then underwent HSCT, but only patients in the gilteritinib arm then resumed treatment with the FLT3 inhibitor; crossover was not permitted. Additionally, salvage chemotherapy was selected prior to randomization and could be one of the following regimens: mitoxantrone, etoposide, and cytarabine; fludarabine, cytarabine, idarubicin, and G-CSF; low-dose cytarabine; and azacitidine.

To be eligible for enrollment, patients with AML must have also harbored a FLT3-ITD or FLT3-TKD mutation, a mean of triplicate Fridericia-corrected QT interval <450 milliseconds at screening based on central reading, and be refractory to induction chemotherapy or in untreated first relapse.

Baseline characteristics were comparable between arms. Overall, the median age was 62 (range, 19-85) and 54% of patients were female. The majority of patients had intermediate-risk cytogenetics (73%) and 88% of patients had FLT3-ITD mutations. Additionally, 20% of patients had underwent prior HSCT, and 82% had received upfront intensive chemotherapy. Thirty-nine percent of patients had primary refractory AML without HSCT and 27% relapsed ≤6 months after composite complete remission (CRc).

The coprimary endpoints were OS and CR/CRh rate; secondary endpoints were event-free survival, CR rate, leukemia-free survival, duration of remission, CRc rate, transplantation rate, brief fatigue inventory, CRh rate, transfusion conversion rate, and transfusion maintenance rate.

In the intent-to-treat population (n = 371), the 1-year OS rates were doubled with gilteritinib at 37% (95% CI, 31%-44%) compared with salvage chemotherapy at 17% (95% CI, 10%-25%).

Results also showed that the CR, CRh, CR with incomplete hematologic recovery, and CR with incomplete platelet recovery rates with gilteritinib compared with salvage chemotherapy were 21% versus 11%, 13% versus 5%, 26% versus 11%, and 8% versus 0%, respectively. Additionally, the CRc rate was 54% with gilteritinib and 22% with salvage therapy.

The overall response rates were 26% with salvage chemotherapy and 68% with gilteritinib, which comprised a 13% partial response rate.

Moreover, the median duration of gilteritinib exposure was significantly longer than that of salvage therapy, at 4.1 months (range, 0.1-29.1) and 0.9 months (range, 0.2-7.1), respectively. The median time to achieve CRc was 1.8 months (95% CI, 0.9-9.95) with gilteritinib and 1.1 months (95% CI, 0.8-2.9) with salvage treatment. The median DOR with gilteritinib was also significantly longer at 11.0 months compared with 1.8 months with salvage therapy.

Regarding safety, all-grade treatment-emergent adverse events were comparable between arms during the first 30 days of treatment; however, there were higher rates of increased levels of alanine aminotransferase (24% vs 7%) and aspartate aminotransferase levels (24% vs 10%) with gilteritinib, which Perl explained were generally of grade 1/2. There were equal rates of anemia (33%), and salvage therapy had higher rates of febrile neutropenia than gilteritinib (32% vs 21%), pyrexia (26% vs 15%), nausea (30% vs 13%), hypokalemia (27% vs 11%), and diarrhea (28% vs 10%).

“This is a new, practice-changing strategy, which is something that we have been missing and needing in the field of acute myeloid leukemia therapy for the entire time I’ve been an oncologist,” said Louis M. Weiner, MD, director of Georgetown-Lombardi Comprehensive Cancer Center, who moderated the press conference. “So, to have something like this is really special and important.”

Perl concluded that combining with gilteritinib with frontline therapy in patients with FLT3-mutant AML may further improve outcomes, trials of which are currently ongoing. These include a phase I trial of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML (NCT02236013) and a phase II/III study of gilteritinib alone, azacitidine alone, or the combination of gilteritinib with azacitidine in patients with FLT3-mutant AML who are unable to receive standard chemotherapy (NCT02752035).

References

1. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CTPL04.
2. FDA Prescribing Information: XOSPATA® (gilteritinib) tablets, for oral use. Published November 28, 2018. https://bit.ly/2SjB8CL. Accessed April 1, 2018.

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