Gilteritinib: 'Paradigm Shift' to Treat FLT3-Mutated AML

Alexander Castellino, PhD

April 03, 2019

Alexander E. Perl, MD

ATLANTA — Single-agent gilteritinib (Xospata, Astellas) was shown to provide significantly longer overall survival (OS) and response rates (ORR) than standard chemotherapy for patients with FLT3-mutated relapsed/refractory acute myeloid leukemia (AML), according to data from the Phase 3 ADMIRAL study reported April 2 at the American Association for Cancer Research (AACR) 2019 annual meeting.

"For these patients with FLT3-mutated AML, gilteritinib represents a new standard of care," Alexander E. Perl, MD, associate professor of hematology/oncology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, told Medscape Medical News.

Gilteritinib is an oral agent that targets FMS-like tyrosine kinase 3 (FLT3). FLT3 is mutated in a third of patients with AML and is a highly aggressive and proliferative disease. Standard chemotherapy, which historically was the only option, provides low remission rates of a short duration and a median survival of 2-4 months, Perl explained.

"The single-agent activity of gilteritinib in patients with relapsed or refractory AML is very impressive," Michael Caligiuri, MD, medical oncologist at the City of Hope Cancer Center in Duarte, California, told Medscape Medical News

He pointed out that this is a real advantage for patients and warrants moving the drug into front-line therapy. He also noted there may be an opportunity for curing some patients with hematopoietic stem cell transplant following treatment with gilteritinib.

Paradigm Shift in Treating FLT3-Mutant AML

The superior survival seen with gilteritinib along with its modest side effects and once daily oral dosing means that it can be given in an outpatient setting, Perl pointed out. "This represents a paradigm shift for salvage therapy in AML," he said.

Mrinal S. Patnaik, MBBS, associate professor of internal medicine at the Mayo Clinic, Rochester, Minnesota, concurred. "It is exciting to see that drugs targeting FLT3 have revolutionized the management of AML," he told Medscape Medical News.

"Four or five years ago it was unimaginable to even think one may at some point be able to treat AML with an oral agent," Patnaik said. "It was all about one size fits all," he said, explaining that patients were then serially treated with chemotherapy regimens.

Now, at least for a group of patients, it is about personalized medicine, he remarked. "We need to celebrate the solid gains we've made," he said and pointed out that patients now have access to several agents that target FLT3 mutations.

Midostaurin was the first FLT3 inhibitor approved in combination with chemotherapy in the front-line setting for patients with FLT3-mutated AML. "But this combination does not induce complete remission," Perl noted. Moreover, use of more potent FLT3 inhibitors such as quizartinib (in development) and sorafenib (off-label use) are associated with significant toxicities and short-lived responses because of the emergence of another resistance mutation in FLT3 — one in the tyrosine kinase domain (TKD).

Patnaik pointed out that gilteritinib is a potent inhibitor that targets two important mutations in FLT3: the internal tandem duplication (ITD) and TKD (type 2 inhibitor).

"It is good to move away from the one-size-fits-all paradigm," he said. He pointed out that there are other unique FLT3 agents in development that will, in future, provide additional options for these patients.

We will likely need to look at mutations associated with AML and decide on the agent that best targets the mutations. "For patients with FLT3-ITD and TKD mutations, gilteritinib fills the void," he said.

Discussant Tapan Kadia, MD, medical oncologist at the MD Anderson Cancer Center in Houston, Texas, noted that with the approval of midostaurin in the front-line setting, the management of patients with relapsed/refractory AML with other FLT3 inhibitors may pose a challenge. He noted that ADMIRAL does not provide this insight as only 12% of patients in ADMIRAL had prior midostaurin exposure because it was approved while ADMIRAL was ongoing. But he pointed out that use of a single-agent FLT3 inhibitor in the front-line setting was associated with a lower response when patients were rechallenged with another FLT3 inhibitor in the relapsed/refractory setting.

Acknowledging Patient Participation

Patnaik noted that a trial such as ADMIRAL is a difficult undertaking. He especially wanted to applaud patient participation in the study. Noting that it was an open-label study, he said it is difficult to accrue patients in studies such as this one where patients have the option of receiving a study drug orally or the comparator, which is given intravenously and associated with significant toxicities.

"Patients who were willing to be randomized need to be congratulated," he said. He pointed out that we do not thank our patients enough and acknowledge their selflessness even though they do not receive the study drug, which may or may not be superior to chemotherapy. 

Gilteritinib Has Already Been Approved

In November 2018, the US Food and Drug Administration (FDA) approved gilteritinib for the treatment of adults with relapsed or refractory AML and an FLT3 mutation detected using an FDA-approved test.

Perl explained that the approval was based on an interim analysis of the safety and response rate seen with gilteritinib in the ADMIRAL study.

ADMIRAL was originally designed with OS as its primary endpoint. During the course of the study, the protocol was amended to include complete remission (CR) and CR with partial hematologic recovery (CRh) as a coprimary endpoint, which was important for the FDA approval, Perl explained.

"We are now showing the final analysis of the ADMIRAL study, including data on overall survival that indicates gilteritinib is superior to standard chemotherapy," Perl said.

ADMIRAL Study Details

ADMIRAL was a Phase 3 study that randomized 371 patients with relapsed or refractory AML to receive oral gilteritinib once daily (n = 247) or salvage chemotherapy (n = 124). Patients achieving remission were allowed to receive a hematopoietic stem cell transplant, following which patients in the gilteritinib group were allowed to receive gilteritinib maintenance. Cross-over was not allowed.

Patients were required to have a centrally confirmed FLT3 mutation (FLT3-ITD or FLT3-TKD) at screening and had to be refractory to induction chemotherapy or in untreated first relapse.

The chemotherapy regimen choices were those typically used as salvage therapy for AML and were at the discretion of each investigator.

Most patients had the FLT3-ITD mutation (88%), 8% had the FLT3-TKD mutation, and 2% had both; 61% of patients had relapsed AML and 39% had refractory disease.

Allogeneic stem cell transplant rate was higher for patients in the gilteritinib group versus salvage chemotherapy, at 26% vs 15%, respectively.

For the first primary endpoint of OS, median OS for patients receiving gilteritinib was 9.3 months compared with 5.6 months for patients receiving chemotherapy. Corresponding 1-year survival rates were 37% and 17%. With a hazard ratio (HR) of 0.64, patients receiving gilteritinib had a 36% reduced risk for death (P = .0007).  

Similar OS benefits were reported for patients with censoring occurring at transplantation: median OS for patients on gilteritinib was 8.3 months and for chemotherapy was 5.3 months (HR, 0.575; P = .0001).

Post-transplantation, patients who received gilteritinib maintenance had a significantly longer survival compared with those who did not resume gilteritinib, at 16.2 months vs 8.4 months (HR, 0.38; P = .024).  

Complete remission with partial hematologic recovery (CR/CRh) was more than double for patients receiving gilteritinib than chemotherapy, at 34% vs 15% (P = .0001). Complete remission rates were almost double for patients on gilteritinib (21%) vs salvage chemotherapy (11%).

Median duration of remission was 11 months for patients receiving gilteritinib and 1.8 months for patients receiving salvage chemotherapy, respectively.

Median event-free survival was 2.8 months and 0.7 months for patients receiving gilteritinib or chemotherapy, respectively.

Survival benefits were seen across numerous subgroups of patients, Perl explained. "The longest survival was in patients who received gilteritinib, proceeded to transplant, and then resumed gilteritinib to prevent relapse," he said.

But long-term survival was uncommon he noted, highlighting the high-risk nature of the study population. He also pointed out that patients randomized to gilteritinib who had previously never been in remission had similar survival rates as patients in the control group.   

Common adverse events in all randomized patients were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Grade ≥ 3 adverse events with gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%).

Treatment-related deaths in patients taking gilteritinib were associated with pneumonia (n = 3), sepsis (n = 3), respiratory failure (n = 3), large intestinal perforation (n = 2), and septic shock (n = 2). QTc prolongation occurred in 12 patients (5%).

Of the 197 patients who were transfusion dependent at baseline, 68 (35%) became transfusion independent for 56 days or more.

What's Next?

Perl told Medscape Medical News that single-agent targeted therapy in the front-line setting is unlikely to generate durable remissions. That is why trials seeking to move gilteritinib into the first-line setting will evaluate the drug in combination with chemotherapy.

He pointed out that both in Europe and the United States, cooperative groups have designed trials to study gilteritinib versus midostaurin, both in combination with intensive chemotherapy. In addition, gilteritinib is being evaluated in the post-transplant maintenance setting.

The study was funded by Astellas Pharma US. In the past 2 years, Perl has received honoraria for serving on advisory boards for AbbVie, Actinium Pharmaceuticals, Agios, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, NewLink Genetics, and Takeda; has received consultancy fees from Astellas, Daiichi Sankyo, Arog, and AbbVie; and his institution has received research funding for him to conduct multi-institutional clinical trials from Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, Daiichi Sankyo, Fujifilm, and Novartis. Caligiuri is on the scientific advisory board of CytoSen Therapeutics and the external advisory board of Cellular Biomedicine Group. 

AACR 2019. Presented April 2, 2019. Abstract CT184.  

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