Practice-Changing Results Seen in Phase III Relapsed/Refractory AML Trial

The novel FLT3 inhibitor gilteritinib improved response and survival outcomes compared with chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML), according to results of a new phase III study. Experts at the American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta, say the results of the phase III ADMIRAL are practice-changing in this patient setting (abstract CT184).

AML is generally a highly chemo-sensitive malignancy, and many patients can be cured with chemotherapy along with transplantation. However, in patients who relapse after primary therapy or are refractory to chemotherapy, “their outcome is dismal,” said Alexander E. Perl, MD, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. “This is a highly aggressive disease that we unfortunately don’t have very good therapeutics to treat.”

Activating FLT3 mutations are present in approximately 30% of AML patients. Gilteritinib is a novel inhibitor that improves on previous FLT3 inhibitors in that it has activity against both FLT3-internal tandem duplication (ITD) and FLT3- tyrosine kinase domain (TKD) D835 mutations, and in earlier studies was well tolerated across a variety of doses with limited QT prolongation, which can be an issue with other agents.

The study included 371 patients randomized to receive either gilteritinib 120 mg/day (247 patients) or salvage chemotherapy (124 patients).

All patients had relapsed or refractory AML and a confirmed FLT3 mutation; the median age in the trial was 62 years, and 54% of patients were female. Most patients (82%) had received aggressive front-line chemotherapy with an anthracycline-based regimen, and 12% had received a prior FLT3-targeted tyrosine kinase inhibitor.

Response and survival outcomes significantly favored the gilteritinib arm. A total of 52 patients who received gilteritinib achieved a complete response (21%), compared with 13 patients in the chemotherapy group (11%). The overall response rate was 68% with the study drug, compared with 26% with chemotherapy. The median duration of response was 11.0 months with gilteritinib, compared with 1.8 months with chemotherapy, and 26% of gilteritinib patients went on to receive hematopoietic stem cell transplantation compared with 15% of chemotherapy patients.

The median overall survival was 9.3 months with gilteritinib and 5.6 months with chemotherapy, for a hazard ratio of 0.637 (95% CI, 0.490–0.830; P = .007). At 12 months, the overall survival rate was 37% with the study drug and 17% with chemotherapy.

Among the most common treatment-emergent adverse events (TEAEs) with gilteritinib were anemia (33%), increased ALT levels (24%), and increased AST levels (24%). With chemotherapy, the most common TEAEs included anemia (33%), febrile neutropenia (32%), and nausea (30%). Perl noted that the toxicity is difficult to compare given that the median treatment duration was substantially longer with gilteritinib, at 4.1 months vs 0.9 months with chemotherapy.

“This is a major change in how we approach patients in the relapsed/refractory setting, because we’re now using molecularly targeted therapies to select patients that may benefit from this approach,” Perl said.

Louis M. Weiner, MD, of the Georgetown Comprehensive Cancer Center at Georgetown University, who was not involved with the study, affirmed the significance of these results. “This is a new, practice-changing strategy, which is something we’ve been needing in the field of AML therapy for the entire time I’ve been an oncologist,” he said during a press conference at the AACR meeting. “To have something like this is really important.”