Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Phase 1b Study

BACKGROUND: The FLT3 tyrosine kinase inhibitor (TKI) gilteritinib improves the survival of patients with relapsed/refractory (R/R) FLT3 mutated (FLT3^mut+) acute myeloid leukemia (AML) compared to standard salvage chemotherapy; however, single agent TKI therapy is not curative and long-term survival remains low. Combination therapy with agents that induce apoptosis may enhance cytotoxicity against FLT3^mut+ and WT clones and potentially delay or prevent drug resistance. Preclinical data demonstrate that the combination of venetoclax with a FLT3 tyrosine kinase inhibitor is highly synergistic, and BCL-2 inhibition by venetoclax directly triggers apoptosis, which may help overcome resistance to FLT3-targeted therapy. Therefore, we sought to define the safety and activity of venetoclax plus gilteritinib in R/R AML.

METHODS: This is a multicenter, open-label, phase 1b clinical trial (NCT03625505) evaluating the safety and efficacy of venetoclax in combination with gilteritinib for patients with relapsed or refractory (R/R) AML. Patients had to have R/R AML and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Here, we present data in patients that had either wild type (WT) or mutated FLT3, and were treated with 400 mg venetoclax in combination with 80 mg or 120 mg gilteritinib daily, from the dose escalation portion of the study. For study purposes, gilteritinib was administered alone for one day. On day two venetoclax was initiated in a three-day ramp-up from 100 to 200 to 400 mg; thereafter, target doses of each were administered, daily, in 28-day cycles unless venetoclax was shortened for cytopenia recovery. Interruptions of venetoclax or both drugs simultaneously were permitted for adverse events (AEs).

RESULTS: Data cutoff was July 10, 2019. Of 15 patients enrolled and treated, 5 had WT FLT3 and 10 had mutant FLT3 (8 ITD, 1 TKD, and one with both included with the ITD group). The median age for all patients was 58 (range: 23-81). Both patients with WT or mutant FLT3 had a median of 2.0 prior lines of therapy, with ranges of 2-4 and 1-4 prior lines, respectively. Six (60%) of the FLT3 mutant patients had previously received a FLT3 blocking TKI (2 of those receiving both midostaurin and sorafenib), and 5 (50%) had prior stem cell transplant (SCT). None of the patients with WT FLT3 were FLT3 inhibitor-experienced, and one patient had prior stem cell transplant. Key treatment emergent grade ≥3 AEs across all patients were: febrile neutropenia (47%), anemia (27%), thrombocytopenia (7%) and neutropenia (7%). One patient receiving 80 mg of gilteritinib had a protocol-defined dose limiting toxicity of prolonged neutropenia, and one receiving 120 mg of gilteritinib was still within the protocol-defined count recovery period at analysis. Seven (47%) patients had venetoclax interrupted, the majority due to neutropenia; 3 (20%) patients had gilteritinib interrupted. No cases of tumor lysis syndrome were observed. Pharmacokinetic studies showed comparable drug levels to those observed with single agent use of each drug. Key efficacy results are shown in the Table. Fifty percent of patients with mutant FLT3 achieved CRc, and another 40% of patients achieved morphologic leukemia free state, for an ORR of 90% (9/10). The ORR in patients with WT FLT3 was 20% (1/5). 0-32); this patient had WT FLT3. Among the 5 patients who achieved CRc, 2 had relapse after documented CRi (at 2.6 months and 1.6 months). Patient monitoring is ongoing, and enrollment in an expansion cohort has also commenced (FLT3 mutant patients treated with 400 mg venetoclax plus 120 mg of gilteritinib); results will be updated for the presentation.

CONCLUSIONS: Venetoclax in combination with gilteritinib was well tolerated and demonstrated blast clearance in 90% of patients with FLT3 mutated AML. The high overall rate of response in patients with FLT3 mutated AML, particularly in patients with previous FLT3 TKI exposure, suggests venetoclax in combination with gilteritinib may be a highly effective treatment option for AML patients with FLT3^mut+, even in patients with relapsed/refractory AML.

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