Pexidartinib Safe, Tolerable for Treatment of Relapsed/Refractory FLT3-Mutated AML

Phase 1/2 study findings show that pexidartinib is safe and well-tolerated in patients with relapsed or refractory acute myeloid leukemia (AML), and yields clinical activity in those with FLT3-ITD mutations (Blood Adv. 2020 Apr 28;4[8]:1711-1721).

“[FLT3] tyrosine kinase inhibitors (TKIs) have activity in [AML] patients with FLT3-[ITD] mutations, but efficacy is limited by resistance-conferring kinase domain mutations,” wrote lead investigator Catherine C. Smith, MD, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, and colleagues.

A total of 90 patients with AML and FLT3-ITD mutations were included in the phase 1/2 trial in which Dr Smith et al evaluated the safety, tolerability, and efficacy of pexidartinib, including 34 patients in the dose-escalation portion (phase 1) and 56 in dose-expansion portion (phase 2).

Patients were given pexidartinib 800 mg to 5000 mg daily in divided doses, and those receiving ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line, according to plasma inhibitory assay.

Although the investigators did not establish a maximum tolerated dose, 3000 mg was chosen as the recommended phase 2 dose.

Ultimately, modified response criteria revealed an overall response rate of 21% across all patients. Approximately 20% of patients given pexidartinib ≥2000 mg had responses, and the overall composite complete response rate was 11%.

There were a total of 6 patients successfully bridged to transplantation, and the median overall survivals of patients treated in dose expansion and responders with complete remission with or without recovery of blood counts were 112 days (90% CI, 77-150 days), and 265 days (90% CI, 170-422 days).

Diarrhea (50%), fatigue (47%), and nausea (46%) were the most common treatment-emergent adverse events.

“Overall, the safety, tolerability, and clinical activity of pexidartinib in the heavily pretreated [relapsed or refractory] AML population described in this study are supportive of the further development of pexidartinib in AML,” Dr Smith and co-investigators concluded.—Hina M. Porcelli