Cabozantinib may help to evade drug resistance in patients with acute myeloid leukemia (AML), according to research published in Cancer.1

Standard cytotoxic chemotherapy remains the standard treatment for AML, though a large proportion of patients relapse and/or develop resistance to conventional therapy, indicating a need for new treatments. FLT3 mutations are, furthermore, associated with a worse prognosis, and while novel FLT3 inhibitors can be effective in AML, resistance to targeted therapy tends to evolve.

For this phase 1, dose-escalation study (ClinicalTrials.gov Identifier: NCT01961765), researchers evaluated the efficacy and toxicity of cabozantinib, a multi-kinase inhibitor of FLT3, MET, VEGFR2, and KIT, among patients with AML. Of 18 enrolled patients, the median age was 68, 16 had relapsed/refractory disease, 2 had newly diagnosed disease, and 5 had detectable FLT3 mutations.

The maximum tolerated dose was determined to be 40 mg, notably lower than for other cabozantinib indications, as dose-limited toxicities were observed with the 60 mg dose.


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No formal marrow responses were observed and the median overall survival was 3.88 months.

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The researchers observed, however, that 4 patients “had a reduction in peripheral blasts during treatment, and 2 of these patients transiently cleared their circulating blasts (1 with an FLT3/ITD mutation).”

Grade 2 or worse toxicities that may have been related to the experimental treatment included fatigue, nausea, transaminitis, and electrolyte imbalance.

The authors concluded that “cabozantinib…effectively inhibits the FLT3/TKD/F691 resistance mutation and may, therefore, play a role in future therapeutic paradigms.”

Reference

  1. Fathi AT, Blonquist TM, Hernandez D, et al. Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. Cancer. 2017 Sep 28. doi: 10.1002/cncr.31038 [Epub ahead of print]