Unfortunately, sunitinib (50 mg, given orally every day for 4 weeks then 2 weeks off) had no drug activity in the 10 patients that had been enrolled between November 2016 and April 2018.3 In fact, the investigators closed the cohort once the 2 patients who were thought to have had stable disease at their 16-week evaluation died due to disease progression shortly thereafter.3

Dr Schilsky concluded, “Our study results do not justify further study of sunitinib in patients with FLT3-amplified mCRC. The negative results might have several potential explanations, including that FLT3 amplifications are not oncogenic, that sunitinib is not a sufficiently potent inhibitor of FLT3, or that other molecular pathways are active that confer resistance to sunitinib in these patients.”

On the other hand, the results from the ADMIRAL study have shifted the treatment paradigm for R/R AML.4 Primary investigator Mark Levis, MD, PhD, professor of oncology and director of the Adult Leukemia Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, told Cancer Therapy Advisor  that “[This study] has changed the standard of care, and it will spur development of new FLT3-targeted therapies and treatment regimens that center on FLT3 inhibition.”

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Late last year, gilteritinib became the first FLT3 inhibitor to be approved by the FDA as monotherapy for patients with R/R AML with FLT3 amplification.4 The approval was based on interim results of the ADMIRAL trial; the data presented at AACR were the final results.2,4 Importantly, the FLT3 receptor is the most commonly mutated kinase in patients with AML and is found in 30% of this population.5,6

In ADMIRAL, patients who had experienced their first relapse or were refractory to initial chemotherapy were randomly assigned to receive continuous 28-day cycles of 120 mg/day gilteritinib or one of the following salvage-chemotherapy (SC) regimens: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA).2

The investigators found that gilteritinib significantly prolonged overall survival compared with SC (9.3 vs 5.6 months; hazard ratio for death = 0.637; P =.0007).2 One-year survival was also improved with gilteritinib vs SC (37.1% and 16.7%, respectively).2 Complete remission rates were 21.1% with gilteritinib and 10.5% with SC (2-sided P =.0106).2 In addition, according to the study authors, gilteritinib “had a favorable safety profile.”2

Of these results, Dr Levis said, “This is only the first step for this drug.” Pretty impressive, considering the results of the TAPUR study in mCRC.

Looking forward, Dr Levis believes FLT3 is a viable target for other cancers, including acute lymphoblastic leukemia “but likely by targeting the wild-type receptor,” he said.

Dr Schilsky noted, “FLT3 mutations have been validated as targets for cancer treatment in AML. Additional research is necessary to determine if these mutations are valid targets in other tumor types.”

References

  1. Laing C, Shi W, Pollner R. FLT3-Explorer: A bioinformatics pipeline for detecting low signal in FLT3 internal tandem duplications in acute myeloid leukemia. Presented at: American Association for Cancer Research Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract 2475/15.
  2. PerlAE, MartinelliG, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Presented at: American Association for Cancer Research Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract CT184.
  3. Alvarez RH, Garrett-Mayer E, Halabi S, et al. Sunitinib (S) in patients (Pts) with metastatic colorectal cancer (mCRC) with FLT-3 alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. Presented at: American Association for Cancer Research Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract CT146/12.
  4. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. US Food and Drug Administration website. https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutatation Updated December 14, 2018. Accessed May 2, 2019.
  5. Joshi SK, Christy S, Ribeiro RS, et al. Extrinsic and intrinsic activation of RAS/MAPK signaling enables resistance to FLT3 inhibitor, gilteritinib, in acute myeloid leukemia. Presented at: American Association for Cancer Research Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract 926.
  6. Lee JK, Scarpa M, Kapoor S, Baer MR. Combined FLT3 and Pim kinase inhibitor treatment downregulates c-Myc early in apoptosis induction in acute myeloid leukemia with FLT3-ITD. Presented at: American Association for Cancer Research Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract 2056/8.