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Targeting of FLT3 AML
QUANTUM-R study, quizartinib monotherapy was com- pared to salvage chemotherapy in patients with R/R FLT3- mutated AML.66 Patients in the quizartinib arm had a sig- nificantly higher (CRc) rate (48%) than patients in the chemotherapy arm (27%) with complete remission with incomplete hematologic recovery (CRi) predominating. Patients in the quizartinib arm were more likely to under- go alloHSCT (32%) than those in the chemotherapy arm (11%). The quizartinib arm also had longer OS compared to the salvage chemotherapy arm (HR 0.76, 95%CI: 0.58- 0.98, P=0.02). The most significant adverse effects in the quizartinib arm were myelosuppression and QTc prolon- gation. The former probably results from quizartinib’s activity against c-KIT, a receptor tyrosine kinase that is closely related to FLT3 and that is present on HSC. The QTc prolongation appears to be dose-dependent and has been a concern at the regulatory level that has delayed quizartinib’s approval (although the drug is approved in Japan). Quizartinib may be particularly effective as part of an induction regimen because of its potency. The QUAN- TUM-first study (clinicaltrials.gov identifier: NCT03250338), a phase III study of 7+3 and quizartinib versus 7+3 alone, has completed enrollment and is likely to be one of the first studies of combined second generation FLT3 inhibitors and chemotherapy to yield results.
Crenolanib
Crenolanib is another potent, class I second generation FLT3 inhibitor that demonstrated clinical efficacy in a phase II trial in the R/R setting.67 In patients who had not previously received a FLT3 inhibitor, it achieved a cytoge- netic CR (CRc) rate of 37% with a partial response (PR) rate of 11%. Amongst patients previously treated with a FLT3 inhibitor, it achieved a CRc in 15% of patients and a PR in 13% of patients. These responses were probably driven by crenolanib’s activity against FLT3 D835 TKD mutations, which frequently develop in patients treated with class II inhibitors.68 The patterns of resistant clones that emerged after crenolanib therapy differed from those seen in cohorts of patients treated with other TKI.69 Secondary FLT3 mutations were rare, but non-responders tended to have mutations in TET2 and IDH1/2, while patients who relapsed on crenolanib acquired mutations in these genes as well as NRAS. Crenolanib also has less activity against c-KIT and therefore is less myelosuppres- sive than quizartinib. In an ongoing phase II trial (clinical- trials.gov identifier: NCT02283177) of crenolanib in combi- nation with chemotherapy (7+3), 85% of patients had a CR and 19 of 27 patients were alive and disease free at a median of 29.3 months of follow up.70
FF-10101
FF-10101 is a novel FLT3 inhibitor that covalently binds to FLT3 at the cysteine residue at 695.71 As a result, it is a potent and irreversible inhibitor of FLT3 that is unaffected by common resistance mutations, including those that occur within the TKD as well as the F691L gatekeeper mutation. It is currently being studied in a multicenter clinical trial (clinicaltrials.gov identifier: NCT03194685).
The potential for improving outcomes of acute myeloid leukemia by targeting FLT3 now and in the near future
The opportunities for more effective targeting of FLT3 will expand with the availability of new FLT3 inhibitors, but practical questions will also arise. Which inhibitor is
best suited for a given clinical scenario? Is there any bene- fit to switching from one inhibitor to another? Should we target non-canonical FLT3 mutations or WT FLT3? Combining FLT3 inhibitors with other novel therapies also has the potential to improve efficacy while reducing toxicity. Finally, there are new immunotherapeutic approaches to targeting FLT3 on the horizon which may further impact the future of mFLT3 AML management.
Selecting the most appropriate FLT3 inhibitor for the patient and the clinical scenario
Determining which FLT3 inhibitor is most effective in the upfront setting is an area of intense interest. A FLT3 inhibitor with greater potency against FLT3 than midostaurin may suppress mFLT3 signaling more effec- tively, leading to better suppression or elimination of the mFLT3 clone. FL is also known to compete with FLT3 inhibitors,72 and a more potent inhibitor might compete more effectively, counteracting the protective effect of endogenous FL. Preliminary data from a phase I study of upfront gilteritinib in combination with chemotherapy demonstrate a 100% CRc in patients with de novo AML. On the other hand, midostaurin’s broader anti-kinase activity may enhance its anti-proliferative effect, especial- ly in the upfront setting when the mFLT3 clone is relative- ly small and the leukemia is heterogeneous.28 Trials com- paring the combination of midostaurin and chemotherapy with second generation inhibitors and chemotherapy are poised to answer this question (clinicaltrials.gov identifiers: NCT04027309 and NCT02400281).
Multiple FLT3 inhibitors are also being investigated in the maintenance setting. Here too, potency is likely to be an asset, but other advantageous characteristics might include favorable toxicity profiles as well as a high thresh- old for the development of resistance. Class II inhibitors, for example, may be less effective in this setting due to the frequency with which mFLT3 clones acquire resistant TKD mutations.
Finally, there may be occasions for switching FLT3 inhibitors. FLT3 inhibitors have different side effect pro- files that may make one more tolerable than another for a given patient. When the duration of treatment is likely to be short (as in the case of pre-transplant therapy), potency may be prioritized over tolerability and susceptibility to the development of resistance, whereas in the mainte- nance setting, these priorities may be inverted. Resistance patterns also differ and the emergence of a TKD mutation in response to treatment with quizartinib for example, might require a switch to a class I inhibitor. There is not yet much data on central nervous system (CNS) penetra- tion, but the presence of CNS disease may also play a role in FLT3 inhibitor selection.
Novel combinations
FLT3 inhibitors are also being studied in combination with a number of other therapeutic partners including HMA/FLT3, Ven/FLT3, HMA/Ven/FLT3, Others + FLT3, IDH + FLT3, and other investigational agents (Table 1). HMA may be well-suited for combination therapy with FLT3 inhibitors as they have synergistic effects in vitro and appear to induce FL expression to a lesser extent than other conventional chemotherapies. Prior to the advent of second generation FLT3 inhibitors, the combination of sorafenib and azacitidine demonstrated an acceptable tox- icity profile and a 46% overall response rate (ORR), lead-
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