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Department of Leukemia
The University of Texas MD Anderson Cancer Center
Naval G. Daver, MD, has disclosed that he has received consulting fees from AbbVie, Agios, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Immunogen, Incyte, Jazz, Karyopharm, Novartis, Otsuka, Pfizer, and Sunesis; and funding for research from AbbVie, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Forty-Seven, Genentech, Glycomimetics, Hanmi, Immunogen, Incyte, Karyopharm, Newave, NOHLA, Novartis, Pfizer, Servier, Sobi, Sunesis, and Trovagene.
Approximately 25-30% of newly diagnosed patients with acute myeloid leukemia (AML) have a FLT3-ITD or FLT3-TKD mutation. The FLT3-ITD (80% of all FLT3 mutations) is prognostic for poorer outcomes. In the past 4 years, the FDA approved 2 FLT3 inhibitors, midostaurin and gilteritinib. Midostaurin was approved in combination with standard 3+7 induction chemotherapy, in a randomized, multicentral phase III study of 3+7 with midostaurin vs 3+7 alone in patients with newly diagnosed FLT3-ITD and/or D8A35 mutations in the frontline setting. Gilteritinib is a more potent and specific second-generation FLT3 inhibitor and was approved based on improved survival as well as improved composite CR/CRh rate, noted in the phase III ADMIRAL study in patients with relapsed/refractory FLT3-ITD–mutated and/or D835-mutated AML, in which gilteritinib was compared with investigator choice salvage chemotherapy.
Although both approved FLT3 inhibitors have improved outcomes for patients with the FLT3 mutations, further improvements are needed. To address this, researchers are investigating not only novel combinations and applications for gilteritinib, but 2 novel second-generation FLT3 inhibitors as well that may add significantly to the FLT3 armamentarium: quizartinib, a very potent FLT3-ITD specific inhibitor that targets FLT3-ITD, and crenolanib, which targets both FLT3-ITD and FLT3-TKD.
Quizartinib in FLT3-Mutated AML
Quizartinib has been in clinical development for more than 7 years and was the first second-generation FLT3 inhibitor to show improved OS vs salvage chemotherapy in patients with relapsed/refractory FTL3-ITD positive AML in a phase III randomized trial. Early studies showed composite remission rates of between 35% and 55%, far higher than we would expect with standard salvage chemotherapy.
More recently, the phase III QuANTUM-R study in relapsed/refractory FLT3-ITD AML randomized patients (N = 367) to single-agent quizartinib vs investigator’s choice chemotherapy (eg, higher-intensity therapies such as FLAG-Ida; mitoxantrone-, etoposide-, or cytarabine-based treatment, or low-intensity therapies such as azacitidine or low-dose cytarabine [LDAC]). Results showed that quizartinib improved the median OS vs chemotherapy and also significantly improved the composite CR (CRc) rate, demonstrating that quizartinib is a potent oral agent FLT3 inhibitor that improved outcomes vs low- or high-intensity salvage chemotherapy. Based on these results, quizartinib was approved in Japan for patients with FLT3-positive relapsed/refractory AML, but given concerns regarding therapeutic equipoise and margin of benefit achieved in the QuANTUM-R study, it was not approved in relapsed/refractory FLT3-ITD AML in the United States or Europe.
Although single-agent quizartinib and single-agent gilteritinib have shown encouraging responses in the relapsed/refractory setting, their durability of responses and overall survival rates need improvement. Although marrow remission rates are in the range of 45% to 55% with single-agent quizartinib or gilteritinib, the median OS is only 6-10 months for these patients, and fewer than 20% of patients are alive at 2 years, with long-term survival mainly seen in patients bridged to allogeneic stem cell transplant.
Novel FLT3 Combinations
To address this, a number of exciting novel combinations with quizartinib, crenolanib, and gilteritinib are currently being evaluated in clinical trials, including frontline combination therapies with high-intensity and low-intensity chemotherapy. The phase III QuANTUM-First trial is testing quizartinib in combination with induction chemotherapy vs induction chemotherapy alone in patients with newly diagnosed FLT3-ITD AML (NCT02668653). This study has recently completed accrual, and we hope to have the topline data in 2021.
In addition, there are novel combinations using second-generation FLT3 inhibitors with the hypomethylating agents azacitidine or decitabine. We (MDACC) presented results of an ongoing study of azacitidine or LDAC in combination with quizartinib in older patients with frontline AML at ASH 2018. The CRc rates were very high, > 80%, with a median OS of greater than 17 months in older patients with frontline FLT3-ITD mutated AML. The number of frontline patients was small (n = 12), but this was quite encouraging survival in an older, unfit FLT3-ITD population receiving low-intensity treatment. In a relapsed/refractory AML population with FLT3-ITD mutations in the same study, the CRc rates with azacitidine or LDAC combined with quizartinib, were approximately 70% and median OS was 12 months, higher than would be expected with single-agent quizartinib in salvage.
Gilteritinib is similarly being investigated in the frontline setting, with the phase III HOVON 156 AML study accruing patients who are randomized to induction 3+7 with gilteritinib or induction 3+7 with midostaurin, with event-free survival as the primary endpoint (NCT04027309). There is also an ongoing randomized phase II study by the preCOG group, evaluating 3+7 plus gilteritinib vs 3+7 plus midostaurin in newly diagnosed FLT3-mutated AML (NCT03836209). This trial has an interesting primary endpoint that has not been used in randomized AML trials: achievement of CRc for FLT3 negativity as measured by PCR. With this endpoint, we will hopefully get an early assessment of whether the addition of gilteritinib to 3+7 gives us deeper responses (usually translated into improved survival) compared with midostaurin plus 3+7.
Similarly, crenolanib is being evaluated in a phase III study of 3+7 plus crenolanib vs 3+7 plus midostaurin (NCT03258931). We hope that in the next few years, one or more of these second-generation FLT3 inhibitors will be available in the frontline setting in combination with induction chemotherapy to improve on current patient outcomes.
FLT3 Inhibitors Plus Venetoclax
There has been major progress in AML therapeutics with the approval of the BCL2 inhibitor venetoclax in combination with azacitidine/decitabine in the frontline setting in older patients considered unsuitable for intensive induction chemotherapy. Our group at MD Anderson have presented preclinical data combining venetoclax with FLT3 inhibitors such as quizartinib, first-generation sorafenib, and gilteritinib, as well as with the triplet combination of azacitidine and venetoclax plus quizartinib or gilteritinib. We demonstrated a high degree of synergy for the combination of FLT3 inhibitors with venetoclax, likely due to the synthetic lethality induced by these combinations, as well as downstream inhibition of MCL1 by FLT3 inhibitors. MCL1 upregulation is emerging as a major pathway of resistance to venetoclax. Studies with all of these combinations are currently open and enrolling.
My colleagues and I presented at the ASH 2019 meeting a multicenter experience of venetoclax with gilteritinib in patients with relapsed FLT3-mutated AML, showing a marrow remission rate of 88%! This is very high, and almost double of what we get with single-agent gilteritinib in patients with relapsed/refractory FLT3-mutated AML who are less heavily pretreated and less frequently exposed to prior FLT3 inhibitors. This suggests that a combination of a second-generation FLT3 inhibitor with venetoclax may be very active, and we look forward to promising updates of such combinations of quizartinib and gilteritinib with venetoclax with or without HMAs at this year’s ASH 2020 meeting.
There are numerous other agents, such as MDM2 inhibitors and PD-L1 inhibitors, that are being combined with quizartinib and gilteritinib. There is robust preclinical data showing synergy of quizartinib with the MDM2 inhibitor milademetan, for example, which has led to a multinational phase I study combining the two, and we are eagerly looking forward to updates (NCT02319369).
In conclusion, 5 years ago, we had no approved treatment in AML targeting FLT3 mutations. Today, we have 2 approved FLT3 inhibitors and 3 second-generation FLT3 inhibitors showing great promise, particularly in novel combinations. The future looks brighter for this challenging patient population.Your Thoughts: What questions do you have regarding FLT3 treatment in AML? Ask us in the comment box below.
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