FLT3

Targeted therapy for FLT3 mutated AML - Educational session at the 2017 ASCO Annual Meeting

On Tuesday 6th June 2017, an Educational Session took place during the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting discussing emerging treatment options for Acute Myeloid Leukemia (AML) subsets.

The first talk during this enthralling session was given by  the chair Richard M. Stone, M.D., from the Dana-Farber Cancer Institute, USA. He discussed the biology of Fms-Like Tyrosine Kinase 3 (FLT3) mutations in AML and gave an overview of early and ongoing trials using novel therapeutic agents targeting FLT3 mutations in AML patients.1

Mutations in the FLT3 gene represent one of the most commonly encountered, and clinically challenging, classes of AML mutations and it is expressed in approximately 30% of patients. There are two types of FLT3 mutations, Internal Tandem Duplication (ITD) in or near the juxtamembrane domain of the receptor and point mutations resulting in single amino acid substitutions occurring within the activation loop of the Tyrosine Kinase Domain (TKD).2 Patients with FLT3-ITD mutations present with a very large disease burden and have a worse prognosis than patients with wild-type FLT3 mutations and thus a key focus for therapy development.

Early studies with single-agent FLT3 inhibitors including midostaurin, lestaurtinib, and tandutinib in patients with advanced FLT3 mutated AML revealed that these agents lacked efficacy possibly due to AML biology. Additionally, these first generation FLT3 inhibitors were protein bound and lacked potency and specificity.

As a result, there has been a vast clinical development of novel therapies for FLT3 mutated AML. Emerging therapy for FLT3 mutated AML in clinical development involves two major streams, including the use of highly specific and potent FLT3 inhibitors such as quizartinib and gliteritinb in advanced AML and the use of first generation FLT3 inhibitors in combination with chemotherapy in newly diagnosed FLT3-positive AML. 

2nd generation FLT3 inhibitors in AML

Quizartinib, which specifically inhibits FLT3-ITD, is currently being evaluated in comparison with salvage chemotherapy in the phase III QuANTUM-R study (NCT02039726) in Relapsed or Refractory (R/R) AML patients, with the primary outcome being Overall Survival (OS). Previous reported results from a phase II study with quizartinib were discussed during the talk. In this study, the safety and efficacy of quizartinib monotherapy was evaluated in a cohort of 134 R/R AML patients (median age = 70 years). Patients were either FLT3-ITD positive (n = 90) or FLT3-ITD negative (n = 42). The key results of the study were: 3

  • Composite Complete Remission (CRc) in FLT3-ITD+ and FLT3-ITD- patients; 53% vs 36%
  • Median CRc duration in FLT3-ITD+ and FLT3-ITD- patients; 10.4 vs 9.3 weeks

Conversely, the phase I/II Chrysalis study (NCT02014558) of gilteritinib, a potent, oral FLT3/AXL inhibitor, in R/R AML patients was discussed. In this study, the safety and efficacy of gilteritinib monotherapy was evaluated in R/R AML patients. The key results of this study were:4

  • Overall Response Rate (ORR) in FLT3 mutated AML patients and wild type FLT3 AML patients; 49% vs 12%

The AML Global Portal interviewed Professor Jessica Altman, Northwestern University, on the molecular response to gilteritinib. She highlighted that the median OS in patients that had achieved a molecular response to gilteritinib was significantly longer than patients that did not achieve a molecular response.

Gilteritinib is currently being evaluated in comparison with salvage chemotherapy in a phase III study (NCT02421939) in R/R AML patients, with the primary outcome of the study being OS.

Richard M Stone highlighted that, although quizartinib and gilteritinib have more specificity for FLT3-ITD, there are still very few true CRs and thus suggested that given the rarity of CR, it might be better to combine FLT3 inhibitors with chemotherapy.

FLT3 inhibitors plus chemotherapy

Multiple studies with sorafenib, a multi-targeted kinase inhibitor, in combination with chemotherapy was then discussed. One of the studies included a phase II trial, by The Alliance for Clinical Trials in Oncology, evaluated sorafenib in combination with 7+3 induction chemotherapy and modified high-dose cytarabine based post-remission therapy in newly diagnosed FLT3 mutated AML patients over the age of 60. The results of this study showed that addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults, more than doubling the 1-year OS compared to historical controls (62% vs 30%, P < 0.0001).5

Then the phase II randomized SORAML trial (NCT00893373) was discussed. In this study, 276 AML patients were randomly assigned to receive standard induction and post-remission chemotherapy with or without sorafenib. The key results of the study were:6

  • Median Event Free Survival (EFS) in patients administered sorafenib (n = 134) and placebo (n = 133); 21 vs 9 months
  • Median Relapse Free Survival (RFS) in patients administered sorafenib and placebo; not reached vs 23 months
  • 3-year OS in patients administered sorafenib and placebo; 63% vs 56%, P = 0.382

The spotlight was then turned to another FLT3 inhibitor, lestaurtinib, and Richard M Stone discussed the analysis of two trials: AML15 (ISRCTN17161961) and AML17 (ISRCTN55675535) performed by Knapper et al. In these studies, lestaurtinib was added to front line chemotherapy in patients with previously untreated AML in order to investigate its effect on clinical outcome of patients. The primary endpoints of these studies were OS and RFS. It was shown that lestaurtinib in combination with first-line chemotherapy in previously untreated AML patients did not have an overall clinical benefit; however, it was a feasible therapeutic option. Additionally, patients with sustained FLT3 inhibitory activity and patients who received azole therapy and gemtuzumab ozogamicin had an improved OS and lower rates of relapse.7

Studies with the recently U.S Food and Drug Administration (FDA) approved FLT3 inhibitor midostaurin was discussed next. In particular, the phase III RATIFY trial (NCT00651261), which is a randomized trial in 717 newly diagnosed FLT3+ AML patients. In this study, patients were randomly assigned to receive either placebo or midostaurin 50mg orally twice daily on days 8–21 of each cycle of induction and consolidation chemotherapy followed by continuous daily midostaurin for up to 12 cycles. The key results of the study were:

  • OS in patients receiving midostaurin and placebo; 74.4 vs 25.6 months, HR = 0.77, P = 0.0074

Additionally, when patients were censored for transplantation analysis, a benefit for midostaurin was observed, especially in patients who underwent transplant in First Complete Remission (CR1).8

Richard M Stone concluded his talk by highlighting other upfront FLT3 inhibitor clinical trials in AML patients including crenolanib in combination with 3+7 chemotherapy which has showed 88% CR in 32 evaluable AML patients.

References
  1. Stone R. M.  Targeting Flt3 Mutations in Acute Myeloid Leukemia. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.
  2. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013; 2013: 220–226. DOI: 10.1182/asheducation-2013.1.220.
  3. Cortes J. et al. Final results of a phase 2 open-label monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years old with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. 2012 Dec 9. 2012 Annual Meeting of ASH. Abstract 48.
  4. Perl E. A. et al. Final Results of the Chrysalis Trial: A First-in-Human Phase 1/2 Dose-Escalation, Dose-Expansion Study of Gilteritinib (ASP2215) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML). 2016 Dec 5. Oral Abstract 1069, 2016 Annual Meeting of ASH, San Diego, Ca.
  5. Uy G.L. et al. Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001). 2015 Dec 6. Oral Abstract 319, 2015 Annual Meeting of ASH, Orlando, FL.
  6. Röllig C. et al. Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial. Blood. 2014; 124:6.
  7. Knapper. S. et al. A randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML. Blood. 2016 Nov 21; DOI: 10.1182/blood-2016-07-730648 [Epub ahead of print].
  8. Stone R.M. et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). 2015 Dec 6. Oral abstract #6: 57th Annual Meeting of the American Society of Hematology, Orlando, FL.