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POST HOC EXPLORATORY ANALYSIS OF TWO PHASE 2 TRIALS OF QUIZARTINIB MONOTHERAPY IN PATIENTS WITH FLT3-ITD MUTATED RELAPSED/REFRACTORY AML AND PRIOR FLT3 TYROSINE KINASE INHIBITOR TREATMENT
Author(s): ,
Jorge Cortes
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Catherine Smith
Affiliations:
University of California, San Francisco,San Francisco,United States
,
Koji Ishizuka
Affiliations:
Daiichi Sankyo, Inc.,Basking Ridge,United States
,
Ken Kobayashi
Affiliations:
Daiichi Sankyo, Inc.,Basking Ridge,United States
,
Meena Arunachalam
Affiliations:
Daiichi Sankyo, Inc.,Basking Ridge,United States
,
Yibin Wang
Affiliations:
Daiichi Sankyo, Inc.,Basking Ridge,United States
,
Deborah Lazzaretto
Affiliations:
Daiichi Sankyo, Inc.,San Diego,United States
Mark Levis
Affiliations:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University,Baltimore,United States
(Abstract release date: 05/17/18) EHA Library. Cortes J. 06/15/18; 214726; PF240
Dr. Jorge Cortes
Dr. Jorge Cortes
Contributions
Abstract

Abstract: PF240

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background

First-generation tyrosine kinase inhibitors (TKIs) such as sorafenib and midostaurin target FMS-like tyrosine kinase 3 (FLT3) in addition to other kinases, and are increasingly used for treatment of FLT3 mutated acute myeloid leukemia (AML). Quizartinib is a highly potent and selective next-generation FLT3 inhibitor with strong clinical anti-leukemic activity in patients with FLT3-internal tandem duplication (ITD) mutated relapsed/refractory (R/R) AML.

Aims

To analyze the clinical activity of quizartinib in patients with prior exposure to first-generation FLT3 TKIs and gain early clinical insights into the potential benefit of agents with varying kinase and safety profiles.

Methods
This post hoc exploratory analysis was performed using data from two phase 2 trials of quizartinib monotherapy in patients with FLT3 mutated R/R AML (Studies (A) NCT01565668, (B) NCT00989261) to assess quizartinib activity in patients with versus patients without prior therapy with first-generation FLT3 TKIs. Patients with FLT3-ITD allelic frequency ≥3% were considered FLT3-ITD positive for this analysis. In both studies, patients received quizartinib for 28-day cycles until relapse, intolerance, or proceeding to hematopoietic stem cell transplant (HSCT). In Study A, patients received 90, 135, or 200 mg of quizartinib daily, administered as quizartinib dihydrochloride and equivalent to 79.5, 119.3, or 176.7 mg free-base, respectively. In Study B, patients received 30 or 60 mg of quizartinib daily, administered as quizartinib dihydrochloride and equivalent to 26.5 or 53 mg free-base, respectively. 

Results

In Study A, 27 of 261 patients with FLT3-ITD mutations received prior sorafenib and/or midostaurin (24 sorafenib, 1 sorafenib and midostaurin, 2 midostaurin). In Study B, 11 of 72 patients with FLT3-ITD mutations received prior TKIs (10 sorafenib, 1 sorafenib and midostaurin). Clinical activity of quizartinib, as demonstrated by composite complete remission (CRc, defined as complete response with or without hematologic and platelet recovery), overall response rates (ORR, defined as CRc + partial responses [PR]), and median survival duration, was meaningful and similar in patients with or without prior TKI treatment (Table).

Conclusion

This analysis demonstrates meaningful clinical activity of quizartinib in patients with FLT3-ITD mutated R/R AML who have prior exposure to first-generation FLT3 TKIs. Limitations are small sample size and post hoc analysis. Additional studies, including mutational analyses, are warranted to further characterize the potential mechanism(s) of response to quizartinib in patients who have failed prior FLT3 TKI.

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, AML, Relapsed acute myeloid leukemia, Tyrosine kinase inhibitor

Abstract: PF240

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background

First-generation tyrosine kinase inhibitors (TKIs) such as sorafenib and midostaurin target FMS-like tyrosine kinase 3 (FLT3) in addition to other kinases, and are increasingly used for treatment of FLT3 mutated acute myeloid leukemia (AML). Quizartinib is a highly potent and selective next-generation FLT3 inhibitor with strong clinical anti-leukemic activity in patients with FLT3-internal tandem duplication (ITD) mutated relapsed/refractory (R/R) AML.

Aims

To analyze the clinical activity of quizartinib in patients with prior exposure to first-generation FLT3 TKIs and gain early clinical insights into the potential benefit of agents with varying kinase and safety profiles.

Methods
This post hoc exploratory analysis was performed using data from two phase 2 trials of quizartinib monotherapy in patients with FLT3 mutated R/R AML (Studies (A) NCT01565668, (B) NCT00989261) to assess quizartinib activity in patients with versus patients without prior therapy with first-generation FLT3 TKIs. Patients with FLT3-ITD allelic frequency ≥3% were considered FLT3-ITD positive for this analysis. In both studies, patients received quizartinib for 28-day cycles until relapse, intolerance, or proceeding to hematopoietic stem cell transplant (HSCT). In Study A, patients received 90, 135, or 200 mg of quizartinib daily, administered as quizartinib dihydrochloride and equivalent to 79.5, 119.3, or 176.7 mg free-base, respectively. In Study B, patients received 30 or 60 mg of quizartinib daily, administered as quizartinib dihydrochloride and equivalent to 26.5 or 53 mg free-base, respectively. 

Results

In Study A, 27 of 261 patients with FLT3-ITD mutations received prior sorafenib and/or midostaurin (24 sorafenib, 1 sorafenib and midostaurin, 2 midostaurin). In Study B, 11 of 72 patients with FLT3-ITD mutations received prior TKIs (10 sorafenib, 1 sorafenib and midostaurin). Clinical activity of quizartinib, as demonstrated by composite complete remission (CRc, defined as complete response with or without hematologic and platelet recovery), overall response rates (ORR, defined as CRc + partial responses [PR]), and median survival duration, was meaningful and similar in patients with or without prior TKI treatment (Table).

Conclusion

This analysis demonstrates meaningful clinical activity of quizartinib in patients with FLT3-ITD mutated R/R AML who have prior exposure to first-generation FLT3 TKIs. Limitations are small sample size and post hoc analysis. Additional studies, including mutational analyses, are warranted to further characterize the potential mechanism(s) of response to quizartinib in patients who have failed prior FLT3 TKI.

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, AML, Relapsed acute myeloid leukemia, Tyrosine kinase inhibitor

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