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4260 Quantum-First (Q-F): Clinical Bridging Study for FMS-like Tyrosine Kinase 3–Internal Tandem Duplication (FLT3-ITD) Companion Diagnostic Development

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
adult, autoimmune disorders, Research, AML, Acute Myeloid Malignancies, clinical trials, Combination therapy, Clinical Research, Diseases, Therapies, Myeloid Malignancies, Technology and Procedures, Study Population, Human, molecular testing
Monday, December 11, 2023, 6:00 PM-8:00 PM

Jaime E Rohrbach, PhD1*, Ken C N Chang, PhD2*, Maha Karnoub2*, Li Liu3*, Yasser Mostafa Kamel4*, Shirin Khambata-Ford2*, Shawn Rivera5*, Jelveh Lameh6*, Ekaterina Rudenko7*, Jordan Thornes8*, Sarah Todt7*, Jason Gerhold8*, Ying Huang, PhD8*, Jeffrey E Miller, PhD8*, Alexander Perl9, Mark J. Levis, MD, PhD10 and Kazumi Ito2*

1Daiichi Sankyo, Basking Ridge, NJ
2Daiichi Sankyo, Basking Ridge
3Daiichi Sankyo, Inc, Basking Ridge
4Daiichi Sankyo, Inc., Basking Ridge
5Navigate BioPharma Services, Inc., Carlsbad
6Navigate BioPharma Services, Inc., Carlsbad, CA
7Invivoscribe, Inc., San Diego
8Invivoscribe, Inc., San Diego, CA
9Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
10Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, MD


Q-F (NCT02668653) showed that the highly potent, selective, type 2 FLT3 inhibitor quizartinib (Q) + standard chemotherapy ± transplantation, followed by Q monotherapy for ≥36 cycles, reduced the relative risk of death by 22.4% vs placebo (P) in newly diagnosed (nd) FLT3-ITD+ AML, with HR of 0.776 and P value of 0.0324 (PMID: 37116523). In Q-F, FLT3-ITD mutation status was determined using a FLT3-ITD mutation detection clinical trial assay (CTA) validated under design control by Navigate BioPharma Services, Inc. We describe the results of the bridging study, aimed to show agreement between the CTA & the LeukoStrat CDx FLT3 Mutation Assay (CDx, by Invivoscribe) in FLT3-ITD+ pt selection and to determine if Q efficacy (overall survival [OS]) was maintained in nd FLT3-ITD+ AML pts from Q-F, if pts had been selected using the CDx.


In both CTA & CDx, DNA, extracted from bone marrow (n=884 each) or peripheral blood (n=139 each), was amplified via PCR and amplicons were detected via capillary electrophoresis. A sample was considered CTA+ if the variant allele frequency (FLT3-ITD/total FLT3) was ≥3% and CDx+ if the signal ratio (SR; FLT3-ITD/FLT3 WT) was ≥0.05. The agreement between CTA & CDx was based on evaluating CTA+ & CTA− samples with the CDx assay. A primary analysis included the CDx detected (CDx+ & CDx−) and the CDx invalid results. A secondary analysis used CDx+ and CDx− results only. To establish agreement between CDx & CTA, positive % agreement (PPA) and negative % agreement (NPA) were determined using CTA results as reference for the agreement analysis set (AAS). Concordance was established if the lower bounds of the 95% CIs for both PPA & NPA exceeded 90% for the analysis that included the invalid CDx results. Median OS in the subgroups was calculated based on Kaplan-Meier estimates. Stratified Cox proportional hazards regression model was used to estimate HRs, 95% CI, and P value.


Full analysis set (N=3468) included all Q-F screened CTA+ pts (n=863), all screened CTA− pts (n=2556), and pts with unknown CTA status not eligible for randomization due to other criteria (n=49). Of these, 1032 pts formed the primary analysis set (PAS), including all pts randomized in Q-F with samples available for CDx testing (N=513: Q, n=254; P, n=259) and a randomly selected subset of CTA− pts (n=519). The ascertainment rate was 95.2% (513/539), as 26 of the 539 pts randomized in Q-F were excluded from the bridging study. Within the PAS, 3 samples were not tested by CDx due to insufficient volume/DNA amount. The AAS (N=1029: CTA+, n=513; CTA−, n=516) included pts in the PAS with valid CTA results and tested with CDx. In the AAS, 6 samples (3 CTA+, 3 CTA−) did not yield valid CDx results, resulting in 1023 CDx-evaluable total pts (CTA+, n=510; CTA−, n=513). Among 510 CTA+ samples, 483 were CDx+. Among 513 CTA− samples, 513 were CDx−. Therefore, 996 samples yielded concordant results, 27 samples yielded discordant results, and 6 samples did not yield a valid CDx result for comparison. Point estimates of PPA & NPA were 94.2% & 99.4%, respectively, with invalid CDx results included in the calculation, and 94.7% & 100%, respectively, without invalid CDx results. The lower bounds of the 95% CIs were all above the corresponding acceptance criterion of 90% for PPA & NPA (Table 1). In Q-F, the prevalence of CTA+ was 24.9% among screened pts (863/3468), whereas in the bridging study, 49.9% (510/1023) of pts were CTA+: this enrichment in CTA+ pts could lead to a biased estimate of the agreement between CDx & CTA when using CDx as reference. The positive predictive value (PPV) and negative predictive value (NPV) of the CDx adjusted for this enrichment ± invalid CDx results, showed that the lower bounds of the 95% CIs were all >95% (Table 1). The efficacy OS analysis in the intent-to-treat (ITT) CDx+ population (ITT CDx+=CTA+ & CDx+; N=483: Q, n=242; P, n=241) demonstrated a clinically relevant OS improvement with Q (median OS of 29.4 months) vs P (median OS of 14.8 months), resulting in 14.6 months prolongation of median OS, with an HR of 0.794 (95% CI 0.621-1.014), corresponding to a 20.6% reduction in relative risk of death (Figure 1).


This study showed 1) agreement between CDx & CTA in identifying nd FLT3-ITD+ AML pts and 2) that OS benefit provided by Q in the ITT CDx+ population is comparable with the OS benefit in the ITT population of Q-F. The LeukoStrat CDx FLT3 Mutation Assay aids in assessing AML pts for Q therapy.

Disclosures: Rohrbach: Daiichi Sankyo: Current Employment, Current holder of stock options in a privately-held company. Chang: Daiichi Sankyo: Current Employment, Current holder of stock options in a privately-held company. Karnoub: Daiichi Sankyo: Current Employment, Current holder of stock options in a privately-held company. Liu: Daiichi Sankyo Inc.: Current Employment. Kamel: Daiichi Sankyo Inc.: Consultancy, Other. Khambata-Ford: Daiichi Sankyo Inc.: Current Employment. Rivera: Navigate BioPharma Services Inc.: Current Employment. Lameh: Navigate BioPharma Services, Inc.: Current Employment. Rudenko: Invivoscribe, Inc.: Current Employment. Todt: Invivoscribe, Inc.: Current Employment. Gerhold: Invivoscribe, Inc: Current Employment. Huang: Invivoscribe, Inc: Current Employment, Current holder of stock options in a privately-held company. Miller: Invivoscribe, Inc: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Perl: Syndax: Research Funding; Genentech: Honoraria; BerGen Bio: Honoraria; Rigel: Honoraria; BMS: Honoraria; Aptose: Honoraria; Immunogen: Honoraria; Actinium: Honoraria; FujiFilm: Research Funding; Beat AML: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Foghorn: Consultancy; Forma: Consultancy; Bayer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levis: FujiFilm: Research Funding; Takeda: Consultancy; Menarini: Consultancy; Jazz: Consultancy; Daiichi-Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Astellas Global Pharma: Research Funding; Pfizer: Consultancy. Ito: Daiichi Sankyo Inc.: Current Employment.

*signifies non-member of ASH