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319 Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001)

Acute Myeloid Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Advances in Targeted Therapy
Sunday, December 6, 2015: 4:30 PM
W110, Level 1 (Orange County Convention Center)

Geoffrey L. Uy, MD1, Sumithra Mandrekar, PhD2*, Kristina Laumann2*, Ben Sanford3*, Guido Marcucci, MD4, Weiqiang Zhao, MD, PhD5, Mark J. Levis, MD, PhD6, Heidi D. Klepin, MD, MS7, Maria R. Baer, MD8, Bayard L. Powell, MD7, Peter Westervelt, MD, PhD1, Daniel J. DeAngelo, MD, PhD9, Wendy Stock, MD10, Clara D. Bloomfield, MD11, John C. Byrd, MD11, Richard M. Stone, MD12 and Richard A. Larson, MD10

1Division of Oncology, Washington University School of Medicine, St. Louis, MO
2Mayo Clinic, Rochester, MN
3Duke University, Durham, NC
4City of Hope, Duarte, CA
5Pathology, The Ohio State University, Columbus, OH
6Johns Hopkins University School of Medicine, Baltimore, MD
7Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC
8Greenebaum Cancer Center, University of Maryland Baltimore, Baltimore, MD
9Dana-Farber Cancer Institute, Boston, MA
10The University of Chicago, Chicago, IL
11The Ohio State University Comprehensive Cancer Center, Columbus, OH
12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML.

The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS.  With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts.

A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo.

This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001).

Disclosures: Uy: Novartis: Research Funding . Off Label Use: Sorafenib for AML. DeAngelo: Novartis: Consultancy ; Ariad: Consultancy ; Bristol Myers Squibb: Consultancy ; Pfizer: Consultancy ; Amgen: Consultancy ; Incyte: Consultancy ; Agios: Consultancy ; Celgene: Consultancy . Stock: Gilead: Membership on an entity’s Board of Directors or advisory committees . Byrd: Acerta Pharma BV: Research Funding . Stone: Celator: Consultancy ; Celgene: Consultancy ; Pfizer: Consultancy ; Roche/Genetech: Consultancy ; Amgen: Consultancy ; Karyopharm: Consultancy ; Abbvie: Consultancy ; AROG: Consultancy ; Merck: Consultancy ; Sunesis: Consultancy , Other: DSMB for clinical trial ; Novartis: Research Funding ; Juno: Consultancy ; Agios: Consultancy . Larson: Bristol-Myers Squibb: Consultancy ; Pfizer: Consultancy ; Ariad: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding .

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