An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

Background: Midostaurin (M) is an oral, multi-targeted, small molecule FLT3 inhibitor that has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant (mut) FLT3 AML. This randomized, double-blinded phase III trial demonstrated a statistically significant overall survival (OS) benefit when M was added to induction and consolidation chemotherapy followed by one year of maintenance compared to standard chemotherapy in patients (pts) with activating FLT3 mutations (Stone et al. NEJM 2017). In this unplanned subset analysis, we sought to evaluate the contribution of the maintenance treatment to overall outcomes. Methods: Between 5/2008 and 10/2011, 3277 previously untreated AML pts (exclusive of APL) age 18-60 years were screened at one of 7 academic labs. 717 pts were randomized for the duration of therapy to M or placebo (P), stratified by FLT3 mut subtype (TKD vs ITD low allelic ratio 0.05-0.7 vs high ratio >0.7). Induction consisted of daunorubicin and cytarabine plus M or P (50 mg orally twice daily, d8-21). Re-treatment with a second course was allowed if residual AML was noted on a d21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of high-dose cytarabine plus M or P (d8-21) followed by 12 4-week cycles (336 days) of maintenance with M or P (50 mg orally twice daily). Allogeneic transplantation (SCT) was allowed, and 182 pts discontinued study drug and underwent SCT in CR1. Landmark disease-free survival (DFS) analyses were performed to understand the impact of M vs P on the subset of CR pts who started maintenance (defined as time from start of maintenance to the first of death or relapse, where pts alive and disease-free were censored at the time they completed the planned maintenance or discontinued study drug early). Landmark DFS analyses were also performed to understand the long-term impact of M vs P on the subset of CR pts who completed all protocol treatment (i.e., time from end of all planned maintenance to the first of death or relapse). Results: All pts are off treatment. Median follow-up is 59 months from enrollment. Data were frozen in March 2016. A CR was achieved within the protocol-specified 60 days by 403 pts (CR60; 56%) with no significant difference between arms (212/360 (59%; 95% CI, 54-64%) on the M arm and 191/357 (54%; 48-59%) on P) (Fisher9s p=0.15); an additional 101 pts achieved CR after 60 days but were excluded from this analysis of maintenance therapy. 174 of the 403 CR60 pts began maintenance therapy still in CR1. Pts remained on their originally assigned double-blind treatment arm, and were not re-randomized. Pretreatment characteristics for these 174 pts were balanced with no significant differences between the maintenance arms (Table); however, they were slightly older, significantly less female, and had more favorable FLT3 mut status and cytogenetics than the 543 pts who did not start maintenance and/or lacked CR60. Adherence to full doses was high on both arms during maintenance (90% for M; 92% for P). Maintenance was well tolerated, and median duration of exposure was the same on both arms (336 days). Discontinuation due to adverse events was infrequent (8% for M; 6% for P). Events during maintenance were reported in 31 pts on M (30%; 30 relapses, 1 death) and 22 pts on P (32%; all relapses). Using a landmark analysis (Figure 1), DFS was not different between the 2 arms during the 12 cycles of maintenance (HR=0.83 for M vs P [95% CI, 0.48-1.43]; p=0.49). At the end of the maintenance portion of the trial, 60 pts (57%) remained on the M arm and 44 (64%) on the P arm. There were 16 post-maintenance DFS events (all relapses) on the M arm and 9 DFS events on the P arm (7 relapses, 2 deaths): 6/35 (17%) with FLT3 -TKD, 15/51 (29%) with ITD-low, and 4/18 (22%) with ITD-high (X2, p=0.4) Using a landmark analysis from the end of maintenance (Figure 2), there was no difference in DFS between the 2 arms (HR=1.4 [95% CI, 0.63-3.3]; p=0.38). DFS at 1-year from end of maintenance was 75% [95% CI, 62-84%] for M and 91% [95% CI, 77-96%] for P. There was no difference between the arms in OS from the time starting maintenance (HR=0.96 for M [95% CI, 0.58-1.59]; p=0.86). Conclusions: The results from this unplanned post-hoc subset analysis of the CALGB 10603/RATIFY trial do not allow conclusions on the value of maintenance therapy. Midostaurin was well-tolerated, but the definitive impact of maintenance strategies with midostaurin will need to be addressed by randomization. Disclosures Larson: Astellas: Consultancy, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Thiede: Bayer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agendix: Employment; Roche: Consultancy. Lo Coco: TEVA: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau. Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity9s Board of Directors or advisory committees; AbbVie, Celgene, Servier: Research Funding. Stone: Roche: Membership on an entity9s Board of Directors or advisory committees; Actinium: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Otsuka: Membership on an entity9s Board of Directors or advisory committees; Orsenix: Membership on an entity9s Board of Directors or advisory committees; Merck: Membership on an entity9s Board of Directors or advisory committees; Arog: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Seattle genetics: Membership on an entity9s Board of Directors or advisory committees; Jazz: Membership on an entity9s Board of Directors or advisory committees; Astellas: Membership on an entity9s Board of Directors or advisory committees; Karyopharm: Membership on an entity9s Board of Directors or advisory committees; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Argenix: Other: DSMB; Agios: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees, Other: DSMB; Fujifilm: Membership on an entity9s Board of Directors or advisory committees; Ono: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Sumitomo: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Cornerstone: Membership on an entity9s Board of Directors or advisory committees.