ALBERT

Description: Introduction: In the phase 3 QuANTUM-R trial, once-daily, oral, highly potent and selective FLT3 inhibitor Q improved clinical benefits vs SC (median overall survival [mOS], 6.2 vs 4.7 mo [HR, 0.76 (95% CI, 0.58-0.98); P = .02]; composite complete remission [CRc], 48% vs 27%; median duration of CRc, 12.1 vs 5.0 wk) in 367 pts with R/R FLT3-ITD AML (Cortes et al. Lancet Oncol, 2019; NCT02039726). Prior to randomization, 25% (Q) and 23% (SC) of pts had 1 prior HSCT. An OS sensitivity analysis, with censoring at the time of any subsequent HSCT during QuANTUM-R, was supportive (mOS, 5.7 vs 4.6 mo [HR, 0.79 (95% CI, 0.59-1.05)]; P = .05). Post hoc analyses of characteristics and clinical outcomes in pts who underwent subsequent HSCT in QuANTUM-R are reported. Methods: Pts aged ≥ 18 y with FLT3-ITD R/R AML receiving Q (60 mg [30-mg lead-in]) or 1 of 3 prespecified high- or low-intensity SC regimens and underwent subsequent HSCT as part of the open-label, randomized QuANTUM-R trial were analyzed. Pts receiving HSCT in the Q arm could resume maintenance Q 30-100 days after HSCT. Decisions to proceed to HSCT and resume Q after HSCT were made per investigator discretion/institutional policies. Results: Of 367 randomized pts, 85 in the Q arm underwent any subsequent HSCT (allogenic HSCT [allo-HSCT], 84 [6 with and 78 w/o additional AML therapy]; autologous HSCT, 1) and 19 in the SC arm underwent any HSCT (5 with and 14 w/o additional AML therapy]). Median age (range) was lower in pts with any HSCT (Q, 49 [19-71] y; SC, 44 [23-67] y) vs pts w/o (Q, 58 [19-81] y; SC, 59 [18-78] y). Q + SC pooled data showed a longer mOS (95% CI) in 104 pts with any HSCT vs 263 w/o (12.2 [10.0-24.1] vs 4.4 [4.1-4.9] mo; P 〈 .0001; Fig 1); 1-year OS probabilities (95% CI) were 50% (40%-60%) vs 13% (9%-18%). Among pts preselected for high-intensity therapy (Q [n = 188] + SC [n = 93]), mOS in the pooled high-intensity group was 11.9 (10.0-24.0) mo with any HSCT vs 4.6 (4.1-5.4) mo w/o. Among pts preselected for low-intensity therapy, 13/57 in the Q arm and 0/29 in the SC arm underwent any HSCT; mOS in the pooled low-intensity group was 32.4 (6.2-NA) mo with any HSCT vs 4.1 (2.7-4.6) mo w/o. In pts with CRc (last recorded response prior to allo-HSCT), mean time (range) to allo-HSCT was 13.3 (5.9-26.9) wk with Q and 12.1 (6.3-28.6) wk with SC. Q + SC pooled data showed that mOS (95% CI) was longer in pts with a CRc prior to allo-HSCT vs pts w/o CRc (20.1 [11.7-NA] vs 8.8 [7.0-11.4] mo). Survival outcomes by treatment were similar regardless of study treatment, with longer mOS in pts with any HSCT vs pts w/o (Q, 11.9 [10.2-25.1] vs 4.5 [4.1-5.4] mo; SC, 12.7 [6.1-NA] vs 4.0 [2.7-5.0] mo); respective 1-year OS probabilities (95% CI) were 50% (39%-60%) vs 13% (8%-20%) and 51% (26%-70%) vs 12% (6%-21%). In the Q arm, mOS (95% CI) was longer in pts with a best response of CRc who resumed Q after allo-HSCT (27.1 [18.2-NA] mo) vs pts not resuming Q (5.4 [4.7-11.4] mo; Fig 2). In 48 pts (62%) in the Q arm resuming Q after allo-HSCT, median time (range) from allo-HSCT to Q resumption was 65 (30-106) d. Four pts (5%) in the Q arm died 〈 30 days after allo-HSCT. As of 2/22/2018, 46 of 78 pts in the Q arm (59%) and 9 of 14 pts in the SC arm (64%) with allo-HSCT w/o additional AML therapy died, primarily due to AML disease progression (Q, 31 [40%]; SC, 7 [50%]). The frequency of treatment-emergent adverse events (TEAEs) was mostly lower in pts resuming Q after allo-HSCT than in the overall Q population (Table 1); TEAEs of interest were similar. Long-term survivor data will be presented. Conclusions: Independent of HSCT, Q improved survival vs SC in pts with FLT3-ITD R/R AML in QuANTUM-R. Q + SC pooled analyses showed longer survival in pts with HSCT vs pts w/o and in pts with CRc prior to allo-HSCT. Importantly, survival post-HSCT was similar in the Q and SC arms, indicating that pts eligible for HSCT were appropriately transplanted, and the higher HSCT rate in the Q arm was beneficial to pts. More pts treated with Q underwent HSCT, likely due to a higher rate and duration of CRc with Q vs SC and better overall fitness. In pts preselected for low-intensity SC at study entry, 13 were able to undergo HSCT after Q treatment. Resumption of Q after HSCT was associated with better survival outcomes and was tolerable. These data illustrate the value of using Q to target the FLT3-ITD mutation as a part of the overall treatment sequence in pts with FLT3-ITD R/R AML. Disclosures Ganguly: Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board; Daiichi Sankyo: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Merus: Consultancy, Honoraria, Research Funding. Krämer:Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Bayer: Research Funding. Levis:Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Daiichi Sankyo Inc: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; FUJIFILM: Consultancy, Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant. Perl:Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Bayer: Research Funding; BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Arunachalam:Daiichi Sankyo: Employment. Gammon:Daiichi Sankyo: Consultancy. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Mires:Daiichi Sankyo: Employment. Namuyinga:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment. Khaled:Omeros: Consultancy; Daiichi Sankyo: Other: Travel support; Alexion: Consultancy, Speakers Bureau.

Description: Background: Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, demonstrated a significant improvement in survival vs SC in FLT3-ITD-positive R/R AML in the global, randomized, phase 3 QuANTUM-R study (Cortes et al. Lancet Oncol, 2019; NCT02039726). Patients with R/R FLT3-ITD-positive AML were randomized 2:1 to receive single agent quizartinib or investigator's choice of pre-selected SC. We investigated the effects of baseline co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission [CRc]) to quizartinib and SC in QuANTUM-R. Methods: We analyzed 37 recurrently mutated genes in AML in baseline bone marrow samples from 304 patients (82.8% of ITT population [N = 367; quizartinib, n = 245; SC, n = 122]) with R/R FLT3-ITD-positive AML using next-generation sequencing and a customized Archer® Core Myeloid panel. Positive mutation status was defined as ≥ 1 mutation detected in the gene region using a VAF cutoff of 2.7%. FLT3-ITD VAF was measured separately by the Navigate BioPharma FLT3 Mutation Assay (polymerase chain reaction-based, VAF cutoff of 3%). Low and high FLT3-ITD VAF were defined as ≤25% and 〉25%, respectively. Results: In addition to FLT3-ITD, 5 key co-mutations were detected: DNMT3Amut (n = 182/304 [59.9%]), NPM1mut (n = 168/304 [55.3%]), TET2mut (n = 98/304 [32.2%]), IDH1/2mut (n = 49/304 [16.1%]) and CEBPAmut (n = 46/304 [15.1%]). Median OS was numerically longer with quizartinib vs SC in patients with DNMT3Amut, TET2mut, IDH1/2mut and NPM1mut, but not CEBPAmut (Table). CRc rates were numerically higher with quizartinib vs SC for each of the 5 key baseline co-mutations. For single gene mutations, the longest median OS was seen in patients with CEBPAmut treated with quizartinib or SC (37 and 37.6 weeks, respectively). As the majority of NPM1mut patients were also DNMT3Amut (138/168, 82%), we examined various permutations of these two mutations. Patients with NPM1wt/DNMT3Amut had significantly longer median OS with quizartinib vs SC (39.3 vs 19.6 weeks, respectively; HR, 0.239; P = 0.003 [Table]) while NPM1mut/DNMT3Amut patients had lower and similar median OS between the 2 arms (23.6 vs 23.4 weeks, respectively). Quizartinib treatment showed significantly longer median OS vs SC in patients with high FLT3-ITD VAF (23.9 vs 17 weeks respectively; HR, 0.689, P = 0.0148), while the median OS in patients with low FLT3-ITD VAF was similar (34.1 vs 26.6 weeks, respectively; HR, 0.857, P = 0.535). Conclusions: This is the first evaluation of the effect of baseline co-mutations on clinical outcomes in a large trial of R/R AML patients with FLT3-ITD mutations treated with quizartinib. Key co-mutations identified in this analysis were found to potentially impact treatment response and OS with quizartinib, relative to SC. Despite relatively low CRc rates in patients with IDH1/2mut, this group-as well as those with NPM1wt-derived the greatest OS benefit from quizartinib compared with SC on QuANTUM-R. CEBPA mutations were associated with high CRc rates and relatively long median OS, regardless of treatment arm. Patients with NPM1mut had a higher CRc rate with quizartinib vs SC, but this did not translate into longer survival on either arm compared with NPM1wt. A high allelic burden of FLT3-ITD at the time of salvage therapy was associated with relatively poorer median OS; quizartinib significantly improved survival of patients with high FLT3-ITD VAF relative to SC. Although these results require confirmation in an independent dataset, the modulatory effects of baseline co-mutations on treatment response and OS with quizartinib appear to differ from other FLT3 inhibitors. Our results indicate that a subset of R/R AML patients may particularly derive clinical benefit from quizartinib. Table Disclosures Perl: Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Ganguly:Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding. Khaled:Omeros: Consultancy; Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support. Krämer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding. Martinelli:Novartis: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Janssen: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Ariad: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria. Russell:Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Chang:Daiichi Sankyo: Employment. Mires:Daiichi Sankyo: Employment. Kato:Daiichi Sankyo, Inc.: Employment; Celgene: Employment, Equity Ownership. Zhang:Daiichi Sankyo: Employment. Korkhov:Precision for Medicine, Inc.: Employment; Daiichi Sankyo: Consultancy. Wang:Precision for Medicine, Inc.: Employment; Daiichi Sankyo: Consultancy. Günnel:Precision for Medicine, Inc.: Employment; Daiichi Sankyo: Consultancy. Sumi:Daiichi Sankyo, Inc.: Employment. Isoyama:Daiichi Sankyo Co, Ltd: Employment. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Berisha:Daiichi Sankyo: Employment. Dos Santos:Daiichi Sankyo: Employment. Levis:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria.

Description: Background. MDM2 is frequently overexpressed in acute myeloid leukemias (AML) and suppresses p53-mediated apoptosis while p53 mutations are relatively rare in AML. MDM2 inhibitors as a monotherapy have shown limited efficacy in clinical trials in AML (~25% response rate) (Andreeff, Clin Cancer Res 2015). XPO1 transports around 300 proteins, including p53 and other tumor suppressors, from the nucleus to the cytoplasm. Overexpression of XPO1 is associated with unfavorable outcomes in AML (Kojima, Blood 2013). p53 activation or XPO1 inhibition have been reported to decrease c-Myc protein levels through diverse mechanisms (Porter Mol Cell 2017 and Tabe PLoSOne 2015). Objective: We investigated anti-leukemia effect of dual MDM2 and XPO1 inhibition, with the intent to maximize the pro-apoptotic functions of p53, using the MDM2 inhibitor milademetan (Daiichi-Sankyo), and selinexor, a recently FDA-approved XPO1 inhibitor or its analog eltanexor (Karyopharm). Results: Treatment with milademetan and selinexor (1:1 molar ratio) induced synergistic apoptosis in AML cell lines with wild-type p53 (ED50, 89.3 ± 18.6 nM, combination index (CI), 0.60 ± 0.08). Activity in p53 mutant AML required 40-fold higher ED50 (3572 ± 1986 nM), reflected in an antagonistic CI of 6.94 ± 3.06. Knockdown of wild-type p53 by shRNA in OCI-AML3 (OCI-AML3 shp53) cells or presence of TP53 mutation (p.R248W) in MOLM-13 cells eliminated the synergistic effects, suggesting that normal p53 function is a major determinant of sensitivity to combined treatment. Next, we treated primary AML samples with milademetan and selinexor or eltanexor and observed that effects were mutation-agnostic (e.g. RAS and FLT3) except for TP53. Combined treatment significantly reduced AUC determined by absolute live cell numbers compared to each drug alone, and induced synergistic apoptosis in primary AML samples with wild-type p53 (ED50 values, 27.2 - 937.4 nM, CI, 0.51 ± 0.07), with similar efficacies in complex and non-complex karyotype AMLs (279.6 ± 94.7 vs 256.6 ± 56.4 nM, P = 0.84). In contrast, combined treatment showed antagonistic effects in primary AML samples with loss-of-function TP53 mutations (CI 〉 1.0). Immature CD34+CD38- AML cells were more susceptible to combined treatment than CD34- AML cells (apoptosis induction, 76.2 ± 6.7% vs 47.5 ± 6.8%, P = 0.0002) Mechanistically, combined inhibition increased p53 protein levels and accumulated p53 but not MDM2 protein in the nucleus compared to each drug alone. Combined treatment induced more TP53 target genes (MDM2, CDKN1A, BBC3, FAS and Bax) in OCI-AML3 cells with control shRNA compared with OCI-AML3 shp53 cells. Combinatorial inhibition showed much enhanced reduction of c-Myc mRNA and protein levels in OCI-AML3 shC cells compared with OCI-AML3 shp53 cells (82% vs 32%). In confirmation, combined inhibition reduced c-Myc protein levels profoundly in wild-type p53 primary AMLs (ANOVA P 〈 0.0001). In contrast, c-Myc reduction was not observed in primary AMLs with p53-inactivating mutations. Intriguingly, OCI-AML3 cells overexpressing c-Myc by lentiviral transduction showed greater sensitivity to XPO1 inhibitors and the combination compared to empty-vector controls, and baseline levels of c-Myc protein also negatively correlated with ED50 for combined treatment in primary AML samples (Spearman R = -0.5357, P = 0.0422). Conclusion: These preclinical data suggest that dual inhibition of MDM2 and XPO1 induces synergistic apoptosis through accumulation of nuclear p53 and suppression of c-Myc in wild-type p53 AMLs. A clinical trial testing this concept in AML is under development. Disclosures Ishizawa: Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Daver:Novartis: Consultancy, Research Funding; Agios: Consultancy; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy.

Description: Introduction: Patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3-ITD mutations have a dismal prognosis and limited treatment options. Given the aggressiveness of FLT3-ITD AML, therapies that produce rapid and sustained disease control are needed. Quizartinib (Q), a once-daily, oral, highly potent and selective FLT3 inhibitor, demonstrated a clinically meaningful overall survival (OS) benefit in pts with R/R FLT3-ITD AML vs salvage chemotherapy (SC; 6.2 vs 4.7 mo [HR, 0.76 (95% CI, 0.58-0.98); P = .02]) in the phase 3 QuANTUM-R trial (NCT02039726; Cortes et al. Lancet Oncol, 2019). In this post hoc analysis, we characterize clinical outcomes in pts who achieved a composite complete remission (CRc) in QuANTUM-R, including pts with CR with incomplete hematologic recovery (CRi) and transfusion independence. Methods: Pts aged ≥ 18 years with FLT3-ITD AML R/R after standard AML therapy, with or without hematopoietic stem cell transplant (HSCT), were randomized 2:1 to Q (60 mg [30-mg lead-in]) or 1 of 3 prespecified SC regimens. Pts receiving HSCT in the Q arm could resume Q after HSCT. Response was assessed per modified International Working Group criteria (Table 1). Transfusion dependence at baseline (BL) was defined as any platelet (PLT) or red blood cell (RBC) transfusion within 28 days of first dose. Post-BL transfusion independence was defined as no PLT or RBC transfusions for any consecutive 56-day period on treatment. Results: Of 367 randomized pts, 245 and 122 were randomized to Q and SC, respectively. Median duration of treatment was 97 days with Q (including post-HSCT resumption) and ranged from 5 to 10 days with SC depending on the regimen. Median follow-up was 23.5 mo. In the intent-to-treat population, CRc was consistent across prespecified subgroups (eg, sex, response to prior therapy, FLT3-ITD variant allele frequency). Median time to CRc was 1.1 mo with Q and 0.9 mo with SC; median duration of CRc was 2.8 mo with Q and 1.2 mo with SC (Table 2). Most responses in both arms were CRi, achieved in 99 pts (40%) in the Q arm and 32 pts (26%) in the SC arm. Peripheral blood counts in pts who achieved CRi are shown in Table 3. Of pts with CRi, 45 (Q) and 13 (SC) underwent HSCT. Outcomes with HSCT included engraftment failure in 11% (Q), rejection in 2% (Q), relapse in 33% (Q) and 46% (SC), and successful transplant in 47% (Q) and 46% (SC) and were unknown in 7% (Q) and 8% (SC). Of the 205 pts in the Q arm who were transfusion dependent at BL, 46 (22%) became transfusion independent post-BL (29 with HSCT; 17 without). Mean (SD) duration of post-BL transfusion independence was 255 (216.6) days. By response, 24 of 91 pts (26%) with CRi, 7 of 48 (15%) with a partial response (PR), and 4 of 47 (9%) with no response (NR) became transfusion independent post-BL; respective mean (SD) durations were 297.6 (268.3), 84.6 (21.7), and 211.3 (111.9) days. Of the 36 pts in the Q arm who were transfusion independent at BL, 20 (55.6%) maintained transfusion independence post-BL (12 with HSCT; 8 without; mean [SD] duration, 208 [203.1] days). Transfusion independence could not be assessed in the SC arm. Transfusion data was not collected after the end of treatment, and most pts in the SC arm were treated for 〈 56 days. In the Q arm, median OS (95% CI) was longer in pts with CRi (7.5 [5.4-9.9] mo) vs pts with PR (6.1 [5.1-7.2] mo) or NR (4.1 [3.3-5.9] mo) (Figure 1); respective medians in the SC arm were 8.8 (6.3-20.8), 7.8 (5.4-28.2), and 3.8 (2.7-4.7) mo. In the 34 pts in the Q arm with a last response of CRi prior to allogeneic HSCT, median OS (95% CI) was 25.1 (9.9-NA) mo; in the SC arm (n = 9), median OS (95% CI) was 20.1 (4.3-NA) mo. In the Q arm, median OS (95% CI) was longer in pts with CRi who became transfusion independent post-BL vs pts who did not (27.1 [10.4-NA] vs 5.3 [4.6-6.4] mo); similarly, median OS (95% CI) was longer in pts who maintained transfusion independence vs pts who did not (25.1 [11.4-NA] vs 9.6 [4.6-NA] mo). Conclusions: Q induced rapid, durable, and consistent tumor control in pts with FLT3-ITD R/R AML irrespective of prior therapy, including HSCT. A high proportion of pts with CRi became eligible for HSCT, the only potential curative treatment option. Moreover, a high proportion achieved durable transfusion independence regardless of HSCT, which is also associated with clinical benefit. These data highlight the clinical benefit of achieving CRi with Q in pts with FLT3-ITD R/R AML, a population with a high unmet need. Disclosures Levis: Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support; Omeros: Consultancy. Krämer:BMS: Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinelli:Novartis: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: trial grant; Amgen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant. Perl:BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau. Choi:Daiichi Sankyo: Employment. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Mires:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding.

Description: The tumor suppressor p53 is inactivated in virtually all cancers, including leukemias, by mutations or deletion of the TP53 gene, or overexpression of negative regulators (e.g., MDM2, MDM4, and XPO1). MDM2 and MDM4 are frequently overexpressed in acute myeloid leukemia (AML), with the highest MDM4 expression as compared to other malignancies. XPO1 transports ~300 proteins, including p53, from the nucleus to the cytoplasm and MDM2 is also a cargo protein transported by XPO1.We previously reported high synergism by MDM2 and XPO1 inhibition in AML (Kojima et al., Blood 2013), with the underlying mechanism yet to be fully investigated. Wp53 was highly accumulated in the nucleus by combined treatment in OCI-AML3 and primary AML cells with MDM2 inhibitor milademetan (DS-3032b) and XPO1 inhibitor selinexor (KPT-330), compared to treatment with individual drugs. Upon MDM2 and XPO1 inhibition, MDM2 was exclusively localized in the cytoplasm, not in the nucleus. Intriguingly, MDM4 also localized exclusively in the cytoplasm, and the dual inhibition markedly reduced the level of cytoplasmic MDM4 (Fig.1). Data suggest that the dual inhibition of MDM2 and XPO1 maximizes the transcriptional activity of p53 by sequestering MDM2 and MDM4 in the cytoplasm, with massive p53 induction in the nucleus. Indeed, the combination treatment dramatically induced p53 targets CDKN1A and MDM2 (i.e.,55-fold and 25-fold, respectively). WPathway analysis from RNA seq of OCI-AML3 cells treated with milademetan, selinexor, and the combination revealed the TP53 pathway was the top upregulated pathway compared with control, or single agent treatments. E2F targets, G2M checkpoint genes and MYC targets were the principal downregulated pathways by the combination treatment. Cell cycle analysis measuring EdU/DNA, Ki-67, p53, p21, and active caspase-3 revealed elimination of S-phase and a population with the highest Ki-67 levels at G2/M phase, with increased percentages of cells in G0 and G2/M phases. The combination treatment markedly reduced Ki-67 levels, suggesting the disruption of DNA synthesis and cell cycle arrest. Furthermore, p53 and p21 levels were increased in both G0 and G2/M cells, along with increased active caspase-3 levels, suggesting apoptosis induction in both highly proliferating and quiescent AML cells. WNext to validate c-Myc inhibition by the combination treatment, we used OCI-AML3 cells transduced with shRNA control (ShC) and shRNA for p53 (Shp53), and MOLM-13 cells with wild-type p53 (WT) and with TP53 p.R248W/R213* mutation (MT), obtained through long-term exposure to MDM2 inhibitor. c-Myc protein levels were significantly reduced in OCI-AML3 ShC cells and MOLM-13 WT cells, but not in OCI-AML3 Shp53 cells or MOLM-13 MT cells. Combined treatment synergistically reduced MYC mRNA and c-Myc protein levels both in the cytoplasm and the nucleus. Consistently, the combination treatment reduced c-Myc levels in primary AML cells with wild-type TP53 as opposed to those with TP53 mutations. Overexpression of c-Myc in OCI-AML3 cells conferred increased susceptibility to the combination treatment. Finally, c-Myc protein levels at baseline had negative correlation with the respective ED50 concentrations that induced apoptosis in 50% of AML blasts. In conclusion: we identified strikingly increased transcriptional activity of p53 which was retained in the nucleus and sequestration of MDM2 in the cytoplasm as novel mechanisms of combined MDM2/XPO1 inhibition. In addition, high c-Myc baseline levels were associated with response to the combinatorial treatment, which also markedly reduced nuclear and cytoplasmic c-Myc levels due to MYC repression by p53 activation. These findings support the translation of combined MDM2 and XPO1 inhibition into clinical trials. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lesegretain:Daiichi-Sankyo Inc.: Current Employment. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy.