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Background: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor with proven single-agent activity and a manageable safety profile in FLT3-ITD R/R AML. In the global, phase ...3 QuANTUM-R study, quizartinib demonstrated a significant survival benefit over salvage chemotherapy(Cortes, et al. Lancet Oncol, 2019; NCT02039726). Additional support for the safety profile of quizartinib at the proposed dosing regimen (60 mg QD with a 30-mg starting dose) is provided by a pooled analysis of over 600 patients with R/R AML.
Methods: We pooled data from four studies: one phase 3 (QuANTUM-R), two phase 2, (ACC220-002 and 2689-CL-2004; Cortes, et al. Lancet Oncol, 2018; Cortes, et al. Blood, 2018), and one phase 1 (CP0001: only patients assigned to continuous daily dosing regimens are included in this analysis; Cortes, et al. J Clin Oncol, 2013) to provide an integrated safety summary of quizartinib monotherapy for the treatment of R/R AML. Treatment-emergent adverse events (TEAEs), on-treatment deaths, and adverse events of special interest (AESIs; QT prolongation and potential ventricular arrhythmias, hepatic disorders, and sequelae of cytopenias such as infections and bleeding) with quizartinib were analyzed.
Results: The pooled data set included 673 patients; 51% were male, and median age was 59 years. Thirty-eight patients were assigned to quizartinib 30 mg, 277 to 60 mg, and 358 to >60 mg up to 300 mg. Overall, median treatment duration was 79 days (range, 1-1296 days) and was longest in the 60-mg dose group (95 days) vs the >60-mg (70.5 days) and 30-mg (66 days) groups. The overall TEAE profile was consistent with the results from the phase 3 QuANTUM-R study. Most on-treatment deaths (215 of 599 evaluable patients 36%; defined as taking place between the first dose and ≤30 days after the last dose) were attributed to AML disease progression (130/599 22%), followed by TEAEs (83/599 14%), which were predominantly respiratory tract infections and events related to sepsis. TEAEs leading to discontinuation of quizartinib occurred in 173/673 patients (26%). In the 60-mg dose group (quizartinib proposed dosing regimen), the only TEAE associated with discontinuation in >2% of patients was pneumonia (6/277 patients 2%). The most frequently reported grade ≥3 TEAEs were febrile neutropenia (240/673 36%), anemia (188/673 28%) and thrombocytopenia (182/673 27%) in the hematologic category and pneumonia (119/673 18%) and sepsis/septic shock (124/673 18%) in the nonhematologic category (Table 1A). In the 60-mg dose group, the most frequent AESI was infection (210/277 76%; Table 1B). Epistaxis and petechiae, mainly grade 1/2, were the most frequently reported hemorrhage TEAEs. TEAEs in the hemorrhage category occurred more frequently in the >60-mg dose group than the 60-mg dose group (215/358 60% and 136/277 49%, respectively). The most frequent serious hemorrhage TEAEs were gastrointestinal hemorrhages (15/673 2%) and intracranial hemorrhage (10/673 2%). QTcF prolongation >500 ms (grade 3) occurred in 75/673 patients (11%), mostly in those receiving quizartinib >60 mg (n = 64) (Table 1C). In the 60-mg dose group, QTcF prolongation >500 ms occurred in 9/277 patients (3%). The median time to onset of QTcF prolongation >500 ms was shorter in the >60-mg dose group than in the 60-mg dose group (9 and 46 days, respectively). Arrhythmias potentially related to QTcF prolongation were infrequent; one event of torsade de pointes, and one event of fatal cardiac arrest (both at doses >60 mg) were observed. No dose effects were seen with hepatic disorders, cardiac arrhythmias, or cardiac failure AESI categories.
Conclusions: The overall safety profile of quizartinib in this R/R AML pooled analysis is consistent with that observed in QuANTUM-R. A reduction in the incidence of QTcF prolongation was noted with lower doses of quizartinib (30 or 60 mg vs >60 mg). There was also a reduced incidence of gastrointestinal symptoms, infections, and bleeding at lower doses of quizartinib (30 or 60 mg vs >60 mg). Results from this pooled analysis demonstrate that quizartinib is well tolerated at the proposed dosing regimen (60 mg QD with a 30-mg starting dose) in patients with R/R AML.
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Cortes:BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Ganguly:Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding. 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. Levis:FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Novartis: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant. Perl:Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Daiichi Sankyo: Consultancy, Honoraria, Other, 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; 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; 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; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; 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.. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau. Choi:Daiichi Sankyo: Employment. Mendell:Daiichi Sankyo, Inc.: Employment. Namuyinga:Daiichi Sankyo: Employment. Pham:Daiichi Sankyo: Employment. Said:Daiichi Sankyo: Employment. Wang:Daiichi Sankyo: Employment. Mitov:Daiichi Sankyo UK Ltd: Employment. Kim:Daiichi Sankyo: Employment. Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support; Omeros: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: R/R FLT3-ITD AML is an aggressive hematologic malignancy with a generally poor prognosis and high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). ...QuANTUM-R (NCT02039726), a large, global, phase 3, randomized, controlled trial, showed that single-agent quizartinib significantly prolonged overall survival (OS) vs salvage chemotherapy (SC) in patients with R/R FLT3-ITD AML after first-line treatment with or without HSCT (Cortes et al, Lancet Oncol 2019). To evaluate both quality and quantity of life for patients with R/R FLT3-ITD AML, we conducted a Q-TWiST analysis of QuANTUM-R data to compare survival between patients receiving quizartinib and SC adjusted for quality of life (QOL).
Methods: The primary analysis cohort was the intent-to-treat (ITT) QuANTUM-R population, which included 367 patients (245 patients receiving quizartinib; 122 patients receiving SC). The secondary analysis cohort was the per-protocol analysis set (PPS), which excluded patients randomized but not treated and patients with major protocol violations who would affect assessment of efficacy endpoints (231 patients receiving quizartinib; 88 patients receiving SC).
Each patient's OS was partitioned into 3 health states: time with any grade 3/4 treatment-emergent adverse events (TEAEs) before relapse (TOX), time without relapse or grade 3/4 toxicity (TWiST), and time after relapse (REL). Q-TWiST was assessed at 104 weeks (approximate median follow-up of QuANTUM-R) as the mean time spent in each state weighted by its respective QOL, represented by health utility (u; 0.0-1.0). Q-TWiST was calculated as follows:
Q-TWiST = u(TWiST) × TWiST + u(TOX) × TOX + u(REL) × REL
for which u(TWiST), u(TOX), and u(REL) represent the utilities applied to the restricted mean time in TWiST, TOX, and REL, respectively.
Relative Q-TWiST gain (ie, Q-TWIST gain divided by mean OS of salvage chemotherapy) of ≥ 15% was considered clinically important, based on published minimally important difference norms (Revicki et al, Qual Life Res 2006).
The base case that assessed the Q-TWiST difference between quizartinib and SC for the ITT population included any grade 3/4 TEAEs and set utilities at commonly assumed values: u(REL) = u(TOX) = 0.5, relative to u(TWiST) = 1.0. A sensitivity analysis was conducted for which u(TOX) and u(REL) were varied from 0.0 to 1.0. The following additional scenarios analyses were conducted: (1) including only treatment-related (TR) grade 3/4 TEAEs, (2) assessing Q-TWiST difference between quizartinib and SC for the PPS cohort, and (3) including only TR grade 3/4 TEAEs for the PPS cohort. 95% CIs were estimated via nonparametric bootstrap.
Results: For the ITT population, quizartinib was associated with a mean OS gain of 8.5 weeks vs SC at 104 weeks from randomization (Table). In base case, the mean (95% CI) Q-TWiST gain at 104 weeks for quizartinib vs SC was 6.7 weeks (1.7-12.3; relative gain, 20.3%), which was statistically significant and clinically meaningful (Table). For the sensitivity analysis for which u(TOX) and u(REL) were varied from 0.0 to 1.0, Q-TWiST gains for quizartinib ranged from 5.0 (uREL = uTOX = 0.0) to 8.5 weeks (uREL = uTOX = 1.0). The relative Q-TWiST gains for quizartinib vs SC remained clinically important, irrespective of the values for u(TOX) and u(REL) and ranged from 15.2% to 25.5% (Figure). In the scenario analyses (Table), (1) when only TR grade 3/4 TEAEs were included, the Q-TWiST gain for quizartinib was 7.4 weeks (2.2-13.0; relative gain, 22.5%), (2) in the PPS cohort, the mean (95 % CI) Q-TWiST gain for quizartinib was 6.9 weeks (0.8-13.5; relative gain, 20.7%), and (3) when including only TR grade 3/4 TEAEs in the PPS, the Q-TWiST gain for quizartinib was 7.5 weeks (1.5-14.2; relative gain, 22.5%).
Conclusions: Quizartinib significantly prolonged quality-adjusted survival vs SC in patients with R/R FLT3-ITD AML after disease control, safety, and QOL were accounted for, providing evidence of meaningful clinical benefit in a patient population with few treatment options. To put these results in perspective, the relative Q-TWiST gains for quizartinib reported herein are larger than nearly 90% of the relative Q-TWiST gains reported in a recent systematic review of 81 Q-TWiST comparisons across 13 cancers (Solem et al, Exp Rev Pharmacoecon Outcomes Res 2018).
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Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Sun Pharma: Research Funding. Ganguly:Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Seattle Genetics: Speakers Bureau. 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. Levis:Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Martinelli:Janssen: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Other: trial grant; Novartis: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant. Perl: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; Jazz: Consultancy, Honoraria, 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.; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, 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; 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.. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau. Botteman:Pharmerit International: Employment, Equity Ownership; Alnylam Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Shah:Merck: Research Funding; Bayer: Research Funding; Pfizer: Research Funding. Luo:Pharmerit International: Employment. Shun:Daiichi Sankyo: Employment. Ray:Daiichi Sankyo: Employment, Equity Ownership.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction: We evaluated the impact of baseline (BL) co-mutations and FLT3-ITD VAF on overall survival (OS) and response (composite complete remission CRc) to quizartinib and SC in the ...phase III QuANTUM-R trial.
Methods: We analyzed 37 recurrently mutated genes in AML in BL samples from 304 patients (pts) (83% of ITT population) 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 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, the prevalence of key BL co-mutations were 59.9% for DNMT3Amut and 55.3% for NPM1mut. Pts with DNMT3Amut treated with quizartinib had significantly longer OS vs SC (6.3 and 5.4 mos, respectively; hazard ratio HR, 0.652), p<.05). Pts with NPM1mut treated with quizartinib had a higher CRc rate than with SC, but similar OS (5.1 vs 4.7 mos, respectively; HR, 0.954, p=.82). Pts with NPM1wt/DNMT3Amut treated with quizartinib had the highest CRc rate and longest median OS (9.0 and 4.5 mos, respectively; HR, 0.239, p=.003). OS benefit with quizartinib relative to SC was more pronounced among pts with high FLT3-ITD VAF than low FLT3-ITD VAF. The OS benefit with quizartinib in pts with NPM1wt/DNMT3Amut was maintained in both low and high FLT3-ITD VAF groups. Similarly, for other DNMT3A/NPM1 co-permutations, OS in both low and high FLT3-ITD VAF groups was consistent with OS in the co-mutation group.
Conclusions: Key co-mutations identified here potentially affect treatment response and OS with quizartinib vs SC. Our results suggest that molecular subsets of R/R AML pts may particularly derive clinical benefit from quizartinib.
TableCRc, %Median OS, monthsQuizartinibSCQuizartinibSCHR95% CIITT Population (N = 367)a48276.24.70.760.58-0.98Single Gene Analyses (n = 304)bDNMT3Amut (n = 182)52376.35.40.6520.44-0.97DNMT3Awt (n = 122)40246.04.60.8490.53-1.37NPM1mut (n = 168)48395.14.70.9540.63-1.44NPM1wt (n = 136)47218.55.10.4850.31-0.76TET2mut (n = 98)34326.22.90.6640.38-1.16TET2wt (n = 206)54306.35.40.7280.51-1.05CEBPAmut (n = 46)44428.58.71.9220.80-4.62CEBPAwt (n = 258)48296.24.50.6130.45-0.84IDH1/2mut (n = 49)32275.53.70.4270.20-0.92IDH1/2wt (n = 255)51316.55.10.750.54-1.04Double Gene Analyses (n = 304)NPM1wt/DNMT3Amut (n = 44)61279.04.50.2390.09-0.61NPM1mut/DNMT3Amut (n = 138)50405.45.40.8370.52-1.34FLT3-ITD VAF AnalysesFLT3-ITD high VAF50195.53.90.6890.51-0.93FLT3-ITD low VAF43467.96.10.8570.53-1.40FLT3-ITD VAF Analyses in Selected MutationsDNMT3Amut high VAF53215.82.70.6260.40-0.98DNMT3Amut low VAF526910.26.40.7370.36-1.51NPM1wt/DNMT3Amut high VAF6409.01.50.01790.002-0.16NPM1wt/DNMT3Amut low VAF555011.36.20.3720.11-1.23aN = 367; quizartinib, n = 245; SC, n = 122bBaseline bone marrow samples were available and viable from 304 of 367 pts in the ITT population
Citation Format: Alexander E. Perl, Jorge E. Cortes, Siddhartha Ganguly, Samer K. Khaled, Alwin Krämer, Giovanni Martinelli, Nigel H. Russell, Ken C. Chang, Kazunobu Kato, Yuhu Yan, Li-An Xu, Sergey Korkhov, Tobias Günnel, Hiroyuki Sumi, Arnaud Lesegretain, Flora Berisha, Derek Mires, Aziz Benzohra, Takeshi Isoyama, Cedric Dos Santos, Mark J. Levis. Effect of co-mutations and FLT3-ITD variant allele frequency (VAF) on response to quizartinib or salvage chemotherapy (SC) in relapsed/refractory (R/R) acute myeloid leukemia (AML) abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 784.
Introduction: Patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) and those who fail to respond to or relapse/progress after treatment with hypomethylating agents (HMA) have limited ...therapeutic options and poor prognosis. PD-L1 expression is upregulated in HR-MDS pts (compared with lower-risk MDS pts) and in those who fail HMA therapy. Combining inhibition of the PD-L1/PD-1 pathway with azacitidine may improve outcomes in MDS.
Methods: We conducted a Phase Ib trial of the anti-PD-L1 monoclonal antibody atezolizumab, with or without azacitidine, in HMA-failure and HMA-naive MDS pts (NCT02508870). The primary objective was to determine the safety and tolerability of atezolizumab as a single agent or in combination with azacitidine. An initial safety evaluation was performed in three cohorts. Cohort A1 (10 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab alone (1200mg IV q3w). Cohort B1 (11 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w) for 6 cycles, followed by atezolizumab maintenance alone (1200mg IV q3w). Cohort C1 (6 pts) consisted of HMA-naive HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w). If atezolizumab alone or in combination with azacitidine was deemed safe and tolerable in Cohorts A1 and B1, an additional 1:1 randomization into two cohorts of 30 pts each (Cohorts A2 and B2) was planned. If the combination of atezolizumab and azacitidine was found to be safe and tolerable in Cohort C1, an additional expansion cohort (Cohort C2) of 14 pts with HMA-naive HR-MDS was planned. Primary endpoints included determining the safety and tolerability of atezolizumab-based regimens in HR-MDS and defining the recommended Phase II dose for the combination.
Results: As of January 2018, 42 HR-MDS pts had been treated with atezolizumab-based regimens: Cohort A, 10 pts; Cohort B, 11 pts; Cohort C, 21 pts. Median age for the entire pt cohort was 76 years (range: 63−89). Median treatment duration for Cohorts A, B, and C was 4.2, 5.5, and 5.8 months, respectively. The overall response rate for Cohorts A, B, and C was 0%, 9% (hematologic improvement HI: 9%), and 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%), respectively. All pts in Cohorts A and B have discontinued therapy, with a median overall survival (OS) of 5.9 months and 10.7 months, respectively. For pts in Cohort C, 8/21 pts remain on therapy, and median OS has not been reached. Grade 3−5 adverse events (AEs) in >10% of pts were primarily hematologic; grade 3−5 febrile neutropenia occurred in 29% of all pts and was particularly common in pts receiving the atezolizumab-azacitidine combination (Cohorts B 36% and C 33% compared with Cohort A 10%; Table 1). In Cohort A, 70% (7/10) of pts died, as did 64% (7/11) of pts in Cohort B and 29% (6/21) of pts in Cohort C. Median time to death was 160 days (Cohort A), 299 days (Cohort B), and 53 days (Cohort C). Timing and causes of death were different in the three cohorts. Causes of death were more commonly from disease progression in Cohorts A and B, while serious AEs accounted for all deaths in Cohort C (Table 2). In addition, deaths within 3 months occurred in 10%, 18%, and 29% of pts in Cohorts A, B, and C, respectively. The high early death rate compared with historical controls observed in HMA-naive HR-MDS patients (Cohort C) led to early termination of the study prior to completing recruitment. Biomarker assessment demonstrated PD-L1 expression on variable proportions of AML blasts in samples from all pts analyzed. However, PD-L1 expression was not associated with clinical response (Figure).
Conclusions: Combination of atezolizumab plus azacitidine in HMA-naive HR-MDS pts had an unfavorable safety profile, which led to early termination. Limited responses were observed with atezo-based regimens (with or without azacitidine) in HMA-failure HR-MDS pts, without excessive or unexpected toxicity. Better understanding of the reasons associated with the differential toxicity profile observed between HMA-naive versus HMA-failure HR-MDS pts will be crucial for potential future developments of this combination.
Gerds:Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy. Khaled:Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding. Lin:Jazz Pharmaceuticals: Honoraria. Pollyea:AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech: Employment. Ma:Genentech: Employment. Medeiros:Genentech: Employment, Equity Ownership. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Yan:Roche: Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
▪
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.
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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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
AZA monotherapy has demonstrated improvement in OS in HR MDS, clinically meaningful and durable responses continue to be limited to a subset of patients (Silverman 2006). One obvious ...strategy is to develop doublet therapy with drugs that are effective monotherapy in HR MDS and can be administered effectively and safely in combination with AZA. Several agents have been combined with AZA in first line therapy for pts with HR-MDS achieving ORR and CR/PR rates that are comparable to AZA monotherapy (ORR 38% and CR/PR of 24%) (Ades ASH 2018; Sekeres JCO 2017). RAS and other signaling molecules in the Ras pathway are frequently mutated in HR MDS and are proposed to drive leukemic transformation (Takahashi 2013). Given that rigosertib interferes with the RAS-binding domain of RAF kinases and inhibits the RAS-RAF-MEK & the PI3Ks pathways (Athuluri-Divakar, Cell 2016), it is an attractive candidate for combination with AZA. Furthermore, in vitro combo of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skiddan AACR 2006). We report updated results from a Phase II study in a subset of patients receiving oral rigosertib in combination with standard dose AZA as first line therapy for HR MDS.
Methods:
In the Phase II study 09-08, a total of 39 treatment-naïve HR MDS/RAEB-t patients received oral rigosertib in combination with standard dose AZA. Rigosertib was given at 840mg/day (560 mg in the morning & 280mg in the afternoon); or 1120mg/day (560 mg in the morning & 560mg in the afternoon or 840 mg in the morning and 280 mg in the afternoon) (Maniar ASH 2018). Responses were determined by 2006 IWG criteria including transfusion independence (56 days without PBC or PLT transfusions). Oral rigosertib was administered on D1-D21 of a 28D cycle. Parenteral AZA 75mg/m2/day was administered for 7days from D8. Patients were evaluable for response if they received 3 cycles of therapy.
Results:
Median age of the pts was 64 years (42-90). IPSS-R score at study entry was 9 were Intermediate, 8 were High and 17 were Very High Risk (VHR). In total 20 pts were transfusion-dependent at study entry. CR/PR responses were observed across all IPSS-R cytogenetic prognostic subgroups: Very Poor 60%, Poor 25%, Intermediate 37.5% & Good 25%. CR/PR responses were also observed across all higher IPSS-R prognostic risk categories: Very High 42%, High 17% and Intermediate 25%.
A summary of clinical benefit/risk is provided in Table 1 below.
Median duration of response was 12.2 mos (0.1-24.2+) and median duration of treatment was 8 mos (1.3-27.3). Time to first and best responses was 1/4 mos. Four pts continue to respond to therapy. 10 AEs led to D/C: urinary tract pain (2), and 1 each for urinary retention, hematuria, hydronephrosis, osteolysis, cerebral haemorrhage, WBC count decreased, neutrophil count decreased, & abd pain. The most frequent AE in table 1, are similar to AEs reported for both rigosertib and AZA as monotherapies, & the GU toxicities were mitigated using specific management guidelines. The majority of MDS pts who experienced AEs ≥Grade 2 were successfully managed and continued to receive the doublet on study.
Conclusion:
The efficacy (90% ORR & 34% CR) and safety of oral rigosertib and AZA in combination is favorable as first line therapy in pts with HMA naïve HR MDS and are comparable to historical results for standard dose AZA monotherapy (ORR 38% and <20% CR). The transfusion independence (TI) of 30% in HR MDS pts is clinically meaningful and needs to be confirmed in a large randomized phase III study. Oral rigosertib in combination with AZA was well tolerated and has now been administered in repetitive cycles for more than two years. Rigosertib is attractive combination partner for AZA because of the oral formulation, non-overlapping toxicity, mechanism of action and synergy. Based on the efficacy results and favorable safety profile, a pivotal Phase III trial in higher-risk HMA naive MDS population is planned.
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Navada:Onconova Therapeutics Inc: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Atallah:Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy. Shammo:Otsuka: Consultancy, Honoraria; CTI Pharma: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Speakers Bureau; Astex Pharma: Research Funding. Griffiths:Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy; Partner Therapeutics: Consultancy; Celgene, Inc: Consultancy, Research Funding. Khaled:Alexion: Consultancy, Speakers Bureau; Omeros: Consultancy; Daiichi Sankyo: Other: Travel support. Adesanya:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Woodman:Onconova Therapeutics, Inc.: Employment. Fenaux:Jazz: Honoraria, Research Funding; Aprea: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Silverman:Medimmune: Research Funding; Celgene: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Hematopoietic cell ...transplantation (HCT) is a recommended treatment for patients with FLT3-ITD(+) AML. However, a high rate of relapse after a HCT is observed when compared to FLT3-ITD(-) patients with the 2 year relapse rate of 30% vs. 16% in FLT3-ITD(+) and FLT3-ITD(-) patients, respectively (Brunet, J. Clin. Oncol. 2012). Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown a high level of single agent activity in nearly 500 patients with FLT3(+) relapsed or refractory AML and is currently in a Phase 3 study.
This Phase 1 study examined maintenance therapy with quizartinib in AML patients (aged 18 years or older) in remission after receipt of an allogeneic HCT. Dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled at each dose level. Two dose levels were tested; dose level 1 (DL1) at 40 mg and dose level 2 (DL2) at 60 mg given daily in continuous 28 day cycles. Dose limiting toxicities (DLTs) were assessed for the first 2 cycles and subjects were allowed to continue up to a maximum of 24 cycles.
Thirteen subjects were recruited and enrollment was completed in June 2013. The median age was 43 (range 23 to 61) years. All subjects had received an HLA-matched allogeneic HCT (3 related and 10 unrelated) a median of 56 (range 41 – 70) days before study enrollment. All subjects were positive for the FLT3-ITD mutation by local testing at the time of diagnosis.
Seven subjects were enrolled at DL1, including one who relapsed after 22 days on study and was replaced per protocol as deemed not evaluable for DLTs. There was 1 DLT of Grade 3 gastric hemorrhage which resolved and the subject was able to continue on a reduced dose (30 mg) of quizartinib. Six subjects were enrolled at DL2, including one subject who experienced 1 DLT of Grade 3 anemia but was able to continue on a reduced dose (30 mg).
Of the 13 total subjects, 10 (77%) received quizartinib for more than a year. Six (45%) subjects are continuing to receive quizartinib currently (15, 16, 18, 18, 23, and 23 cycles) and 2 (15%) subjects have completed 24 cycles. Three subjects (23%) discontinued due to AE: Grade 4 neutropenia (Cycle 4), Grade 2 corneal epithelium defect (Cycle 9), and Grade 3 autoimmune hemolysis (Cycle 15); 1(8%) discontinued for disease relapse (Cycle 1) and 1 (8%) for protocol non-compliance (Cycle 13).
The most common (≥20%) treatment-related adverse events (AEs) were diarrhea (38%; 5 subjects), neutropenia (31%; 4 subjects), nausea (23%; 3 subjects) and leukopenia (23%; 3 subjects).
This is the first study conducted to determine whether or not quizartinib can be safely administered as post-transplant maintenance therapy in patients with AML. The data from this study support the use of post-transplant maintenance therapy with quizartinib and show early evidence indicating a reduced relapse rate with only 1 relapse reported out of 13 subjects, which compares favorably to historical reference data. No MTD was identified but 60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory subjects (J Cortes, Blood (ASH Annual Meeting Abstracts) 2013 Abstract). Quizartinib maintenance has been included in the current Phase 3 QUANTUM-R study comparing quizartinib vs. salvage chemotherapy in relapsed or refractory FLT3-ITD(+) AML.
Sandmaier:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Khaled:Ambit Bioscience Corporation: Research Funding; Astellas Pharma, Inc: Research Funding. Oran:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Gammon:Ambit Bioscience Corporation: Employment, Equity Ownership. Trone:Ambit Bioscience Corporation: Employment, Equity Ownership. Frankfurt:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Pracinostat, a potent oral Class I, II, IV histone deacetylase (HDAC) inhibitor, exhibited modest single-agent activity in relapsed AML. Inhibition of histone deacetylation and DNA ...hypermethylation induces re-expression of silenced genes in myeloid malignancies in a synergistic fashion. A pilot study of pracinostat with azacitidine (AZA) in myelodysplastic syndromes showed the combination to be active and well tolerated (Blood2012;120:3821). We conducted a Phase 2 study to evaluate pracinostat + AZA in patients ≥65 years with AML not eligible for induction chemotherapy. Minimum 1-year survival data were reported previously (Blood 2015;126:453). Here we report long-term survival and response analyses.
Methods: Main eligibility: Age ≥65, untreated de novo or secondary AML, ≥20% bone marrow (BM) blasts, not candidate for intensive therapy due to co-morbidities and/or AML features, intermediate or high-risk cytogenetics, and no prior treatment with HDAC inhibitors or hypomethylating agents. Treatment consisted of pracinostat 60 mg orally 3 days/week on alternate days for 3 weeks and AZA 75 mg/m2 subcutaneously or intravenously daily for 7 days, with cycles repeated every 28 days until disease progression, lack of response or poor tolerability. The primary endpoint was a composite complete response rate (cCR) of CR + CRi+ MLFS by IWG criteria. Response was assessed at the end of Cycles 2, 4, 6 and then every 3 cycles or when clinically indicated. Secondary endpoints included overall response rate (cCR + PR), duration of response and overall survival (OS). Study registered under NCT01912274.
Results: Between December 2013 and December 2014, 50 patients were enrolled at 15 U.S. sites. Baseline characteristics: Median age 75 years (range 66-84 years); 33 de novo and 17 secondary AML; 27 intermediate-risk and 21 high-risk cytogenetics and 2 not known; median BM blasts 40% (range 20%-89%), ECOG performance status 0-1 in 84% and 2 in 16%. The median number of treatment cycles was 6.5 (range 1-24+). A CR was achieved in 21 patients (42%), CRi in 2 (4%), and MLFS in 3 (6%) for a cCR rate of 52%. Median time to BM blasts <5% was 57 days (range 25-243 days) and exceeded 168 days (6 cycles) in 3 patients (12%). Median duration of cCR is 13.2 months (95% CI 10.9-21.5 months), with 6 of 26 patients (23%) continuing on therapy for a periods ranging from 20.5 to 29.5 months. With a median follow-up of 21 months, the median OS is 19.1 months (95% CI, 10.0-not reached). One-year and 2-year OS are 62% and 45%. Non-protocol therapies (NPT) were administered in 23 patients (46%). There was no effect on OS after censoring survival duration at the start of NPT. Response and OS by population subsets are summarized in Table 1. Non hematologic adverse events Grade ≥3 reported in >5% of patients: Fatigue 34%; anorexia 10%, cellulitis, pneumonia, asthenia and sepsis in 8%; urinary tract infection, nausea, back pain, hypoxia, hyponatremia, and syncope in 6%. Grade ≥ 3 hematologic toxicities in> 5% of patients: thrombocytopenia 46%; febrile neutropenia 44%; neutropenia 36%; anemia 30%; pancytopenia 6%. The 30-day and 60-day mortality rates were 2% and 10%.
Conclusions: Pracinostat + AZA led to a high rate of responses in elderly patients with AML. Responses were durable and observed irrespective of age, cytogenetics risk, ECOG performance status, and de novo or secondary AML. Marrow remission was typically achieved early, but prolonged exposure was required in some patients to maximize response. The results compare favorably with historical single-agent AZA data in a similar AML population. A phase 3 study of AZA +/- pracinostat in untreated patients with AML unfit for standard induction chemotherapy is starting.
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Atallah:Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Arellano:Cephalon: Research Funding. Odenike:Geron: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghalie:MEI Pharma: Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current view is that treatment failures of AML patients are due to persistence of leukemia stem cells (LSCs). The presence of FMS-like tyrosine kinase-3 (FLT3) Internal tandem duplication (ITD) ...is associated with poor prognosis. But, FLT3 tyrosine kinase inhibitors (TKI) demonstrate transient clinical activity in FLT3-ITD+ AML patients. Persistent FLT3-ITD+ AML LSC represent a source of relapse. There is a pressing need to target LSC and improve outcomes for FLT3-ITD+ AML patients.
PRMT1, the predominant arginine methyltransferase, has been implicated in pathogenesis of AML rare subtype (i.e., acute megakaryoblastic leukemia). Herein, we show that PRMT1 protein expression is significantly increased in LSC-enriched AML CD34+CD38- cells relative to the counterparts of normal peripheral blood stem cells (PBSC) (AML n=9, normal n=8, p=0.0004,). Following PRMT1-knockdown (KD), AML CD34+ cells (n=15) demonstrated varying degrees of apoptosis while the survival of normal cells were not affected. Interestingly, we observed significant apoptosis-induction in a subset of samples bearing FLT3-ITD mutation (6 out of total 15) upon PRMT1-KD (ShCtrl 13.9±3.6%, ShPRMT1 32.5±4.6%, p<0.001). PRMT1-KD induced apoptosis was also more evident in cord blood (CB) CD34+ cells expressing FLT3-ITD (ShCtrl 19.4±1.3%, ShPRMT1 45.2±2.5%, p<0.001) relative to that of FLT3-WT (ShCtrl 27.47±1.8%, ShPRMT1 36.9±1.6%, p=0.0167). In 293T cells ectopically overexpressing FLT3-WT or FLT3-ITD, co-immunoprecipitation (co-IP) indicated greater interaction between PRMT1 and FLT3-ITD. Through RNA-Seq profiling two AML lines (MV4-11, OCI-AML3) plus one FLT3-ITD transduced CB CD34+ cells with PRMT1-KD, we obtained a differentially-regulated gene set as a “PRMT1 signature”. This signature was enriched in FLT3-ITD+ AML relative to FLT3-WT AML according to ssGSEA analysis using two AML datasets (GSE14468, GSE10358), indicating PRMT1 may cooperate with FLT3-ITD regulating AML maintenance.
Given that PRMT1 directly interacts with FLT3-ITD, we next asked whether PRMT1 catalyzes FLT3-ITD protein methylation. Through mass-spectrometry analysis of a FLT3-ITD+ AML specimen and in vitro methylation assay, we identified that PRMT1 catalyzes FLT3-ITD arginine (R) methylation (Me) at two conserved residues, 972 and 973. Using in-house R972/973 Me antibody, we validated the expression of FLT3 R-Me in FLT3-ITD AML speciemens (7 out of 7). To test R-Me function, we transduced MLL-AF9 (MA9) overexpressing murine c-Kit+ cells with methylation-deficient FLT3-ITD (R972/973K, arginine R to lysine K) construct, and found that MA9 cells expressing R972/973K underwent more apoptosis than that of WT FLT3-ITD (WT FLT3-ITD 9.7±1.1%, R972/973K 23.7±2.1%, p=0.003). The double transformed cells were further transplanted into recipients for leukemia development. Mice receiving MA9 cells expressing R972/973K exhibited longer survival (median survival: WT FLT3-ITD 36 days, R972/973K 50 days, p=0.002, n=6). Mechanistically, expression of R972/973K did not affect the total tyrosine phosphorylation level of FLT3-ITD. Additionally, FLT3-ITD R-Me expression persisted after a TKI (AC220) treatment. These facts indicated that FLT3-ITD R-Me function is independent of FLT3-ITD kinase activity. We then used a FLT3-ITD+ patient derived xenograft (PDX) model to assess the effects of TKI and PRMT1 inhibition. Following engraftment >1% in peripheral blood, we divided mice (n=24) into 4 groups and treated each with vehicle, MS023 (a type I PRMT inhibitor, ACS Chem Biol. 2016;11:772-781) (160 mg/kg/i.p), AC220 (10 mg/kg/i.g) or combination for 4 weeks. MS023 treatment downregulating FLT3 R-Me levels enhanced elimination of FLT3-ITD AML cells by AC220 treatment (AC220 24.6±13.4% vs combination 7.6±6.5%, p=0.02, n=6). At 16 weeks post-secondary BMT, significant AML burden in single drug treated transplants was observed, but less AML cells were detected in combination-treated transplants (AC220 52.3%, vs combination 25.4%, p<0.001, n=6). MS023 had little effect on long-term in vivo engraftment of CD34+ from a human CB specimen (vehicle 76.3±5.9%, MS023 72.2±3.4%, p=0.21, n=5).
In summary, our study demonstrated PRMT1 overexpression contributes to AML stem/progenitor cell survival possibly through FLT3-ITD methylation, supporting further exploration into how PRMT1-mediated FLT3 methylation governs LSC survival.
Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Introduction:FLT3-ITD mutations are among the most common molecular abnormalities in AML, occurring in ≈ 25% of pts. These driver mutations are associated with high leukemic burden and poor ...prognosis, eg, high risk of relapse, decreased response to salvage therapy, and shorter overall survival (OS). Pts with R/R FLT3-ITD AML have a worse prognosis and represent a population with high unmet medical need. Q is a once-daily, oral, highly potent and selective FLT3i shown in phase 2 trials to have promising single-agent antileukemic activity and a manageable safety profile. QuANTUM-R was the first global, phase 3, randomized controlled trial (NCT02039726) to show that an FLT3i prolonged OS compared with salvage chemotherapy (SC) in pts with R/R FLT3-ITD AML. Final efficacy and safety data from this pivotal phase 3 trial are reported.
Methods: Pts aged ≥ 18 years with FLT3-ITD AML refractory to or relapsed (duration of first remission
≤ 6 mo) after standard AML therapy, w/wo hematopoietic stem cell transplant (HSCT) were randomized 2:1 to receive Q (60 mg 30-mg lead-in) or 1 of 3 preselected investigator's choice (IC) SC: low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; Q and LoDAC were given until lack of benefit, unacceptable toxicity, or HSCT. Prior therapy with midostaurin was allowed, but all other FLT3i were not. Pts receiving HSCT in the Q arm could resume Q after HSCT. Primary and secondary endpoints were OS and event-free survival (EFS), respectively. Sensitivity analyses for OS and EFS were conducted: (1) using the per-protocol set (randomized and treated patients without major protocol deviations), (2) censoring at HSCT, (3) censoring at the use of other postbaseline FLT3i (for OS only). Predefined subgroup analyses of OS were also performed. Exploratory endpoints included response rates, duration of CRc, and transplant rate.
Results: 367 pts were randomized; 245 to Q and 122 to IC SC (LoDAC, n=29; MEC, n=40; FLAG-IDA, n=53). Four pts randomized to Q and 28 pts randomized to SC did not receive therapy. Median follow-up was 23.5 mo. Six pts were still on initial Q treatment at data cutoff vs 0 in the SC arm. Treatment groups were well balanced for baseline characteristics, including age, response to prior therapy, transplant history, and FLT3-ITD allelic burden.
OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; stratified log-rank test, 1-sided P=0.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo, with an estimated 12-mo OS probability of 27% vs 20% in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; stratified log-rank test, 1-sided P=0.1071); median EFS was 6.0 (95% CI, 0.1-8.3) vs 3.7 (95% CI, 0.4-5.9) wk, respectively. Sensitivity analyses of OS and EFS all supported benefit of quizartinib compared with SC, as did OS analyses across subgroups, including varying allelic ratio, prior HSCT, AML risk score, and response to prior therapy (Tables 1 and 2, Figure).
CRc was 48% (95% CI, 42%-55%) and 27% (95% CI, 19%-36%) in Q and SC arms (nominal P=0.0001), respectively. Duration of CRc was 12.1 (95% CI, 10.4-27.1) vs 5.0 (95% CI, 3.3-12.6) wk. Transplant rate was 32% and 12% in Q and SC arms (nominal P<0.0001), respectively; of 79 eligible pts, 49 (62%) resumed single-agent Q after HSCT (15 ongoing Q treatment at data cutoff). Median duration of post-HSCT Q was 129 d.
Rates of treatment-emergent adverse events (TEAEs) were comparable between the 2 arms, despite higher total drug exposure in Q vs SC arms (101.9 vs 3.7 patient-years pt-y, respectively). Exposure-adjusted TEAEs were 2.3 vs 25.2 per pt-y, respectively. Most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Only 2 pts discontinued Q due to QTcF prolongation. QTcF >500 ms (grade 3) by central laboratory was 3% in the Q arm; no grade 4 QTcF occurred. Q-treated pts post-HSCT had a similar AE profile to those overall.
Conclusions: This report confirms the survival benefit observed with single-agent Q compared with SC in pts with R/R FLT3-ITD AML and the favorable Q safety profile, providing evidence of meaningful clinical benefit in pts who have few options. These results are paradigm changing in the R/R FLT3-ITD AML treatment setting.
Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Khaled:Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Perl:Arog: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ganguly:Amgen: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau. Russell:Daiichi Sankyo: Consultancy; Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kramer:Daiichi Sankyo: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Dombret:Daiichi Sankyo: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding; Agios: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma: Honoraria, Research Funding; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria. Jonas:Accelerated Medical Diagnostics: Research Funding; Incyte: Research Funding; Esanex: Research Funding; LP Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding. Leung:Novartis: Speakers Bureau; Daiichi: Research Funding. Mehta:Daiichi Sankyo: Honoraria. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Radsak:Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Other: Travel grant; TEVA: Consultancy; Daiichi Sankyo: Honoraria, Other: Travel grant; Gilead: Other: Travel grant; Celgene: Honoraria, Other: Travel grant; Takeda: Consultancy. Arunachalam:Daiichi Sankyo: Employment. Holmes:Daiichi Sankyo: Employment. Kobayashi:Daiichi Sankyo: Employment. Namuyinga:Daiichi Sankyo: Employment. Ge:Daiichi Sankyo: Employment. Yver:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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