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PURPOSE Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. METHODS This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043 ). RESULTS Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). CONCLUSION Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.

Introduction: TP53 gene mutations (m TP53), found in up to 20% of MDS or AML pts and 30-40% of therapy-related (TR) MDS/AML cases, represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) are the frontline standard of care, with CR rates of ~20% and median OS of < 12 months. APR-246 is a novel, first-in-class small molecule that reactivates the mutant p53 protein and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in m TP53 cancer cells. We previously reported the Phase 2 results of 2 parallel trials of APR-246+AZA (Sallman et al and Cluzeau et al., JCO 2021). We now report analyses of the combined Phase 2 cohorts and long-term follow-up. Methods: This is a multicenter, international collaboration of the US MDS clinical research consortium and the GFM of HMA-naïve m TP53 higher-risk MDS, MDS/MPN and oligoblastic AML (≤ 30% blasts) pts (NCT03072043/NCT03588078). Pts received APR-246 4500mg IV (days 1-4) + AZA 75 mg/m 2 SC/IV x 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective was CR rate by International Working Group (IWG) 2006 criteria. Secondary objectives included ORR, OS, outcome following allogeneic hematopoietic stem cell transplant (allo-HSCT), with serial high depth next generation sequencing (NGS, 0.1% cutoff) for evaluation of measurable residual disease (MRD). Results: As of July 15, 2021, 100 pts had been enrolled with a median age of 68 years (range, 34-87; 47% male). By WHO, 74 pts had MDS, 22 AML-MRC and 4 CMML/MDS-MPN; 83% complex karyotype (CK) and 88% were CK and/or biallelic for TP53 mutations; 92% had a TP53 missense mutation in the DNA binding domain. In 63 pts, TP53 was the only mutation detected (i.e. isolated m TP53). Median time on treatment was 6 cycles (1-25+) with 5 pts ongoing and 23 pts who proceeded to allo-HSCT. Non-hematologic treatment (Tx)-related adverse events (AEs) in ≥20% of pts included nausea/vomiting (58%), ataxia (26%), and dizziness (23%). Neurologic AEs were reversible in 100% of cases. Febrile neutropenia occurred in 37% of pts. Thirty and 60-day mortality was 1% (n=1) and 7% (n=7), respectively. Dose reductions of APR-246 and AZA occurred in 16% and 1% of pts, respectively, with only 1 treatment discontinuation due to a treatment-related AE. By intention-to-treat (ITT) analysis, ORR by IWG was 69% with 43 CR, 1 PR, 10 marrow CR (mCR)+HI, 9 HI alone, and 6 with mCR. Of non-responders, 6 had stable disease and 7 pts had progressive disease. The median duration of CR/PR was 10.6 months (95% CI 8.8-12.3, 23+ months ongoing). CR/PR rate for MDS was 49% (36/74), 36% for AML (8/22) and 0% for MDS/MPN (0/4) with an ORR rate of 70%/64%/75%, respectively. Isolated m TP53 was predictive for a higher CR rate (52% vs 30%; P=.04). Patients who had biallelic TP53 or CK had a significantly higher CR rate vs pts without (49% vs 8%; P=0.01). On serial TP53 NGS using a VAF cutoff of 5%, 40 pts achieved NGS negativity with 6 pts MRD negative (VAF < 0.1%). Of NGS negative pts (TP53 VAF At data-cutoff by ITT analysis with a median follow up of 27.8 months, median OS was 11.8 months (95% CI 9.4-14.3). Pts undergoing allo-HSCT had a median OS of 16.1 months (95% CI 14-18.1). Impact of response and NGS clearance was evaluated by landmark analysis at 6 months. Pts achieving CR/PR or NGS negativity had improved OS (15.8 vs 10.1 months; P=0.002; Fig 1A). Additionally, pts who became MRD negative had a 2-year OS of 50% vs 23% (P=0.21). Although allo-HSCT was not predictive of OS in the overall cohort by landmark analysis (14.7 vs 14.4 months; P=0.15; Fig 1B), significant OS improvement was noted in allo-HSCT pts based on CR/PR or NGS negativity (P=0.002; Fig 1C). Notably, pts who achieved CR/PR/NGS negativity and were bridged to allo-HSCT had a median OS that was not reached (95% CI 10.4-NR) vs 9.1 months (95% CI 7.4-NR) in allo-HSCT pts who did not achieve this response (P=0.01). Conclusions: In this international, combined analysis of P2 APR-246+AZA pts, the combination was well-tolerated with high response rates in m TP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HSCT, validating NGS clearance as a critical biomarker of allo-HSCT outcomes in m TP53 pts. Figure 1 Figure 1. Disclosures Sallman: Intellia: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Komrokji: BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Novartis: Honoraria; Geron: Honoraria; Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sebert: BMS: Consultancy; Abbvie: Consultancy. Steensma: Novartis: Current Employment. Roboz: Astellas: Consultancy; Otsuka: Consultancy; Blueprint Medicines: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Jasper Therapeutics: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Janssen: Research Funding; AstraZeneca: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Mesoblast: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Astex: Consultancy; Actinium: Consultancy; Roche/Genentech: Consultancy. Sekeres: BMS: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; PharmaEssentia: Honoraria; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Raffoux: ASTELLAS: Consultancy; ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Blueprint: Honoraria; Kura: Research Funding; Taiho: Honoraria; Stemline: Honoraria. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kantarjian: Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas Health: Honoraria; Jazz: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Taiho Pharmaceutical Canada: Honoraria. List: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy; CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company. Ades: Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria. Lancet: BerGenBio: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; AbbVie: Consultancy. Fenaux: Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Introduction: TP53 gene mutations (mTP53), found in up to 20% of MDS or AML pts and 30-40% of therapy-related (TR) MDS/AML cases, represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) are the standard of care with CR rates of ~20% and median OS of 7-8 months. APR-246 is a novel, first-in-class small molecule that selectively induces apoptosis in mTP53 cancer cells via thermodynamic stabilization of the p53 protein and shifting equilibrium toward the wild-type conformation. We previously reported the Phase 1b results of APR-246+AZA with no DLTs, transcriptional activation of p53 targets and high response rates, identifying a Phase 2 (P2) dose of 4500mg days 1-4 (Sallman et al., ASH 2018). We report herein the planned, completed phase 2 results. Methods: This is a multicenter Phase 1b/2 trial of APR-246+AZA in HMA-naïve mTP53 higher risk MDS, MDS/MPN and oligoblastic AML (≤ 30% blasts) pts (NCT03072043). P2 pts received APR-246 4500mg IV (days 1-4) + AZA 75 mg/m2 SC/IV x 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was CR rate by International Working Group (IWG) 2006 criteria. Secondary objectives included ORR, OS, outcome following allogeneic hematopoietic stem cell transplant (allo-HSCT), and both next generation sequencing (NGS) and p53 immunohistochemistry (IHC) to monitor clonal suppression and remission depth as prognostic covariates. For minimal residual disease (MRD) analysis, a custom target-capture NGS assay was developed using unique molecular Identifiers for error correction with a 0.1% limit of detection. Results: As of July 15, 2019, 55 pts were enrolled (6 P1; 49 P2) with a median age 66 years (34-85; 47% male). By WHO, 40 pts had MDS, 11 AML-MRC and 4 CMML/MDS-MPN; 85% had complex cytogenetics and 33% TR-MDS/AML. All pts had higher risk disease by IPSS-R (7% Intermediate, 24% High, 69% Very High). Fifty pts (91%) had a TP53 missense mutation in the DNA binding domain with multiple mutations in 18 (33%), and median variant allele frequency (VAF) of 25%. In 34 pts (62%), TP53 was the sole mutation. Median time on treatment is 154 days (11-392) with 8 pts ongoing. Eighteen pts (33%; 40% of evaluable pts) discontinued study treatment to proceed to allo-HSCT. Treatment (Tx)-related AEs in ≥ 20% of pts included nausea/vomiting (58%), dizziness (31%), constipation (24%), neuropathy (22%), leukopenia (22%) and thrombocytopenia (20%; all G1/G2 except cytopenias (G3/G4). Tx-related febrile neutropenia and anemia occurred in 9% and 5% of pts with no other G3/G4 event in >1 pt. Thirty and 60 day mortality was 2% (n=1) and 6% (n=3), respectively. At data cutoff, 45pts were response evaluable with a median follow up of 10.5 months (Fig 1A). ORR by IWG was 87% (39/45) with 24 CR (53%), 8 marrow CR (mCR)+HI (18%), 3 HI alone (7%), and 4 with mCR (9%). Of 6 non-responders, 4 had stable disease and 2 pts had progressive disease. Median time to response was 2.1 months (0.1-5.4) and median duration of response of 6.5 months. CR rate for MDS was 61% (20/33), 50% for AML (4/8) and 0% for MDS/MPN (0/4) with an 88% ORR rate for MDS/AML and 75% for MDS/MPN. An isolated mTP53 was predictive for a higher CR rate (69% vs 25%; P=.006) with a trend for higher ORR (93% vs 75%; P=.17). Additionally, pts with >10% p53 IHC+ BM-MNC was a covariate associated with higher CR rate (66% vs 13%; P=.01). Complete and partial cytogenetic response occurred in 41% (n=18) and 18% (n=8) of pts, respectively. On serial TP53 NGS using a VAF cutoff of 5%, 39% (n=21) of patients achieved NGS negativity, which was associated with improved OS (12.8 vs 9.2 months; P=.02). In NGS- pts, the median MRD VAF at maximum clearance was 0.63% (0.0%-5%) with 5 pts (11%) MRD negative. By intention-to-treat analysis, median OS was 11.6 months (95% CI 9.2-14) with significantly longer OS in responding pts (12.8 vs 3.9 months; P Conclusions: APR-246+AZA is a well-tolerated combination with high response rates in mTP53 MDS/AML. Response durations are promising accompanied by a high fraction of cytogenetic and deep molecular remissions leading to encouraging outcomes post-HSCT. These data support the ongoing, randomized phase 3 study of APR-246+AZA versus AZA alone in mTP53 MDS (NCT03745716). Disclosures Sallman: Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. 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. Steensma:Stemline: Consultancy; Pfizer: Consultancy; Aprea: Research Funding; H3 Biosciences: Other: Research funding to institution, not investigator.; Astex: Consultancy; Arrowhead: Equity Ownership; Onconova: Consultancy; Summer Road: Consultancy. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: 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; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Celltrion: 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; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Jazz Pharma: Consultancy; Abbvie: Consultancy; Menarini: Consultancy. Sweet:Incyte: Research Funding; Celgene: Speakers Bureau; Pfizer: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Stemline: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Korbel:Aprea Therapeutics: Employment. Attar:Aprea Therapeutics: Employment. Kantarjian:Astex: Research Funding; Amgen: Honoraria, Research Funding; Ariad: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Fenaux:Aprea: Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji:JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau; Agios: Consultancy.