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246 Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Treatment of High Risk Myelodysplastic Syndrome
Hematology Disease Topics & Pathways:
Clinical Trials, Acute Myeloid Malignancies, AML, Clinical Research, Clinically Relevant, Diseases, Therapies, Myeloid Malignancies
Saturday, December 11, 2021: 3:15 PM

David A. Sallman, MD1, Rami S. Komrokji, MD2, Amy E. DeZern, MD3, Marie Sebert, MD, PhD4*, Guillermo Garcia-Manero, MD5, Ramy Rahmé, MD6*, David P. Steensma, MD7*, Jacqueline Lehmann che8*, Gail J. Roboz, MD9, Isabelle Madelaine, PharmD10*, Mikkael A. Sekeres, MD11, Pierre Peterlin12*, Kendra Sweet, MD13, Odile Beyne Rauzy14*, Andrew T. Kuykendall, MD15, Christian Recher, MD16, Amy F McLemore, M.S.17*, Aspasia Stamatoullas18*, Ling Zhang, MD19*, Lise Willems20*, Qianxing Mo, PhD21*, Emmanuel Raffoux, MD22*, Lisa Nardelli2*, Celine Berthon, MD, PhD23*, Najla Al Ali, MS24, Bruno Quesnel, MD, PhD25, Eric Padron, MD26, Greg Korbel, PhD, MBA27*, Eyal C. Attar, MD27, Hagop Kantarjian, MD5, Alan F. List, MD28, Lionel Ades, MD, PhD29, Jeffrey E. Lancet, MD30, Pierre Fenaux, MD, PhD31 and Thomas Cluzeau, MD, PhD32

1Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
2Malignant Hematology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
4Department of Clinical Hematology, Hôpital saint louis, Paris, France
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6Saint Louis Hospital, Paris, France
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
8Pharmacy department, Hospital Saint Louis, Paris, France
9Division of Hematology Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
10Pharmacy Department, Saint Louis Hospital, APHP, Paris, France
11Division of Hematology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL
12Clinical Hematology, HOPITAL HOTEL DIEU ET HME, NANTES CEDEX 1, France
13Department of Hematology and Oncology, Moffitt Cancer Center, Tampa, FL
14Oncopôle Toulouse, Toulouse, France
15Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
16Service d'Hématologie, CHU de Toulouse - Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
17Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
18Service d' Hématologie, Centre Henri Becquerel, Rouen, FRA
19Department of Hematopathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
20Department of Hematology, APHP, Hôpital Cochin, Paris, France
21H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
22Hématologie clinique, Hôpital Saint-Louis, Paris, France
23Hematology Department, Lille University Hospital, Lille, France
24Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL
25Service des Maladies du Sang, Hôpital Huriez, Centre Hospitalier Universitaire de Lille, LILLE, France
26Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
27Aprea Therapeutics, Boston, MA
28Precision BioSciences, Inc., Durham, NC
29Institut Univeristaire d'Hematologie, Hopital Saint Louis, Paris, France
30Department of Malignant Hematology, H. Lee Moffitt Cancer Ctr. & Rsrch. Institute, Tampa, FL
31Hôpital Saint-Louis, Paris, France
32CHU of Nice, Hematology department, Cote D’Azur University, Nice Sophia Antipolis University, Nice, France

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 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 mTP53 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 mTP53 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/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), 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 mTP53). 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 mTP53 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 <5%), best response was CR/PR in 78% (n=31), mCR+HI in 15% (n=6), mCR in 5% (n=2) and HI in 3% (n=1). The median # of cycles in NGS negative and positive pts was 10 and 4, respectively (P<0.0001). All MRD negative pts received at least 5 cycles of therapy (5-15).

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 mTP53 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 mTP53 pts.

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: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: 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; Takeda: 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: Astellas: Consultancy, 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Kuykendall: CTI Biopharma: Honoraria; Incyte: Consultancy; BluePrint Medicines: Honoraria, Research Funding, Speakers Bureau; Celgene/BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Abbvie: Honoraria; Prelude: Research Funding; 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.

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