Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes

Abstract

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.

Conflict of interest statement

David A. SallmanConsulting or Advisory Role: Celyad, Agios, Abbvie, Aprea AB, Bristol-Myers Squibb, Gilead Sciences, Intellia Therapeutics, Kite Pharma, Magenta Therapeutics, Novartis, SyndaxSpeakers' Bureau: Agios, Incyte, Bristol-Myers SquibbResearch Funding: Celgene, Jazz PharmaceuticalsPatents, Royalties, Other Intellectual Property: Intellectual Property Patent for LB-100 in MDS Amy E. DeZernConsulting or Advisory Role: Celgene, Novartis, Gilead SciencesResearch Funding: Celgene, Astex PharmaceuticalsTravel, Accommodations, Expenses: Abbvie Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbvieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol-Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, Abbvie, Bristol-Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck David P. SteensmaStock and Other Ownership Interests: Arrowhead Pharmaceuticals, Sage TherapeuticsHonoraria: Daiichi Sankyo, Summer Road, Stemline Therapeutics, Celgene, Astex PharmaceuticalsConsulting or Advisory Role: Pfizer, Janssen Oncology, Agios, Onconova Therapeutics, Geron, Astex PharmaceuticalsResearch Funding: Aprea AB, Celgene/BMS, H3 Biomedicine Gail J. RobozConsulting or Advisory Role: Amphivena, Janssen, Amgen, Astex Pharmaceuticals, Celgene, Genoptix, MedImmune, Novartis, Pfizer, Abbvie, Argenx, Array BioPharma, Bayer, Celltrion, Jazz Pharmaceuticals, Orsenix, Genentech/Roche, Sandoz, Actinium Pharmaceuticals, Astellas Pharma, Eisai, Bayer, Daiichi Sankyo, MEI Pharma, Otsuka, Takeda, Roche, Agios, Trovagene, GlaxoSmithKline, Bristol-Myers Squibb, Helsinn Therapeutics, MesoblastResearch Funding: Abbvie, Agios, Astex Pharmaceuticals, Celgene, CTI, Karyopharm Therapeutics, MedImmune, MEI Pharma, Moffitt, Novartis, Onconova Therapeutics, Pfizer, Sunesis Pharmaceuticals, Tensha Therapeutics, Cellectis, Janssen, AmphivenaTravel, Accommodations, Expenses: Amphivena, Astex Pharmaceuticals, Janssen, Pfizer, Array BioPharma, Novartis, Abbvie, Jazz Pharmaceuticals, Celgene, Celltrion, Roche/Genentech, Sandoz, Bayer, Clovis Oncology, Amgen, Sunesis Pharmaceuticals, Eisai, Agios Mikkael A. SekeresConsulting or Advisory Role: Celgene, Millennium, Syros PharmaceuticalsResearch Funding: Takeda, Pfizer, Bristol-Myers Squibb Thomas CluzeauConsulting or Advisory Role: Abbvie, Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche, Takeda, Syros PharmaceuticalsSpeakers' Bureau: Novartis, Amgen, Sanofi, Astellas PharmaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Pfizer, Sanofi Kendra L. SweetLeadership: ImmtechConsulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Novartis, Takeda, Stemline TherapeuticsResearch Funding: Incyte Kathy L. McGrawResearch Funding: Genentech, Celgene Eric PadronHonoraria: Stemline Therapeutics, Blueprint MedicinesSpeakers' Bureau: Novartis, Taiho PharmaceuticalResearch Funding: Incyte, Bristol-Myers Squibb, Kura Oncology Greg KorbelEmployment: Aprea Therapeutics, IncLeadership: Aprea Therapeutics, IncStock and Other Ownership Interests: Aprea Therapeutics, Inc Eyal C. AttarEmployment: Agios, Aprea ABLeadership: Aprea ABStock and Other Ownership Interests: Agios, Aprea ABConsulting or Advisory Role: TeladocTravel, Accommodations, Expenses: Aprea AB, Agios Hagop M. KantarjianHonoraria: Abbvie, Amgen, ARIAD, Bristol-Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol-Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, Abbvie, Agios, Cyclacel, Immunogen, Jazz Pharmaceuticals Jeffrey E. LancetStock and Other Ownership Interests: ArvinasConsulting or Advisory Role: Jazz Pharmaceuticals, Astellas Pharma, Abbvie, Agios, BerGenBio, Daiichi Sankyo, ElevateBioResearch Funding: Pfizer Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Alan F. ListHonoraria: Celgene, Aileron Therapeutics, Cellular Biomedicine GroupConsulting or Advisory Role: Celgene, Cellular Biomedicine Group, Aileron Therapeutics, Acceleron Pharma, International Personalized Cancer Center, Precision Biosciences, CTI BioPharma Corp, Prelude TherapeuticsResearch Funding: CelgeneTravel, Accommodations, Expenses: Celgene, Cellular Biomedicine GroupOther Relationship: Thousand Talents Award Rami S. KomrokjiStock and Other Ownership Interests: AbbvieConsulting or Advisory Role: Novartis, Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Abbvie, Geron, Acceleron PharmaSpeakers' Bureau: Jazz Pharmaceuticals, Bristol-Myers Squibb, AgiosTravel, Accommodations, Expenses: Incyte, Jazz Pharmaceuticals, Bristol-Myers Squibb, AgiosNo other potential conflicts of interest were reported.

Figures

FIG 1.

(A) Heat map of individual patient baseline risk characteristics including molecular and genetic features and best response to treatment, and (B) matchstick plot of TP53 mutation types and locations by best response. AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CR, complete remission; DBD, DNA-binding domain; HI, hematologic improvement; INT, intermediate; IPSS-R, revised International Prognostic Scoring System; mCR, marrow complete remission; MDS, myelodysplastic syndromes; MDS/MPN, myelodysplastic syndromes/myeloproliferative neoplasms; NE, not evaluable; NR, not reported; ORR, overall response rate; PD, progressive disease; PRD, proline-rich domain; REG, C-terminal regulatory domain; SD, stable disease; TAD, transactivation domain; TET, tetramerization domain.

FIG 2.

(A) Treatment response and duration for all 45 response-evaluable patients, (B) TP53 variant allele frequency by best response, and (C) serial p53 IHC positivity by best response. AE, adverse event; AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CR, complete remission; HI, hematologic improvement; IHC, immunohistochemistry; mCR, marrow complete remission; MDS, myelodysplastic syndromes; MDS/MPN, myelodysplastic syndromes/myeloproliferative neoplasms; NE, not evaluable; NR, not reported; SD, stable disease; VAF, variant allele frequency.

FIG 3.

Kaplan-Meier curves for OS (A) in intention-to-treat population, (B) in patients with response versus no response by landmark analysis at 4 months, and (C) in patients with CR and non-CR response versus no response by landmark analysis at 4 months. CR, complete remission; OS, overall survival.