Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors

H Park, G I Shapiro, X Gao, A Mahipal, J Starr, M Furqan, P Singh, A Ahrorov, L Gandhi, A Ghosh, D Hickman, P D Gallacher, A Wennborg, E C Attar, M M Awad, S Das, E E Dumbrava, H Park, G I Shapiro, X Gao, A Mahipal, J Starr, M Furqan, P Singh, A Ahrorov, L Gandhi, A Ghosh, D Hickman, P D Gallacher, A Wennborg, E C Attar, M M Awad, S Das, E E Dumbrava

Abstract

Background: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).

Patients and methods: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt.

Results: Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease.

Conclusions: The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.

Keywords: clinical trial; eprenetapopt; p53; pembrolizumab; solid tumors.

Conflict of interest statement

Disclosure HP reports research funding from Ambrx, Aprea Therapeutics, Array BioPharma, BJ Bioscience, Bristol Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD-Serono, Genentech, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Merck, Mirati, Novartis, Oncologie, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, and Xencor Inc. GIS reports research funding from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology, and has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen and Xinthera, and holds a patent entitled, ‘Dosage regimen for sapacitabine and seliciclib’, also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, ‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition’, together with Liam Cornell. XG reports consulting or advisory roles for Exelix, Bayer, Guardant Health, and Flare Therapeutics, and research funding (to institution) from Arvinas, Exelixis, Pfizer, Harpoon therapeutics, Aprea Therapeutics, Takeda, Aravive, Merck, Poseida therapeutics, TopAlliance BioSciences Inc., Janssen, Novartis, and Silverback Therapeutics. AM reports participation on an advisory board for QED Therapeutics and Taiho Oncology. JS reports research funding from Aprea Therapeutics, Macrogenics, Rafael Therapeutics, Xencor, Cardiff Oncology, Merus Therapeutics, Daiichi-Sanyko, and Amgen, and consulting for Advanced Accelerated Applications, Ipsen, Pfizer, Taiho, Tersera, Natera, and Cancer Expert Now. MF reports participation on an advisory board for Mirati, AstraZeneca, Pfizer, and Beigene. PS reports participation on an advisory board for Janssen, EMD Soreno, Aveo, and Seattle Genetics. LG reports participation in scientific advisory boards for Xilio, Surface Oncology, Mersana, Beigene, Bristol Myers Squibb, Eisai, and Tentarix; consultancy for Tempus, TwentyEight-Seven Therapeutics, and Pliant Therapeutics; and is a member of the Board of Directors for Bright Peak Therapeutics. AG reports research support (drugs) from Aprea Therapeutics and consultancy for Adivo Associates. DH, PDG, AW, ECA, and MMA report current employment and equity holder (publicly traded company) with Aprea Therapeutics. SD reports receiving honoraria for consultancy for AAA/Novartis, Ipsen, and TerSera Therapeutics. EED reports grants from Bayer Pharmaceuticals, Immunocore, Amgen, NCI, Aileron Therapeutics, Compugen, TRACON Pharmaceuticals, Unum Therapeutics, Immunomedics, Bolt Biotherapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen, Mereo BioPharma, and Sanofi, Astex Therapeutics during the conduct of the study, and personal fees and other from Bolt Biotherapeutics and Catamaran Bio outside the submitted work. AA has declared no conflicts of interest.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Patient disposition. EPR, eprenetapopt; PEM, pembrolizumab.

References

    1. Levine A.J., Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9(10):749–758.
    1. Sharma M.D., Rodriguez P.C., Koehn B.H., et al. Activation of p53 in immature myeloid precursor cells controls differentiation into Ly6c(+)CD103(+) monocytic antigen-presenting cells in tumors. Immunity. 2018;48(1):91–106.
    1. Ghosh A., Michel J., Dong L., et al. TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models. Cancer Res. 2019;79:4843.
    1. Zhang Q., Bykov V.J.N., Wiman K.G., Zawacka-Pankau J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9(5):439.
    1. Degtjarik O., Golovenko D., Diskin-Posner Y., Abrahmsén L., Rozenberg H., Shakked Z. Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ) Nat Commun. 2021;12(1):7057.
    1. Bykov V.J.N., Zhang Q., Zhang M., Ceder S., Abrahmsen L., Wiman K.G. Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front Oncol. 2016;6:21.
    1. Peng X., Zhang M.Q., Conserva F., et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013;4:e881.
    1. Lehmann S., Bykov V.J., Ali D., et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30(29):3633–3639.
    1. Sallman D.A., DeZern A.E., Garcia-Manero G., et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021;39(14):1584–1594.
    1. Cluzeau T., Sebert M., Rahme R., et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myelodysplasies (GFM) J Clin Oncol. 2021;39(14):1575–1583.
    1. Merck Sharp & Dohme Corp KEYTRUDA® (pembrolizumab) injection, for intravenous use. Prescribing information. Available at.
    1. Ghosh A, Redmond D, Michels J, et al. p53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models. Poster presented at: the American Association for Cancer Research Annual Meeting 2019; March 29-April 3; Atlanta, GA. Poster 4843.
    1. Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247.
    1. Fradet Y., Bellmunt J., Vaughn D.J., et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019;30(6):970–976.
    1. Fuchs C.S., Doi T., Jang R.W., et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5)
    1. Ghosh A, Michel J, Venkatesh D, et al. Activating canonical p53 functions in tumor-associated macrophages improves immune checkpoint blockade efficacy. American Association for Cancer Research Annual Meeting. April 8-13, 2022; New Orleans, LA. Abstract 250/216.
    1. Venkatesh D, Michels J, Liu C, et al. APR-246 enhances tumor immunogenicity even in the absence of p53. American Association for Cancer Research Annual Meeting. April 8-13, 2022; New Orleans, LA. Abstract 1291/1291.
    1. The TP53 Database (R20, July 2019) Available at.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner