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Poster session 01

666P - Final results of phase I/II study of NUC-7738 as monotherapy and in combination with pembrolizumab: Anti-tumor immune response in PD-1 inhibitor-resistant patients

Date

14 Sep 2024

Session

Poster session 01

Topics

Clinical Research;  Tumour Immunology;  Translational Research;  Immunotherapy

Tumour Site

Melanoma

Presenters

Sarah Blagden

Citation

Annals of Oncology (2024) 35 (suppl_2): S482-S535. 10.1016/annonc/annonc1589

Authors

S. Blagden1, M. Elshani2, S.N. Symeonides3, A. Skolariki1, N.R. Haris4, Z.Y. Boh3, A. Dickson2, I.H. Um2, Y. Zhang2, F.G. McKissock5, E. Oelmann5, J. Bloss5, N. Cook6, T.R..J. Evans7, R. Plummer4, D.J. Harrison2

Author affiliations

  • 1 Oncology Dept., Churchill Hospital - Oxford University Hospitals NHS Foundation Trust, OX3 7LE - Oxford/GB
  • 2 School Of Medicine, University of St Andrews, KY16 9TF - St Andrews/GB
  • 3 Edinburgh Cancer Centre, University of Edinburgh, EH8 9YL - Edinburgh/GB
  • 4 Sir Bobby Robson Research Unit, Newcastle Freeman Hospital - Newcastle Upon Tyne Hospitals NHS Foundation Trust, NE7 7DN - Newcastle-upon-Tyne/GB
  • 5 Oncology, NuCana plc, EH12 9DT - Edinburgh/GB
  • 6 Department Of Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 7 Institute Of Cancer Sciences, University of Glasgow, G12 8QQ - Glasgow/GB

Resources

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Abstract 666P

Background

NUC-7738 is a phosphoramidate modification of 3’-deoxyadenosine (3’-dA) designed to generate high intracellular levels of the anti-cancer metabolite 3’-dATP. Our translational studies show that NUC-7738 disrupts RNA polyadenylation, leading to alterations in protein and non-coding RNA levels and promoting anti-tumor immunity.

Methods

NUC-7738 monotherapy was explored in Phase 1 dose escalation (n=38) and Phase 2 dose refinement (n=11) in pts with advanced solid tumors. NUC-7738 + pembrolizumab (Phase 2) was then investigated in 12 pts with metastatic cutaneous melanoma (1-3 prior lines, including ≥1 PD-1 inhibitor). Paired biopsies were taken pre- and post-treatment to evaluate changes in the TME with long read RNA sequencing and multiplex immunofluorescence.

Results

NUC-7738 monotherapy demonstrated a favorable safety profile and evidence of anti-tumor activity in solid tumors. The MTD and RP2D were determined to be 1350 mg/m2 and 1125 mg/m2 respectively. In the NUC-7738 + pembrolizumab cohort of pts with melanoma, resistant to prior PD-1 inhibitors, 2 PRs were observed at 8 weeks (-55%; DOR 8 months) and 24 weeks (-32%; DOR 2 months, remains on treatment). Seven additional pts had SD for >3 months (range; 3-11). The DCR at 8 weeks was 75%. Four pts remain in PFS follow up. Nausea (9 pts), ALT increased (6 pts), and diarrhea (6 pts) were the most frequent TRAEs (mostly Grade 1 or 2). Four pts had Grade 3 TRAEs: abdominal pain & diarrhea; vomiting & fatigue; hypotension & adrenal insufficiency; AST/ALT increased; GGT increased & immune-mediated hepatitis. One pt had a Grade 4 TRAE of AST/ALT increased. Evaluation of paired biopsies revealed that NUC-7738 disrupted RNA polyadenylation, particularly in long non-coding RNA; mRNA pathway analysis showed evidence of increased T cell activation and antigen presentation post-treatment.

Conclusions

NUC-7738 has a favorable safety profile with promising anti-tumor activity as monotherapy and in combination with pembrolizumab. By disrupting RNA polyadenylation, NUC-7738 alters mRNA half-life and expression of immune regulatory proteins, leading to anti-tumor immune response in patients with PD-1 resistance.

Clinical trial identification

NCT03428958.

Editorial acknowledgement

Legal entity responsible for the study

NuCana.

Funding

NuCana.

Disclosure

S. Blagden: Financial Interests, Personal, Other, Honoraria: Amphista, Theolytics, UCB, Rapport Global; Financial Interests, Personal and Institutional, Research Funding: NuCana, Redx Pharma, UCB, Mina Therapeutics, Astex, Nurix, BerGenBio, MSD Oncology; Financial Interests, Personal, Advisory Board: UCB, Oxford Investment Consultants. M. Elshani: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. S.N. Symeonides: Financial Interests, Institutional, Advisory Board: Ellipses, Medannex, Eisai, MSD, Pfizer, Merck Serono, Duke Street Bio, Exscientia, Grey Wolf Therapeutics, Roche; Financial Interests, Institutional, Invited Speaker: Ipsen, MSD, Roche, Eisai; Financial Interests, Institutional, Other, Independent Data / Safety Monitoring: Valley Health, Exscientia, Grey Wolf Therapeutics; Financial Interests, Institutional, Full or part-time Employment, Medical Advisor in CRUK's Cente for Drug Development: Cancer Research UK (charity); Financial Interests, Institutional, Research Grant: MSD, Verastem; Financial Interests, Institutional, Coordinating PI: MSD, BioNTech, Nouscom; Financial Interests, Institutional, Steering Committee Member: Roche, Nucana, Sapience Therapeutics, BioLineRx, Boston Pharmaceuticals, Sierra Oncology, Incyte, Scancell, Medannex; Non-Financial Interests, Member of Board of Directors, Non-profit organisation connecting stakeholders in cancer drug development: Cancer Drug Development Forum; Other, Conference attendance (no personal gain): Ipsen, EUSA, MSD, BioNTech. A. Skolariki: Financial Interests, Personal and Institutional, Research Grant: NuCana. A. Dickson, F.G. McKissock, E. Oelmann, J. Bloss: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. N. Cook: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Local PI: Taiho, Roche, AstraZeneca, Avacta, Bayer, Eisai, UCB, Boeringher, Stemline; Financial Interests, Institutional, Coordinating PI: RedX, Orion, Starpharma, Loxo Oncology; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Other, Committee chair: Cancer Research UK. T.R.J. Evans: Financial Interests, Institutional, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Boards - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo, Incyte; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences, AstraZeneca; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. D.J. Harrison: Financial Interests, Personal, Full or part-time Employment: NuCana; Financial Interests, Institutional, Research Funding: NuCana; Financial Interests, Personal, Stocks/Shares: NuCana. All other authors have declared no conflicts of interest.

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