Abstract C032: NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study

Abstract

Abstract Background: 3’-deoxyadenosine (3’-dA) is a natural nucleoside analogue that demonstrated potent anti-cancer activity in vitro but was not successfully developed in the clinic due to rapid breakdown and limited activation to the anti-cancer metabolite (3’-dATP). NUC-7738 is a phosphoramidate modification of 3’-dA designed to overcome these shortcomings and generate higher levels of 3’-dATP. Primarily, 3’-dATP disrupts RNA polyadenylation and can cause metabolic stress, blockade of cell division and apoptosis. Secreted forms of PD-L1, associated with resistance to PD-1 inhibitors, are partially controlled by alternative polyadenylation and were found to be reduced by NUC-7738 in vitro and in some patient (pt) samples. NuTide:701 is a two-part, Phase 1/2 clinical study designed to establish the RP2D of NUC-7738 monotherapy and to investigate NUC-7738 at the RP2D in combination with pembrolizumab. NUC-7738 monotherapy has shown a favourable safety profile and anti-tumour activity (prolonged SD and tumour reductions). Here we focus on the Phase 2 NUC-7738 + pembrolizumab part of the study. Methods: Pts with advanced/metastatic cutaneous melanoma who had progressed on 1- 2 prior lines, one of which may have contained immunotherapy, are included in the ongoing NUC-7738 + pembrolizumab cohort and receive NUC-7738 1125 mg/m2 Q1W (with option to escalate to 1350 mg/m2 beyond C2D8) and pembrolizumab 200 mg/m2 Q3W until progression. In pts with accessible disease, biopsies were taken prior to and 28 days after initiation of treatment to assess tumour levels of NUC-7738 and its metabolites and evaluate changes in the tumour microenvironment. Results: At the time of data cut-off, 4 pts with cutaneous melanoma have received NUC-7738 + pembrolizumab. To date, 1 pt experienced reversable Grade 4 transaminitis, related to pembrolizumab, and 2 pts experienced Grade 3 abdominal pain, diarrhoea and fatigue. At the time of writing, all 4 remain on treatment, 1 pt has SD and 8 additional pts are being recruited. Conclusions: NUC-7738 has a favourable toxicity profile as monotherapy and has been well-tolerated to date in combination with pembrolizumab. Available clinical and translational data for all pts treated with NUC-7738 + pembrolizumab will be presented. Clinical trial information: NCT03428958 Citation Format: Sarah P Blagden, Stefan N Symeonides, Aglaia Skolariki, Noor Md Haris, Zhuang Boh, In Hwa Um, Mustafa Elshani, Alison L Dickson, Ying Zhang, David J Harrison, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Natalie Cook, TR Jeffry Evans, E. Ruth Plummer. NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C032.