83 Tumor immune microenvironment characterization from pre- and post-dose tumors collected from a phase 1/2 study of NDI-101150, a hematopoietic progenitor kinase 1 (HPK1) inhibitor

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Background NDI-101150, an oral, selective, small molecule inhibitor of HPK1, is being studied as monotherapy and in combination with pembrolizumab. HPK1, a MAP4K family kinase, negatively regulates T-, B-, and dendritic cells, with preclinical studies showing immune reactivation following treatment.1 In an ongoing phase 1/2 study in patients with advanced solid tumors, NDI-101150 treatment resulted in an acceptable safety profile and preliminary evidence of clinical benefit.2 In treated patients, the target engagement biomarker pSLP76 was inhibited by >50% in a whole blood assay at steady state for all cohorts, a level predicted preclinically to be efficacious. Here, we report immunophenotyping results from tumor biopsies collected pre- and post-treatment. Methods To explore the potential mechanism of action for NDI-101150, pre- and post-treatment (day 28) biopsies were mandated in the monotherapy expansion cohorts of the ongoing phase 1/2 study (NCT05128487). Analyses included a custom 12-plex U-VUE® panel (Ultivue), bulk RNA-sequencing (Tempus xR), and GeoMx® Digital Spatial Profiling (DSP; Cancer Whole Transcriptome). Additionally, tissue-associated pSLP76 was analyzed using a 2-plex (CD3 and pSLP76) immunofluorescent assay. Results As of May 15, 2024, matched pre- and post-dose biopsies were available from two patients with renal cell carcinoma (RCC) and two patients with gastric/gastroesophageal (G/GEJ) cancer. In three of the four matched samples, including an RCC patient with partial response and another with stable disease, tissue CD3+/pSLP76+ cells were reduced ≥75% post-treatment. Utilizing the immunofluorescent 12-plex assay, patients with reduced pSLP76 had increased expression (>2-fold [range 2.2–20.3X]) of CD4, CD8, granzyme B, and PD-1 post-treatment. When comparing different immunophenotypes of T-cell activation, >10-fold cell density increases were observed in CD8+/granzyme B+/Ki-67+ and CD8+/PD-1+ populations. In one patient with G/GEJ without modulation of tissue pSLP76, no changes in individual markers or immunophenotypes were observed. DSP analysis of RCC biopsies demonstrated that in CD45+ regions, immune gene expression increases were observed post-treatment, including upregulation of genes associated with activated cytotoxic T-cells (e.g. CD8A, CCL5, and HLA-DBP1). Finally, bulk RNA-sequencing demonstrated an increase in CD8+ T-cell signatures post-treatment, consistent with other methods. Characterization of an additional seven matched biopsy pairs is ongoing and will be presented. Additionally, correlation of baseline samples with clinical outcomes will explore potential predictive biomarkers. Conclusions Preliminary results from translational analyses support the proposed mechanism of action for NDI-101150, including inhibition of the proximal PD biomarker pSLP76, as well as modulation of the tumor immune microenvironment through increased CD8+ T-cell recruitment and activation. Acknowledgements This study is being sponsored by Nimbus Therapeutics (Nimbus Discovery Inc. on behalf of Nimbus Saturn Inc.). Medical writing services were provided by Melody Watson of Bioscript Stirling Ltd, Macclesfield, UK, and funded by Nimbus Therapeutics (Nimbus Discovery Inc. on behalf of Nimbus Saturn Inc.). Trial Registration NCT05128487. References Ciccone D, Kuo F-S, Boiko S, et al. NDI-101150 is a potent and highly selective hematopoietic progenitor kinase 1 (HPK1) inhibitor that promotes a robust and broad anti-tumor immune response. JITC 2023;11(Suppl. 1):1340. Noel M, Demel K, Srivastava B, et al. Phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: clinical update. ASCO 2024:P3083. Ethics Approval This multicenter study was approved by the relevant Ethics Board at each study site. All participants gave informed consent before taking part.

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