Background NDI-101150 is a potent, selective, oral inhibitor of hematopoietic progenitor kinase 1 (HPK1), with an immunotherapy mechanism distinct from checkpoint inhibitors. NDI-101150 activates the anti-tumor activity of T-cells, B-cells, and dendritic cells, even under immunosuppressive conditions.

Methods This first-in-human, multicenter, open-label, phase 1/2, dose escalation/expansion trial is assessing NDI-101150 (50–200 mg once-daily in 28-day cycles) alone and in combination with pembrolizumab (200 mg/dose) in patients with relapsed or metastatic solid tumors. NDI-101150 monotherapy expansion cohorts in patients with RCC, non-small cell lung cancer, and gastric/gastroesophageal cancer are also being assessed. Here, we report safety and pharmacokinetic data, as of March 18, 2024, from the dose escalation/expansion phase as well as efficacy data in patients with RCC. Updated data, including for additional patients with RCC, will be presented.

Results The safety analysis set comprised 59 patients. The most common any-grade adverse events considered related to NDI-101150 (TRAEs) were nausea, diarrhea, vomiting, and fatigue; most TRAEs were grade ≤2 (table 1). The most frequent any-grade immune-related TRAEs (IR-TRAEs) (as reported by the investigators) were diarrhea, vomiting, rash, constipation, and nausea; six (10.2%) patients experienced a grade ≥3 IR-TRAE including colitis, aspartate aminotransferase increased, hypersensitivity, immune-mediated lung disease, platelet count decreased, and proteinuria.

There were eight response-evaluable patients with RCC across the escalation and expansion monotherapy cohorts, seven of whom had received immune checkpoint inhibitors as prior lines of therapy. NDI-101150 demonstrated an overall response rate of 25%, which included a complete response in one patient at 50 mg and a partial response in another patient at 100 mg. Additionally, a disease control rate of 75% (best overall response of stable disease [SD] or better) was observed, which included durable SD (≥6 months) for 21 months in a patient at 140 mg.

Nearly dose-proportional increases in exposure were observed on day 1 of cycle 1 across NDI-101150 50–150 mg, with steady state achieved between days 15 and 28. Pharmacokinetic exposure profiles for monotherapy and combination arms were similar. By day 15 of cycle 1, sustained inhibition of pSLP76, a biomarker of HPK1 inhibition, of >50% relative to pre-treatment levels (predicted to achieve efficacy in nonclinical models) was observed at all doses tested.

Conclusions The observed safety profile and preliminary clinical benefit in patients with RCC support continued evaluation of NDI-101150 as a differentiated next-generation immunotherapeutic in RCC and potentially other tumor types.

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.

Ethics Approval This multicenter study was approved by the relevant Ethics Board at each study site. All participants gave informed consent before taking part.