Ongoing phase 1/2 trial of the hematopoietic progenitor kinase 1 (HPK1) inhibitor NDI-101150 as monotherapy or in combination with pembrolizumab: Clinical safety and efficacy update in clear cell renal cell carcinoma (ccRCC).

4537 Background: NDI-101150 is a potent and selective oral inhibitor of HPK1, a serine/threonine kinase that acts as a negative regulator of immune cell function. Pre-clinically, NDI-101150 can enhance immune cell function, leading to potent anti-tumor immunity. Methods: NDI-101150 is currently being investigated in a first-in-human, multi-center, open-label, phase 1/2 trial (NCT05128487) in patients with advanced solid tumors, as a monotherapy (50–200 mg once daily [QD]) or in combination with pembrolizumab (50–100 mg QD NDI-101150 + 200 mg Q3W pembrolizumab). Results: As of 20 November 2024, 106 patients were dosed [NDI-101150 monotherapy (n = 94) or NDI-101150 + pembrolizumab (n = 12)]. The tumor types were RCC (n = 38), NSCLC (n = 17), gastric/GEJ (n = 12), and other solid tumors (n = 39). We report here updated safety data in all patients from monotherapy and combination arms (n = 106), and efficacy data in patients with ccRCC (n = 29) receiving NDI-101150 monotherapy. NDI-101150 monotherapy was generally well tolerated, with 150 mg identified as the maximum tolerated dose. The most common treatment-related adverse events (TRAEs) of any grade were nausea (39%), diarrhea (35%), vomiting (29%), fatigue (27%), and anemia (11%). Grade ≥3 TRAEs occurred in 13 (14%) patients, of which only 1 (1%) patient experienced a grade 4 TRAE. The safety profile was comparable in the combination cohort, with 2 (17%) patients experiencing Grade ≥3 TRAE. 20 of the 29 ccRCC patients who received 50, 100, 140, or 150 mg of NDI-101150 monotherapy were response-evaluable. The objective response rate was 15.0% [CR, n = 1 and PR, n = 2]. Clinical benefit rate (CR + PR + SD ≥6 months) was 25%, which includes 2 patients who experienced durable SD for ~9 months and ~25 months. The disease control rate (CR+PR+SD) was 60%. The ccRCC patients had received a median of 2 (1-9) lines of prior therapy. A nearly dose-proportional increase in NDI-101150 exposure was observed at day 1, with steady state achieved by day 15. At all doses tested, steady state exposures inhibited the pharmacodynamic biomarker pSLP76 by > 50% and for a period consistent with preclinical efficacy predictions. To demonstrate proof of biology, a custom 12-plex immunofluorescence panel and the GeoMx whole transcriptomic assay were utilized. By day 28, on-treatment tumor biopsy samples showed immune activation when compared to pre-treatment samples, including an increased infiltration of activated CD8+ T-cells and dendritic cells. Conclusions: NDI-101150 continues to demonstrate an acceptable safety profile and encouraging antitumor activity in patients with ccRCC, supporting continued clinical development of NDI-101150 as monotherapy and in combination with other agents as a promising next-generation immunotherapy oral small molecule. Clinical trial information: NCT05128487 .