Novel HP1K Inhibitor Shows Favorable Responses in ccRCC, Solid Tumors

The HPK1 inhibitor NDI-101150 achieved “impressive” single-agent activity and a manageable safety profile as a monotherapy and in combination with pembrolizumab (Keytruda) among patients with advanced solid tumors, including clear cell renal cell carcinoma (ccRCC), in a phase 1/2 trial (NCT05128487) published in Cell Reports Medicine.¹

Among patients treated with NDI-101150 in the response-evaluable population (n = 77), patients with RCC experienced the best response outcomes. Specifically, among 22 patients with clear cell histology, 3 (13.6%; 95% CI, 2.9%-34.9%) experienced a response, including 1 patient who attained a complete response (CR) in the 50 mg cohort. The 2 partial responses (PRs) among this ccRCC population occurred in the 100 mg cohort.

An additional 3 patients experienced durable stable disease for approximately 8, 11, and 25 months, for a clinical benefit rate of 27.3% (95% CI, 10.7%-50.2%). A total of 12 patients experienced disease control for a rate of 54.5% (95% CI, 32.25%-75.6%).

“We studied a very hard-to-treat population,” said David Braun, MD, PhD, assistant professor of medicine (medical oncology), pathology, and urology, the Louis Goodman and Alfred Gilman Yale Scholar, and the study’s lead author, in a news release on the study findings.² “The fact that this drug was clinically active and leading to some responses is really encouraging.”

Patients with advanced solid tumors (n = 106), including ccRCC, non-ccRCC, gastric or gastroesophageal junction (G/GEJ) cancer, and non–small cell lung cancer (NSCLC), among others, were assigned to receive NDI-101150 alone or in combination with pembrolizumab. A total of 53 patients were enrolled in the dose escalation phase and received 50 mg, 100 mg, 140 mg, 150 mg, or 200 mg of once daily NDI-101150, or 50 to 100 mg of NDI-101150 with 200 mg of pembrolizumab given intravenously every 3 weeks. An additional 53 patients were treated in the dose expansion phase; those with RCC were given 100 mg or 150 mg of NDI-101150, and those with G/GEJ cancer were given 100 mg, both without pembrolizumab.

Those who received NDI-101150 in the study were enrolled between November 3, 2021, and November 11, 2024, of whom 94 received NDI-101150 monotherapy and 12 received additional pembrolizumab. RCC (36%), NSCLC (16%), and G/GEJ cancer (11%) accounted for the most common tumor types, with others including pancreatic, colorectal, endometrial, melanoma, ovarian, anal, tonsil, uterine, chondrosarcoma, and soft tissue sarcoma. A total of 56.4% of patients were male, and the median age was 66 years (range, 21-90).

The primary end point of phase 1 of the study was the incidence of dose-limiting toxicities (DLTs); in part 2 of the study, it was objective response rate.³ Secondary end points included incidence of adverse effects (AEs), plasma concentration, area under the concentration-time curve, progression-free survival, and duration of response.

Among patients in the monotherapy cohort, 79% experienced any-grade treatment-related AEs (TRAEs), the most common of which included nausea (43%), diarrhea (35%), vomiting (29%), fatigue (29%), and anemia (11%). A total of 14% of patients experienced grade 3 or higher TRAEs, including 1 grade 4 aplastic anemia event. In the 200 mg arm, 3 patients experienced DLTs, including acute kidney injury, pneumonitis, and fatigue, all grade 3 in severity. The maximum tolerated dose (MTD) was identified as 150 mg.

In the combination pembrolizumab cohort, the investigators noted that the safety profile was similar, with 8% of patients experiencing grade 3 or higher constipation and elevated aspartate aminotransferase. Combinability was feasible up to 100 mg of NDI-101150, with no MTD established.

"Advanced kidney cancer used to be a uniformly deadly disease, so the fact that these drugs are helping people generally live much longer and potentially even curing a small number of people is really important,” Braun added in the release.²

References

1. Braun DA, Noel MS, Moy RH, et al. HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: phase 1/2 trial results. Cell Rep Med. Published May 6, 2026. doi:10.1016/j.xcrm.2026.102789
2. Beckman I. Novel drug shows promise for treating advanced kidney cancer. News release. Yale School of Medicine. May 7, 2026. Accessed May 11, 2026. https://tinyurl.com/y88msfts
3. A study of NDI 1150-101 in patients with solid tumors. ClinicalTrials.gov. Updated November 25, 2026. Accessed May 11, 2026. https://tinyurl.com/mryufu7j