NDI-101150 Demonstrates Antitumor Activity, Safety in Heavily Pretreated RCC

Treatment with NDI-101150 monotherapy showed antitumor activity in a subset of patients with heavily pretreated renal cell carcinoma (RCC) and was generally well tolerated both alone and in combination with pembrolizumab (Keytruda) among patients with advanced solid tumors, according to data from a phase 1/2 study (NCT05128487) shared in a poster presentation at the 2024 SITC Annual Meeting.

As of August 12, 2024, NDI-101150 monotherapy produced an objective response rate of 18% among 17 patients with RCC, comprising 1 complete response (CR; 6%) and 2 partial responses (PR; 12%). All patients with a CR or PR had progressed on 1 or more prior checkpoint inhibitors. Additionally, the clinical benefit rate was 29% and the disease control rate was 65%. Stable disease was achieved by 47% of patients, 12% of which were considered durable; progressive disease was experienced by 35%.

“NDI-101150 was generally well tolerated,” study authors wrote in the poster. “NDI-101150 continues to demonstrate encouraging antitumor activity in patients with RCC and an acceptable safety profile, supporting continued clinical evaluation of NDI-101150…as a promising next-generation immunotherapy small molecule.”

NDI-101150 is a potent, selective oral inhibitor of HPK1, an immuno-oncology target with a pivotal role in T-cell activation and tumor microenvironment modulation. In preclinical studies, the inhibition of HPK1 enhanced T-cell receptor signaling, promoting immune responses against cancer cells. Preliminary clinical analyses of the agent showed an acceptable safety profile and early signals of efficacy in patients with advanced solid tumors. Therefore, investigators evaluated NDI-101150 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

This multicenter, open-label, dose-escalation/ dose-expansion trial is designed to determine the recommended phase 2 dose (RP2D) of NDI-101150 and assess the agent’s efficacy across specific tumor types. In the dose-escalation phase, investigators are evaluating the safety, tolerability, and RP2D of NDI-101150 alone and in combination with pembrolizumab in all-comers with advanced solid tumors. In the dose-expansion phase, cohorts are stratified by tumor type, including RCC, non–small cell lung cancer, and gastric/gastroesophageal junction cancers.

In the monotherapy arm of the study (n = 76), NDI-101150 is administered once daily at escalating doses ranging from 50 mg to 200 mg. In the combination arm (n = 12), NDI-101150 is administered at a dose of 50 mg or 100 mg alongside 200 mg of pembrolizumab once daily.

At the data cutoff, 53 patients had been dosed in the dose escalation cohorts, with 41 receiving NDI-101150 monotherapy and 12 receiving NDI-101150 plus pembrolizumab; 35 patients had been dosed in the NDI-101150 monotherapy dose expansion cohorts. Additionally, the efficacy analysis set was comprised of 17 patients, all of whom were patients with RCC, 1 or more post-baseline assessment, and who received NDI-101150 monotherapy.

The median age of patients enrolled onto the trial was 66 years (range, 21-87) and 57% of patients were male. The most common tumor types were RCC (n = 24; 27%), NSCLC (n = 14; 16%), gastric/GEJ (n = 10; 11%), and colorectal cancer (n = 7; 8%).

The median number of prior treatments in the safety analysis set (n = 88) was 3 (range, 1-10); in the efficacy analysis set, which comprised the RCC cohort, the median number of prior treatments was 3 (range, 1-7).

One or more any-grade adverse effects (AE) related to NDI-101150 (TRAEs) were observed in 80% of patients in the safety analysis set. Overall, the most common any-grade TRAEs were nausea (41%), diarrhea (34%), vomiting (31%), and fatigue (26%). Additional TRAEs reported include anemia (8%), blood creatine increase (6%), constipation (6%), platelet count decrease (6%), pruritus (6%), abdominal pain (5%), decreased appetite (5%), and rash (5%).

Grade 3 TRAEs occurred in 14% of patients and consisted of fatigue (2%), diarrhea (1%), constipation (1%), colitis (1%), hypersensitivity (1%), aspartate aminotransferase level increase (1%), platelet count decrease (1%), hypokalemia (1%), acute kidney injury (1%), proteinuria (1%), dyspnea (1%), hypoxia (1%), immune-mediated lung disease (1%), pneumonitis (1%), and nephritis (1%). Additionally, 1 patient (1%) experienced a grade 4 TRAE of aplastic anemia; all other TRAEs were grade 1 or 2.

The most frequent any-grade immune-related (IR)–TRAEs, as determined by the investigator, included diarrhea (7%), vomiting (5%), rash (5%), colitis (3%), and nausea (3%). In total, 9% of patients experienced at least 1 grade 3 or higher IR-TRAE, most of whom were receiving NDI-101150 at 200 mg (33%). Grade 3 IR-TRAE's included acute kidney injury (1%), aplastic anemia (1%), elevated aspartate aminotransferase (1%), colitis (1%), hypersensitivity (1%), hypoxia (1%), immune-mediated lung disease (1%), platelet count decrease (1%), pneumonitis (1%), and nephritis (1%).

Reference

Sommerhalder D, Demel K, Noel MS, et al. Ongoing phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: clinical safety update and renal cell carcinoma (RCC) efficacy analysis. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX.