The inhibition of Hematopoietic Progenitor Kinase 1 (HPK1) is gaining traction as a method to boost the effectiveness of immune checkpoint inhibitors (ICIs) in treating solid tumors. Preclinical studies suggest that HPK1 inhibitors can enhance the antitumor activity of ICIs, leading to the development of combination strategies aimed at improving patient outcomes. Several HPK1 inhibitors are currently in phase 1/2 trials to evaluate their ability to expand on the efficacy of ICIs.
HPK1 as a Target for Immuno-Oncology
HPK1, a serine/threonine kinase crucial in hematopoiesis and a member of the MAP4K family, has become a promising target because its inhibition can alleviate T-cell exhaustion, enhance T-cell functionality, and improve immunotherapy efficacy. It acts as an intracellular negative regulator primarily in hematopoietic lineage cells, negatively regulating T cells, B cells, and dendritic cells. Loss of HPK1 kinase activity leads to increased cytokine secretion, enhanced T-cell signaling, and improved viral clearance, which has been observed to restrain tumor growth.
According to Dr. Anita Scheuber, Senior Vice President and Therapeutic Area Head of Oncology at Nimbus Therapeutics, there is significant interest from both large and small companies in studying HPK1 inhibitors, recognizing their potential to engage immune cells beyond just T cells, including B cells and dendritic cells.
Challenges in targeting HPK1 include limited selectivity, uncertainty regarding the non-kinase scaffold functions of HPK1, and insufficient immune stimulation. NDI-101150, a novel inhibitor, is currently under investigation in phase 1/2 trials and has shown early efficacy, particularly in patients with renal cell carcinoma (RCC).
NDI-101150: Early Clinical Efficacy
NDI-101150, an oral, highly selective, small molecule HPK1 inhibitor, is being evaluated both as a monotherapy and in combination with pembrolizumab (Keytruda) in a phase 1/2 trial (NCT05128487). The dose-escalation phase assessed the monotherapy and doublet in patients with advanced solid tumors, while the expansion phase is evaluating both regimens in disease-specific cohorts.
Early clinical efficacy signals during dose escalation, including a complete response (CR) at the lowest dose, led to a focus on specific patient populations in the expansion cohort. Currently, there are three active dose expansion cohorts open for RCC, non-small cell lung cancer (NSCLC), and gastric/gastroesophageal junction indications. Two different doses are being tested in the RCC cohort due to the early signals observed.
Data presented at the 2024 American Society of Clinical Oncology Annual Meeting included results from 44 patients in the dose-escalation cohort (as of March 18, 2024) and 15 patients in the expansion cohorts. Among response-evaluable patients who received NDI-101150 monotherapy (n = 30), 16.7% experienced clinical benefit. One patient with clear cell RCC achieved a CR approximately 15 weeks after the first dose at 50 mg, with disease progression occurring approximately 40 weeks later. Another patient with clear cell RCC treated with the 100-mg dose experienced an ongoing partial response.
Most activity has been observed in RCC, with other cohorts still early to report. Some tumor shrinkage has been noted in other tumor types, although patients did not achieve partial or complete responses at the time of the report. Of the eight enrolled patients with RCC, six achieved a best overall response of stable disease (SD) or better, and one patient experienced SD for 21 months. Additionally, SD lasting at least six months occurred in three patients: one with RCC, one with pancreatic cancer, and one with endometrial cancer. An increase in activated CD8-positive cells and dendritic cells was also observed in on-treatment biopsies compared to archival biopsies.
Combination Strategies and Safety
Combination therapy cohorts with pembrolizumab are ongoing. HPK1 inhibition increases PD-1 expression on T cells, potentially synergizing with PD-1 inhibitors. In a phase 1 trial (NCT04649385), the addition of BGB-15025 to tislelizumab-jsgr (Tevimbra) showed early efficacy, with an objective response rate of 18.4% in patients treated with the doublet (n = 49), compared to no responses in the BGB-15025 monotherapy arm (n = 60). The disease control rate was 57.1% with the combination vs 35.0% with the monotherapy.
Safety findings for NDI-101150 showed that the most common any-grade treatment-related adverse events (TRAEs) in the safety population (n = 59) were diarrhea (39.0%), nausea (39.0%), vomiting (30.5%), fatigue (23.7%), and anemia (8.5%). The 200-mg dose of the agent was not tolerated. TRAEs greater than grade 3 were rare and mostly immune-related.
Ongoing and Future Studies
The combination of BGB-15025 plus tislelizumab is under evaluation in the phase 1b expansion portion of the trial, and a phase 2 international umbrella study (NCT05635708) in patients with NSCLC is also ongoing. New findings on NDI-101150, including efficacy data from the RCC patient population, will be presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting. The experimental HPK1 inhibitor GRC 54276 is being evaluated in a first-in-human phase 1/2 trial (NCT05878691), and another first-in-human phase 1/2 study (NCT04521413) is enrolling patients with advanced solid malignancies to receive the HPK1 inhibitor CFI-402411 as monotherapy and in combination with pembrolizumab.
Despite advancements in RCC treatment, there remains a significant unmet need for patients who relapse on standard-of-care therapies. The observed activity with NDI-101150 is encouraging, highlighting the urgent need for new drug solutions in oncology.
