ASCO 2025 | New HPK1 inhibitor shows promise in treating advanced kidney cancer after PD-1 therapy failure

There’s a substantial clinical need for patients who have progressed on anti-PD-1 therapy, and in kidney cancer, we really don’t have another effective immune therapy after that. And so there’s an ongoing search. And in the laboratory, in mice, there’s been a lot of promise of this target HPK1. This is a target within T cells, but also in B cells and dendritic cells that really limit immune activity. So in a mouse, knocking out that gene has really improved anti-cancer activity. So the question is, would this translate into humans? So this was a first-in-human study, a phase 1-2 of a very specific HPK1 inhibitor, NDI-101-150, across solid tumors, but really with clinical activity in kidney cancer. Briefly, this was safe, both as a monotherapy, but actually in combination with pembrolizumab as well, sort of highlighting its potential combinability. And it really did show clinical activity within clear cell renal carcinoma. One patient had a complete response, two patients had partial responses, and an additional three patients had stable disease that was really long lasting. In one case, up to about two years. And so this shows that even in an anti-PD-1 refractory setting, which all of these patients were, immunotherapies still have viability in clinical activity. I think importantly, this drug also demonstrated clear on-target activity, a specific measure for this protein, which is phosphorylation of SLP76, and this drug really hit its target. And within the tumor microenvironment as well, it led to an influx of cytotoxic and proliferative CD8 T cells. So overall, this is a new mechanism for immune therapy, showed promise in preclinical settings, and this is really the first clinical setting where it’s shown clinical activity and on-target activity.