GFH375, an oral inhibitor targeting both the GTP- and GDP-bound states of KRAS G12D, was tested in a phase 1 dose-escalation and expansion trial in 74 patients with advanced solid tumours carrying the mutation, most with pancreatic ductal adenocarcinoma. The confirmed objective response rate was 35.1% (13/37) in pancreatic cancer, with median progression-free survival of 5.5 months and median overall survival of 9.9 months; in non-small cell lung cancer the response rate was 35.7%. Grade 3 or worse treatment-related adverse events occurred in 36.5% of patients, with one treatment-related death from septic shock.
Why it is interesting: KRAS G12D is the commonest RAS mutation and long considered undruggable; a single-agent response rate above 30% in previously treated pancreatic cancer is the first signal of that changing.