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Oncogenic KRAS mutations, particularly the G12D variant, are the most common drivers of pancreatic ductal adenocarcinoma (PDAC), accounting for roughly 40% of cases and predicting a poorer prognosis. This mutation is a crucial target for new therapies aiming to improve outcomes in this aggressive cancer type. GFH375 is a novel oral targeted therapy specifically designed to selectively inhibit KRAS G12D. It has shown encouraging early results in patients with previously treated advanced PDAC, offering new hope where treatment options have been limited.

Promising Clinical Trial Results

In an ongoing phase I/II study, 66 patients with KRAS G12D-mutant PDAC received daily doses of GFH375. The results so far have been remarkable: the objective response rate reached 41%, while the disease control rate stood at 97%. After a median follow-up of 141 days, progression-free survival at three months was 83%. Considering most participants had undergone multiple prior lines of therapy, these findings indicate the potential of GFH375 to deliver significant clinical benefit in a heavily pre-treated population.

Manageable Safety Profile

GFH375 demonstrated a manageable safety profile. Common treatment-related side effects included diarrhoea, neutrophil count decreases, nausea, and anemia, with few severe events leading to dose reduction or discontinuation.

Biomarker Insights and Future Outlook

Analysis of circulating tumour DNA revealed that 71% of patients had detectable KRAS G12D mutations in plasma, often accompanied by co-mutations in TP53, CDKN2A, and SMAD4. These biomarker findings may provide valuable insights into treatment response and disease progression. GFH375 continues to be evaluated in this trial and could represent a new targeted option for KRAS G12D–mutant pancreatic cancer as longer-term data emerge. Further study will clarify GFH375’s full potential and impact.

Reference

Zhou A et al. Efficacy and safety of GFH375 monotherapy in previously treated advanced KRAS G12D-mutant pancreatic ductal adenocarcinoma. ESMO; 17-21 October, Berlin, Germany.