At the ESMO 2025 Congress, researchers presented exciting new developments in pancreatic cancer (PC) treatment, including advances in targeted therapy with a special focus on a promising KRAS inhibitor for tumours with the KRAS G12D mutation, as well as encouraging results with antibody-drug conjugates (ADCs) and oncolytic viruses.

Key Highlights:

Targeted Therapies and Biomarkers

• KRAS G12D-targeted therapy: KRAS mutations, particularly the G12D variant, are the most common on pancreatic ductal adenocarcinoma (PDAC) and predicting a poorer prognosis. 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. In an ongoing clinical trial, 66 patients with advanced PDAC carrying the KRAS G12D mutation were treated with a new pill called GFH375. The results showed that about 41% of patients had their tumours shrink, 97% saw their disease either improve or stay stable and after 141 days of follow-up, 83% of patients were still doing well at the 3-month mark. GFH375 demonstrated a manageable safety profile. Common treatment-related side effects included diarrhoea, neutrophil count decreases, nausea, and anaemia with few severe events leading to dose reduction or discontinuation. Most of these patients had already tried several other treatments, so these results suggest that GFH375 could offer real hope for people with few remaining options.

Antibody-drug conjugates (ADCs) and Oncolytic Viruses:

• Telisotuzumab adizutecan (ABBV-400 or TEMAB-A), an antibody-drug conjugate (ADC), showed promising activity in a phase I basket study, with nearly 25% of previously treated patients with advanced or metastatic PDAC responding to treatment, meaning their tumours shrank.  In 42 patients who received TEMAB-A in the second-line setting, the response lasted about 7 months and patients went about 5.4 months before their cancer started growing again. Patients (15) who had previously received gemcitabine–nab-paclitaxel responded better (40%) than those (26) who had FOLFIRINOX (15%). Treatment-related adverse events (TRAEs) led to discontinuation of treatment in 14% of patients, pause in 38% and dose reductions in 48% of patients. Overall, the results are encouraging and show that TEMAB-A may offer hope for patients with few treatment options.

• The VIRAGE trial used a new oncolytic adenovirus VCN‑01 (zabilugene almadenorepvec) added to standard chemotherapy (gemcitabine–nab-paclitaxel) in patients with newly diagnosed metastatic PDAC. It was a randomized trial, meaning patients were randomly assigned to different treatment groups and also open-label, so both doctors and patients knew which treatment they were receiving. Patients who received VCN-01 with chemotherapy lived longer and responded better to treatment than those who got chemotherapy alone. About 40% of patients responded to the combination treatment, compared to 31% with chemotherapy alone. On average, patients lived 10.8 months with the combination treatment, versus 8.6 months with chemotherapy alone. Treatment-related adverse effects (TRAEs) after the first VCN-01 dose were transaminase (liver enzymes) increases (15.1%) and flu-like symptoms (13.2%).

Early detection and surveillance, liquid biopsy:

• The “Breaking boundaries in pancreatic cancer” session included talks on surveillance in risk populations (e.g., genetic predisposition, family history of PC or carry inherited genetic mutations such as CDKN2A, BRCA2, PALB2, or ATM, and precursor lesions) and the emerging role of liquid biopsy both in early disease and advanced settings.
• As mentioned by Prof. Thierry Conroy in his ESMO Award lecture “When science meets hope: Breakthroughs in academic pancreatic cancer trials”, a major barrier in PDAC remains late diagnosis (50-60% present with metastatic disease), limiting curative opportunities. Conroy highlighted that early diagnosis and surveillance must become a central focus in the fight against PC. He called for the development of reliable tumour markers and effective tools for early detection, describing these as among the most urgent unmet needs in the field. Another theme in his lecture was the importance of quality of life and multidisciplinary care. His message combined optimism and realism: science is bringing new hope, but continued collaboration and innovation are essential to truly transform outcomes in pancreatic cancer.

References

Zhou A et al. Efficacy and safety of GFH375 monotherapy in previously treated advanced KRAS G12D-mutant pancreatic ductal adenocarcinoma. ESMO Congress 2025 – Abstract 915O

Harding JJ, et al. Phase 1 basket study of telisotuzumab adizutecan (ABBV-400; TEMAB-A), a c-MET protein–targeting antibody-drug conjugate: results from patients (pts) with pancreatic ductal adenocarcinoma (PDAC). ESMO Congress 2025 – Abstract 2214MO

Garcia-Carbonero R, et al. VIRAGE trial: Randomized Phase IIB, open-label, study of nab-paclitaxel and gemcitabine with/without intravenous VCN-01 in patients with metastatic pancreatic cancer (mPDAC). ESMO Congress 2025 – Abstract 2216MO

Author:

Ana Martins