What question did this study set out to answer?

The study aims to evaluate the efficacy of INCB161734, a KRAS G12D inhibitor, in combination therapies for pancreatic ductal adenocarcinoma (PDAC).

April 4, 2026Open Access

109P Zongertinib for previously treated HER2-mutant advanced non-small cell lung cancer: A single center experience

Puntos clave

The study aims to evaluate the efficacy of INCB161734, a KRAS G12D inhibitor, in combination therapies for pancreatic ductal adenocarcinoma (PDAC).
Conducted phase 1 study involving mouse models with subcutaneous PDAC tumors.
Tested combinations of INCB161734 with various chemotherapies and immune checkpoint inhibitors.
Assessed anti-tumor activity in both immune-competent and immune-deficient mice.
Combination therapies, especially with chemotherapy, significantly improved anti-tumor activity compared to monotherapy.
Greater tumor growth inhibition was observed with INCB161734 and cetuximab than with INCB161734 alone.
90% of animals treated with INCB161734 and anti-PD-(L)1 antibodies showed complete or near-complete tumor regressions.

Resumen

Background: KRAS G12D mutation is found in 40% of pancreatic ductal adenocarcinomas (PDACs); however, there are no approved agents targeting KRAS G12D .INCB161734 is a potent, selective, and orally bioavailable KRAS G12D inhibitor being assessed in a phase 1 study (NCT06179160).Early efficacy outcomes for KRAS G12D inhibitors, including INCB161734, are encouraging, although fewer than half of PDAC patients experience clinical response.We investigated whether INCB161734 combination therapies might improve therapeutic outcomes.Methods: INCB161734-based combinations were tested in mice bearing subcutaneous PDAC tumours (xenograft and/or syngeneic).Combinations included INCB161734 with chemotherapy (gemcitabine + nab-paclitaxel or 5-fluorouracil + irinotecan + oxaliplatin + leucovorin), the epidermal growth factor receptor (EGFR) antagonist cetuximab, or anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies.Animal studies were conducted under the supervision of the INCYTE Institutional Animal Care and Use Committee.Results: INCB161734 with either chemotherapy regimen improved anti-tumour activity compared with monotherapy.Chemotherapy combinations were more effective in immune-competent than immune-deficient mouse models, suggesting an immunomodulatory aspect of KRAS G12D inhibition.INCB161734 + cetuximab resulted in greater tumour growth inhibition than monotherapy, likely by preventing EGFRinduced (re)activation of wild-type RAS signalling.Finally, combining INCB161734 with anti-PD-(L)1 antibodies resulted in complete or near-complete tumour regressions in 90% of treated animals, with 80% of animals remaining tumour-free for 60 days after the end of treatment, further suggesting an immunomodulatory impact KRAS G12D inhibition.All combinations were well tolerated. Conclusions:These results demonstrate that KRAS G12D blockade via INCB161734 combined with chemotherapy, EGFR signalling disruption, or immune checkpoint blockade via PD-1/PD-L1 may have the potential to improve therapeutic efficacy in PDAC.

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