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Two KRAS G12D inhibitors — INCB161734 and VS-7375 — are delivering impressive early results in one of oncology's toughest cancers. In combination with standard chemotherapy, INCB161734 hit response rates as high as 89% in first-line pancreatic ductal adenocarcinoma (PDAC). Meanwhile, VS-7375 monotherapy achieved a 50% confirmed response rate in second-line PDAC — with two complete responses. Both drugs are now advancing to phase 3 trials.
Two KRAS G12D inhibitors are generating significant momentum in pancreatic cancer, a disease historically resistant to targeted therapy. Updated phase 1 data for INCB161734 — presented at the 2026 ESMO Congress — showed that when combined with standard chemotherapy (gemcitabine/nab-paclitaxel or mFOLFIRINOX), the oral KRAS G12D inhibitor achieved objective response rates of 69% and 89%, respectively, in first-line advanced or metastatic PDAC. Disease control rates hit 96–100%, and 6-month progression-free survival reached 80–90%. Molecular responses (≥90% reduction in KRAS G12D variant allele frequency) were seen in approximately 70% of patients.
Separately, VS-7375 from Verastem Oncology posted a 50% confirmed ORR in second-line PDAC at the 900 mg dose, including two complete responses — a rare achievement in this setting. Its safety profile was notably favorable, with only 2% of patients discontinuing due to adverse events.
By the Numbers
Why it matters: KRAS G12D mutations drive approximately 40% of PDAC cases, yet targeted treatment options have been nearly nonexistent. These early results suggest a potential paradigm shift is on the horizon, with phase 3 trials (DAWN-303 for INCB161734 and TARGET-D 301 for VS-7375) now underway or planned.
