Dr Garrido-Laguna on the Efficacy and Safety of QTX3034-Based Combinations in KRAS G12D–Mutated CRC

“Both the depth and the rate of responses were improved with the addition of the [FOLFOX] backbone [to QTX3034 plus cetuximab].”

Ignacio Garrido-Laguna, MD, PhD, MBA, the Founding Chair of the Department of Early Therapeutics at Moffitt Cancer Center, discussed preliminary findings from a phase 1 trial (NCT06227377) evaluating the oral, G12D-preferring KRAS inhibitor QTX3034 in combination with cetuximab (Erbitux) with or without mFOLFOX6 in patients with KRAS G12D–mutated colorectal cancer, as well as where QTX3034-based combinations may fit among emerging KRAS G12D inhibitors.

At the 2026 ESMO Congress, Garrido-Laguna presented early phase 1 data for QTX3034, an oral, G12D-preferring multi-KRAS inhibitor. The study tested QTX3034 with cetuximab, with or without mFOLFOX6, in patients with KRAS G12D–mutated colorectal cancer (CRC). In an interview, he discussed what chemotherapy added, how it affected tolerability, and where the regimen may fit in a growing field.

Garrido-Laguna said that adding the FOLFOX backbone to QTX3034 plus cetuximab improved both the depth and rate of responses. The triplet produced a 50% objective response rate among 10 evaluable patients, including 1 complete response. The doublet produced a 25% objective response rate among 20 evaluable patients, with no complete responses. He cautioned that the numbers are small and more patients are needed. The complete response occurred in a chemotherapy-naive patient, while most patients who received the triplet had previously been treated with oxaliplatin.

Most treatment-related adverse effects were grade 1 or 2. Grade 3 or higher events rose from 24% with the doublet to 43% with the triplet at 1200 mg twice daily. Garrido-Laguna called the increase relatively mild. No patients stopped the triplet because of toxicity, and dose reductions rose from 14% with the doublet to 29% with the triplet, which he considered in line with other RAS inhibitors.

Garrido-Laguna noted these are the first data combining a RAS inhibitor with a chemotherapy backbone in CRC. He also acknowledged a limitation: QTX3034 targets KRAS in its inactive “off” state, but G12D-mutant KRAS mostly sits in the active “on” state. Additional data presented at the meeting demonstrated an objective response rate of 36% with INCB161734 plus cetuximab in heavily pretreated KRAS G12D–mutant CRC, vs 25% for QTX3034 plus cetuximab. While cautioning against cross-trial comparisons, he suggested inhibitors targeting both states may have an advantage.

Notably, the combination of QTX3034 plus cetuximab has received FDA fast track designation for KRAS G12D–mutated CRC, and investigators plan to explore it in earlier lines of therapy.