The designation covers QTX3034 plus cetuximab with or without FOLFOX; phase 1 data showed a 25% confirmed ORR with the doublet in CRC and PDAC.
The FDA has granted fast track designation to QTX3034, an oral multi-KRAS inhibitor with preferential activity against the G12D variant, in combination with cetuximab (Erbitux) with or without FOLFOX (folinic acid, fluorouracil, and oxaliplatin) for the treatment of patients with KRAS G12D–mutated colorectal cancer (CRC).¹
Clinical data for the regimens will be presented in a rapid oral session on October 24, 2026, at the
“We believe this represents the first fast track designation based on clinical data for a KRAS G12D-targeted therapy in CRC,” Perry Nisen, MD, PhD, chief executive officer of Quanta Therapeutics, stated in a news release.
QTX3034 is a noncovalent, allosteric inhibitor of multiple KRAS variants, with preferential activity against KRAS G12D. It binds KRAS in its inactive state.² Inhibiting RAS(ON)–mitogen-activated protein kinase signaling induces compensatory feedback through EGFR, and upstream EGFR blockade is proposed to make trapping KRAS in the inactive state more efficient. Preclinical data presented at the 2023 AACR-NCI-EORTC conference showed synergy between QTX3034 and cetuximab in CRC and pancreatic ductal adenocarcinoma (PDAC) cell line–derived xenograft mouse models.
A phase 1 trial (NCT06227377) enrolled patients with locally advanced or metastatic cancers with a KRAS G12D mutation identified by local testing who had either progressed on standard therapy or were not candidates for it.2 QTX3034 monotherapy was evaluated in patients with advanced solid tumors, and the combination with cetuximab was evaluated in those with CRC, PDAC, or non–small cell lung cancer.
In part 1a, QTX3034 was escalated from 75 mg to 1200 mg twice daily in 42 patients, and in part 1b, 29 patients received cetuximab in combination with QTX3034 at 150 mg to 1200 mg twice daily (1200 mg, n = 12), guided by a Bayesian logistic regression model. The primary objectives were to assess safety and tolerability of QTX3034 and to identify the maximum tolerated dose (MTD) or recommended phase 2 dose of the agent. Secondary objectives included pharmacokinetics and antitumor activity.
At the September 23, 2025, data cutoff, 71 patients had been treated, with a median age of 57 years (range, 29-87), and 63% of patients had received at least 2 prior lines of therapy. The median safety follow-up was 7.0 months (range, 0.7-15.0), and the combination cohort (n = 29) comprised 20 patients with CRC (69%) and 9 with PDAC (31%).
QTX3034 Plus Cetuximab in KRAS G12D–Mutated Tumors: Highlights
Data presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics showed that QTX3034 at 1200 mg twice daily plus cetuximab produced an objective response rate (ORR) of 33%, including 3 confirmed responses (25%), across patients with CRC (n = 5) and PDAC (n = 7). The disease control rate (DCR) was 83% in the combined cohort and 60% in the CRC cohort. In the CRC cohort, the ORR was 40%, including 1 confirmed response.
Among evaluable patients treated with QTX3034 monotherapy at 1200 mg twice daily (n = 15), the confirmed ORR (cORR) was 13%, with both responses in patients with endometrial cancer (n = 2/3), and the DCR was 80%. No confirmed responses occurred in patients with PDAC (n = 8), although 6 of these patients (75%) had stable disease (SD).
In the combination cohort with QTX3034 dosed at 1200 mg twice daily (n = 12), the 33% ORR included unconfirmed responses with potential to confirm. In the CRC cohort, 1 patient had SD, and 2 had progressive disease (PD). In the PDAC cohort, the cORR was 29%, the DCR was 100%, and no patient had PD.
Reductions of more than 90% in KRAS G12D circulating tumor DNA were dose dependent, occurring in 47% of patients treated at any dose (n = 43) and 57% of those treated at 1200 mg twice daily (n = 23).
QTX3034 was orally bioavailable, and the 1200-mg twice-daily dose achieved more than 90% target inhibition. Treatment-related adverse effects (TRAEs) of any grade occurred in 86% of evaluable patients receiving QTX3034 monotherapy (n = 42), with grade 3 or higher TRAEs in 7% of patients. TRAEs were reported in 93% of evaluable patients receiving the combination (n = 29), with grade 3 or higher TRAEs in 24% of patients. The most common TRAEs were low-grade gastrointestinal effects, and additional grade 3 TRAEs with the combination included anaphylactic and infusion-related reactions attributed to cetuximab.
Dose reductions because of TRAEs occurred in 14% of patients receiving QTX3034 monotherapy and 21% of those receiving the combination, and 1 patient receiving QTX3034 monotherapy discontinued the agent because of a TRAE. No dose-limiting toxicities were observed, and the MTD was not reached.
Dose expansion in the phase 1 trial is ongoing in patients with endometrial cancer, PDAC, and CRC. Additional combinations, including with standard-of-care therapy, are also under exploration.
