601TiP - A multicenter randomized clinical trial evaluating the negative hyperselection of patients with RAS/BRAF wild-type metastatic colorectal cancer who are eligible for anti-EGFR therapy

Background

Currently, the treatment of mCRC is chosen following the routine RAS/BRAF testing, with cetuximab/panitumumab (anti-EGFR) or bevacizumab (Bev) added to chemotherapy used as primary systemic treatment options. Findings from PARADIGM and PRESSING have suggested resistance mechanisms to anti-EGFR beyond RAS/BRAF, and the efficacy of systemic treatment for mCRC based on other mutations is unclear. To test the hypothesis of a negative hyperselection (HS) of mCRC pts for optimizing anti-EGFR, a randomized trial was initiated.

Trial design

This is a multicenter randomized trial evaluating the contribution of HS (mutations beyond RAS/BRAF V600) to anti-EGFR resistance. Pts with untreated left-sided RAS/BRAFV600-wt mCRC who are candidates for anti-EGFR are eligible. Pts will be randomized in 1:1 ratio to cohorts A (n≈177) or BC (n≈177). Pts in cohort A will receive FOLFOX + anti-EGFR. Upon treatment completion, pts in cohort A will undergo comprehensive genomic profiling (GP), and will be divided into cohort A1 (n≈120) - HS-pts and cohort A2 (n≈40), HS+. Pts recruited to cohort BC will start FOLFOX, and will undergo CGP. Based on the results of CGP, pts will be further randomized to cohorts B (n≈120, HS-) or C (n≈40, HS+). In addition to FOLFOX, in cohort B, pts will receive anti-EGFR, and in cohort C, pts will either continue FOLFOX alone or in combination with Bev. Treatment outcomes in cohorts A2 vs C, and A vs BC will be compared. Pts will be treated until PD, withdrawal, death or toxicity. The primary endpoint is PFS in the ITT, secondary endpoints are the frequency of TRAE, ORR, OS, PFS per protocol. Liquid biopsy will be collected before 1L therapy and at the time of PD to evaluate mechanisms of resistance. RAS, RIT1, BRAF (class I, II), RAC1, RAF1, ARAF, AKT1, PTEN, PIK3CA (ex 20), ERBB2/3, MET, EGFR (ECDmut), POLE (EDmut), MSI will be analyzed (CGP via NGS). Time to event data will be analyzed using Kaplan-Meier curves. A Cox proportional hazards model will be used to calculate the HR, 95% CIs and p-value.

Clinical trial identification

NCT06226857.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Moscow Department of Health.

Disclosure

All authors have declared no conflicts of interest.