EGFR S492R

P2, N=59, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=59, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2024 --> Jan 2024 | Trial primary completion date: Jul 2024 --> Jan 2024

P2, N=59, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2023 --> Jul 2024

P2 | "This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892."

"The 23 common mutations detected in the BRAF and NRAS genes using this assay have significant impact on therapeutic selection. Somatic variants in the BRAF gene have been found in 37%-50% of all malignant melanomas, whereas somatic variants in the NRAS gene are found in 13%-25% of all melanomas. The Biocartis Idylla system offers a simple and rapid method to obtain somatic mutation information in these two genes that are of clinical importance."

The evolved cetuximab variants (Ctx-VY, Ctx-Y104D and Ctx-W52D) with one or two amino acid substitutions in the complementarity-determining region inherit the optimized physical and chemical properties of cetuximab to a great extent, thus ensuring their druggability. Our data collectively show that structure-guided and phage-assisted evolution is an efficient and general approach for reversing receptor mutation-mediated resistance to therapeutic antibody drugs.

P2, N=84, Recruiting, M.D. Anderson Cancer Center | Unknown status --> Recruiting | Trial completion date: Dec 2021 --> Jul 2024 | Trial primary completion date: Dec 2021 --> Jul 2023

Plasma ctDNA analysis before treatment may allow selection of patients who could benefit. ClinicalTrials.gov Identifier: NCT04561336.

These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.

Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade. The detection of these mutations in cfDNA is a promising approach to predict treatment response and secondary resistance.