Circulating tumour DNA-guided second-line targeted therapy for patients with metastatic colorectal cancer after failure of first-line cetuximab-based treatment: A prospective, phase II trial

Background The genetic profile of metastatic colorectal cancer (mCRC) can dynamically change after treatment with cetuximab. This study prospectively evaluated the efficacy of second-line targeted therapies according to the molecular characteristics of circulating tumour DNA (ctDNA) in mCRC patients. Methods This phase II trial included mCRC patients who failed after cetuximab-based first-line treatment. CtDNA analysis was performed to guide second-line targeted therapies. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), as well as safety and tolerability. Results Between April 8, 2021, and December 11, 2022, 24 patients were enrolled; 50% were males, and the median age was 57 years. Treatment regimens included bevacizumab (58.3%), cetuximab (37.5%), and a combination of trastuzumab and pyrotinib (4.2%). KRAS mutations were present in 12.5% of patients, whereas BRAF mutations were not detected. HER2 amplification occurred in 4.2% of the patients. The ORR for all patients was 45.8%, and the DCR was 87.5%. The median PFS was 10.2 months, and the median OS was 24.9 months. For RAS/BRAF wild-type patients who received bevacizumab, the ORR was 40.0%, and the DCR was 90.0%. For those receiving cetuximab, the ORR was 44.4%, and the DCR was 77.7%. The mPFS was 12.6 months and 7.4 months for patients who received bevacizumab or cetuximab, respectively (p = 0.854). The median OS was 27.1 months and 19.9 months for the bevacizumab and cetuximab groups, respectively (p = 0.417). In addition, no grade 4 or 5 treatment-related adverse events were reported. Conclusions CtDNA is a promising biomarker for guiding second-line treatment decisions in mCRC patients. For patients with a continuous RAS/BRAF wild-type status, bevacizumab-based second-line treatment might be more advantageous than cetuximab-based treatment. ClinicalTrials.gov Identifier: This study was registered on ClinicalTrials.gov with NCT04831528 (https://clinicaltrials.gov/search?term=NCT04831528). Trial registration: www.clinicaltrials.gov (NCT04831528).