Circulating tumor DNA in decision-making of patients with metastatic colorectal cancer after failure of first-line treatment containing cetuximab: A single-center, phase II trial.

Abstract

e15584 Background: Genetic status is constantly changing after receiving cetuximab. To analyze the molecular characteristics in mCRC after first-line treatment containing cetuximab and adjust second-line targeted therapy strategies, we conducted this prospective study. Methods: Patients with measurable mCRC were enrolled. Main eligibility criteria included initial RAS and BRAF wild-type genetic status on tumor tissue; prior first-line regimens including cetuximab, and then showed progression disease. The ctDNA status was detected: bevacizumab would be applied if there was RAS mutation; the combination of vemurafenib, cetuximab and irinotecan would be used if there was BRAF mutation; trastuzumab would be used if there was HER2 amplification; cetuximab or bevacizumab would be applied according to investigators discretion if no related secondary variation. The primary endpoint was ORR; secondary endpoints were DCR, PFS, OS, safety and tolerability. Results: Twenty-two patients were enrolled from Apr 8, 2021 to Nov 18, 2022. Fifty percent (11/22) were males and the median age was 56.5 years. 59.1% (13/22) patients received bevacizumab, 36.4% (8/22) patients received cetuximab, and 4.5% (1/22) patients received trastuzumab and pyrotinib. 52 variations were detected in 22 patients before second-line therapy, with a positive rate of 95.5%. TP53 (90.9%, 20/22) was the most mutated gene, followed by APC (86.4%, 19/22). The percentage of secondary KRAS mutation was 9.1% (2/22), BRAF mutation was 0, ERBB2 amplification was 4.5% (1/22), and ERBB2 mutation was 9.1% (2/22). For 8 patients with serial ctDNA detection, the number of gene variation was decreased during disease remission (10 vs. 23) and increased again during progression (23 vs. 10). The ORR was 40.9% (9/22) for all patients. And it was 38.5% (5/13) and 37.5 % (3/8) separately for patients received bevacizumab or cetuximab (p = n.s.). The DCR was 86.4% (19/22) for all patients. And it was 92.3% (12/13), and 75% (6/8) for patients received bevacizumab or cetuximab separately (p = 0.013). The median PFS was 8.6 months in all patients. And it was 11.6 months and 4.6 months separately in patients received bevacizumab or cetuximab (p = 0.013). The median OS was 12.4 months in all patients. And it was 14.5 months and 11 months separately in patients received bevacizumab or cetuximab (P = 0.27). In addition, no difference in treatment related serious adverse advents grade 3-5 was observed. Conclusions: Circulating Tumor DNA is a promising biomarker for assessing treatment efficiency and guiding second-line treatment decisions in patients with mCRC. The bevacizumab-based second line treatment increases DCR and PFS than continuously cetuximab-based treatment, and had a better tendency in OS. Clinical trial information: NCT04831528 .