Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE‐3)

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin‐fixed mCRC samples from patients of the FIRE‐3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post‐hoc analysis. Median overall survival (OS), progression‐free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild‐type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14‐1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab‐based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti‐VEGF or anti‐EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti‐EGFR antibodies were observed in only one‐third of patients. What's new? Secondary resection for initially unresectable metastatic colorectal cancer (mCRC) is associated with improved prognosis. Predicting opportunities for secondary resection, however, depends on the discovery of molecular changes in primary tumor and corresponding metastatic tumor tissue. Here, mutational profiles were investigated for mCRC patients in the FIRE‐3 trial, a study of FOLFIRI plus cetuximab or bevacizumab as first‐line therapy for irresectable mCRC. Of nine mCRC patients undergoing cetuximab therapy who experienced changes in tumor mutational profile, one‐third became resistant to cetuximab. For patients treated with anti‐VEGF and anti‐EGFR antibodies, mutational profiles were similar before and after treatment and following secondary resection.