Second-line irinotecan followed by third-line cetuximab plus irinotecan versus second-line cetuximab combined with irinotecan in treatment of oxaliplatin/5-FU failure RAS/RAF wild-type mCRC patients: A randomized phase II study.

148 Background: After failure of first-line oxaliplatin (LOHP)/5-FU for metastatic colorectal cancer (mCRC), irinotecan (CPT-11) is the standard second-line chemotherapy. Cetuximab (C225) plus CPT-11 can improve efficacy in RAS/RAF wild-type patients, even after CPT-11 failure. This study was designed to evaluate whether a sequential strategy of second-line CPT-11 monotherapy followed by third-line C225 plus CPT-11 (s-IRI-CetuIRI) could provide more treatment lines and longer cumulative progression-free survival (PFS), compared to using combined C225 and CPT-11 (c-CetuIRI) directly in the second-line setting. Methods: RAS wild-type, cetuximab-naive mCRC patients after failure of first-line LOHP/5-FU were randomized to s-IRI-CetuIRI arm and c-CetuIRI arm, according to the stratification factors of primary tumor location and numbers of metastatic lesions. The primary endpoint was PFS (defined as the sum of second and third-line PFS in s-IRI-CetuIRI arm, and second-line PFS for c-CetuIRI arm). Results: Between November 2019 and November 2024, 42 eligible patients were enrolled in the study. The main primary tumor side was on the left side, with 68.4% (13/19) in the s-IRI-CetuIRI group and 78.3% (18/23) in the c-CetuIRI group. 21% (4/15) and 30.4% (7/23) of patients received bevacizumab in their previous treatment in both groups. At a median follow-up of 30.5 months (range 22.1-38.8 months), the median PFS (12.1 months vs 4.97 months, P=0.036) and OS (41.23 months vs 21.97 months, P=0.001) were significantly longer in the s-IRI-CetuIRI group than in the c-CetuIRI group. Subgroup analysis showed that patients with 1-2 metastases had better PFS and OS when treated with s-IRI-CetuIRI (P=0.043 and 0.001, respectively). Patients with left-sided primary tumors also had a longer PFS trend in the s-IRI-CetuIRI group (P=0.057) and better survival (P=0.043). Conclusions: The results of the study suggest that the sequential strategy of third-line C225 plus CPT-11 after second-line CPT-11 monotherapy has better survival than direct combination therapy in the second-line setting, especially in patients with low metastatic lesion burden and left-sided primary tumor site. Clinical trial information: NCT04833036 .