Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third‐line setting. The intention‐to‐treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next‐generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS‐WT and RAS‐MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy. What's new? Metastatic colorectal cancer (mCRC) typically is treated with weekly cetuximab or biweekly cetuximab plus irinotecan administration. Whether these regimens should be altered or would yield greater benefit in light of mCRC RAS mutation status remains uncertain. This investigation of mCRC patients treated with cetuximab plus irinotecan in a third‐line setting shows that both safety and efficacy can be maintained when cetuximab is reduced to biweekly administration and when administration time is shortened for cetuximab plus irinotecan. Moreover, mCRC mutations were linked to survival, with patients carrying wildtype RAS surviving longer than those with RAS and BRAFV600E mutations. [Correction added on 8 January 2021, after first online publication: the last sentence has been amended to improve readability.]