Background: Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC). Patients and methods: The randomized phase II CAVE-2 GOIM trial compared two rechallenge regimens in RAS/BRAF wild-type mCRC (cetuximab monotherapy or in combination with avelumab). Patients were selected according to baseline plasma circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) by FoundationOne Liquid CDx. Primary endpoint was overall survival (OS). Results: From August 2022 to December 2024, 156 out of 328 screened patients were randomly assigned in a 2 : 1 ratio to cetuximab plus avelumab (arm A, 104 patients) or cetuximab (arm B, 52 patients). Median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 4.3-6 months] in arm A versus 4.3 months (95% CI 3.5-5.5 months) in arm B [hazard ratio (HR) 0.78, 95% CI 0.55-1.10, P = 0.158]. Median OS (mOS) was 14.8 months (95% CI 12.1-18.3 months) in arm A versus 12.9 months (95% CI 11 months-not evaluable) in arm B (HR 1.00, 95% CI 0.65-1.52, P = 0.983). A pre-planned exploratory analysis evaluated the impact of genomic pathogenic variants on therapeutic efficacy in the EGFR pathway. In the whole study population, 124/156 patients had tumors without any genomic alteration in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, and ERBB2 ('negative hyperselection'). These patients had significantly improved mPFS [5.35 months (95% CI 4.4-5.9 months) versus 3.65 months (95% CI 2.8-4.8 months); HR 0.62, 95% CI 0.42-0.92, P = 0.017] and mOS [15.0 months (95% CI 12.6-19.9 months) versus 11.1 months (95% CI 8.6-15.6 months); HR 0.61, 95% CI 0.39-0.97, P = 0.037] compared with patients having at least one pathogenic variant ('positive hyperselection'). Similarly, improved objective response rate, mPFS, and OS were observed for each treatment arm in patients with 'negative hyperselection'. Conclusion: Addition of avelumab does not increase efficacy of cetuximab rechallenge. Liquid biopsy CGP identifies patients who benefit from anti-EGFR rechallenge supporting its implementation in the continuum of care of mCRC.
Cetuximab rechallenge in molecularly selected metastatic colorectal cancer: the randomized CAVE-2 GOIM trial
Martini, G;Troiani, T;De Vita, F;Martinelli, E;Ciardiello, F;Napolitano, S
2025
Abstract
Background: Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC). Patients and methods: The randomized phase II CAVE-2 GOIM trial compared two rechallenge regimens in RAS/BRAF wild-type mCRC (cetuximab monotherapy or in combination with avelumab). Patients were selected according to baseline plasma circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) by FoundationOne Liquid CDx. Primary endpoint was overall survival (OS). Results: From August 2022 to December 2024, 156 out of 328 screened patients were randomly assigned in a 2 : 1 ratio to cetuximab plus avelumab (arm A, 104 patients) or cetuximab (arm B, 52 patients). Median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 4.3-6 months] in arm A versus 4.3 months (95% CI 3.5-5.5 months) in arm B [hazard ratio (HR) 0.78, 95% CI 0.55-1.10, P = 0.158]. Median OS (mOS) was 14.8 months (95% CI 12.1-18.3 months) in arm A versus 12.9 months (95% CI 11 months-not evaluable) in arm B (HR 1.00, 95% CI 0.65-1.52, P = 0.983). A pre-planned exploratory analysis evaluated the impact of genomic pathogenic variants on therapeutic efficacy in the EGFR pathway. In the whole study population, 124/156 patients had tumors without any genomic alteration in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, and ERBB2 ('negative hyperselection'). These patients had significantly improved mPFS [5.35 months (95% CI 4.4-5.9 months) versus 3.65 months (95% CI 2.8-4.8 months); HR 0.62, 95% CI 0.42-0.92, P = 0.017] and mOS [15.0 months (95% CI 12.6-19.9 months) versus 11.1 months (95% CI 8.6-15.6 months); HR 0.61, 95% CI 0.39-0.97, P = 0.037] compared with patients having at least one pathogenic variant ('positive hyperselection'). Similarly, improved objective response rate, mPFS, and OS were observed for each treatment arm in patients with 'negative hyperselection'. Conclusion: Addition of avelumab does not increase efficacy of cetuximab rechallenge. Liquid biopsy CGP identifies patients who benefit from anti-EGFR rechallenge supporting its implementation in the continuum of care of mCRC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
