Comprehensive genomic profiling by liquid biopsy in refractory metastatic colorectal cancer patients who are candidate for anti-EGFR rechallenge therapy: findings from the CAVE-2 GOIM trial

D Ciardiello; L Boscolo Bielo; F Pietrantonio; G Martini; T Troiani; E Martinelli; S Natangelo; M F Bosco; S Pisconti; C Nisi; G Tortora; L Salvatore; A Sartore-Bianchi; S Siena; L Blasi; M Messina; E Ongaro; A Zaniboni; C Pinto; L Antonuzzo; A Avallone; N Normanno; G Santabarbara; M G Zampino; R Berardi; A A Cogoni; S Leo; C Lotesoriere; T P Latiano; E Maiello; N Fazio; G Curigliano; R Bordonaro; F De Vita; F Ciardiello; S Napolitano

doi:10.1016/j.esmoop.2025.105491

Comprehensive genomic profiling by liquid biopsy in refractory metastatic colorectal cancer patients who are candidate for anti-EGFR rechallenge therapy: findings from the CAVE-2 GOIM trial

ESMO Open. 2025 Jun 23;10(7):105491. doi: 10.1016/j.esmoop.2025.105491. Online ahead of print.

Authors

D Ciardiello¹, L Boscolo Bielo², F Pietrantonio³, G Martini⁴, T Troiani⁴, E Martinelli⁴, S Natangelo³, M F Bosco³, S Pisconti⁵, C Nisi⁵, G Tortora⁶, L Salvatore⁶, A Sartore-Bianchi⁷, S Siena⁸, L Blasi⁹, M Messina⁹, E Ongaro¹⁰, A Zaniboni¹¹, C Pinto¹², L Antonuzzo¹³, A Avallone¹⁴, N Normanno¹⁵, G Santabarbara¹⁶, M G Zampino¹⁷, R Berardi¹⁸, A A Cogoni¹⁹, S Leo²⁰, C Lotesoriere²¹, T P Latiano²², E Maiello²², N Fazio¹⁷, G Curigliano², R Bordonaro²³, F De Vita⁴, F Ciardiello⁴, S Napolitano⁴

Affiliations

¹ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy. Electronic address: davide.ciardiello@ieo.it.
² Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
³ Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
⁴ Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
⁵ Medical Oncology Unit, San Giuseppe Moscati Hospital, Statte, Italy.
⁶ Medical Oncology Unit, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Medical Oncology Unit, Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy.
⁷ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Division of Clinical Research and Innovation, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
⁸ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
⁹ Medical Oncology Unit, A.R.N.A.S. Ospedali Civico di Cristina Benfratelli (PA), Palermo, Italy.
¹⁰ Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
¹¹ Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy.
¹² Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
¹³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Medical Oncology Unit, Careggi University Hospital, Florence, Italy.
¹⁴ Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
¹⁵ IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Mendola, Italy.
¹⁶ Medical Oncology Unit, San Giuseppe Moscati Hospital, Avellino, Italy.
¹⁷ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
¹⁸ Department of Medical Oncology, Marche Polytechnic University, Ancona, Italy.
¹⁹ Medical Oncology Unit, University Hospital (AOU) of Sassari, Sassari, Italy.
²⁰ Medical Oncology Unit, Ospedale Vito Fazzi, Lecce, Italy.
²¹ Medical Oncology Unit, National Institute of Gastroenterology, IRCCS de Bellis Research Hospital, Castellana Grotte, Italy.
²² Medical Oncology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
²³ Medical Oncology Unit, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy.

PMID: 40555076
DOI: 10.1016/j.esmoop.2025.105491

Abstract

Background: Biomarker-guided therapies are needed for patients with refractory metastatic colorectal cancer (mCRC). Liquid biopsy (LBx) circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) could contribute to the clinical tailoring of molecular targeted therapies for these patients.

Patients and methods: The CAVE-2 GOIM trial is a randomized phase II trial assessing the efficacy of adding avelumab to cetuximab compared with cetuximab monotherapy as anti-epidermal growth factor receptor (EGFR) rechallenge in refractory ctDNA RAS/BRAF^V600E wild-type mCRC patients. Baseline plasma ctDNA CGP was carried out using the Foundation One Liquid CDx.

Results: LBx-based CGP was available for 324 patients out of 328 screened. A total of 1969 pathogenic variants (PVs) were detected. One hundred and thirty-five cases (41.7%) had single RAS/BRAF^V600 PVs, with 24 tumors (17.6%) having multiple RAS/BRAF^V600 PVs. Of 166 RAS/BRAF^V600 PVs, 95 (57.2%) consisted of subclonal alterations {median variant allele frequency [VAF] of 0.37% [interquartile range (IQR) 0.18%-1.0%] versus median VAF of 4.0% [IQR 0.65%-11.25%] in 71 cases of clonal PV; P < 0.0001}. Single RAS/BRAF^V600 alterations had higher clonality compared with co-occurring RAS/BRAF^V600 alterations [12.8% (IQR 1.93%-56.0%) versus 0.67% (IQR 0.37-3.35), P < 0.0001]. Among other genes potentially involved in anti-EGFR drug resistance, 174 non-RAS/BRAF^V600 PV were observed with 73 cases having both co-occurring RAS/BRAF^V600 and non-RAS/BRAF^V600 PV, while in 43 cases only non-RAS/BRAF^V600 PV were detected. Tumors harboring co-occurring non-RAS/BRAF^V600 PV had significantly lower clonality as compared with RAS/BRAF^V600 PV [1.52 (0.46-8.88) versus 17.0 (3.75-71.0), P < 0.0001]. Finally, a total of 332 genomic alterations with therapeutic relevance according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) were detected for 171 patients (52.7%). Of these, 120 tier I alterations were detected among 111 (34.3%) patients, which included high tumor mutational burden (≥10 mut/Mb, n = 101), BRAF^V600E (n = 11), KRAS^G12C (n = 7), and RET^fusion (n = 1).

Conclusions: LBx-based CGP might guide the appropriate use of anti-EGFR drug rechallenge or of other therapeutically actionable gene alterations in refractory mCRC.

Keywords: avelumab; cetuximab; colorectal cancer; comprehensive genomic profiling; liquid biopsy.