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Cited by 426Colorectal Cancer Treatments and StudiesColorectal Cancer Surgical TreatmentsGenetic factors in colorectal cancer

The DOI matches its Crossref record; 36 of the 38 references it cites were found in a registry or an index.

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial

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Cremolini, Chiara, Rossini, Daniele, Dell’Aquila, Emanuela, Lonardi, Sara, Conca, Elena, Del Re, Marzia, Busico, Adele, Pietrantonio, Filippo, Danesi, Romano, Aprile, Giuseppe, Tamburini, Emiliano, Barone, Carlo, Masi, Gianluca, Pantano, Francesco, Pucci, Francesca, Corsi, Domenico C., Pella, Nicoletta, Bergamo, Francesca, Rofi, Eleonora, Barbara, Cecilia, Falcone, Alfredo, Santini, Daniele·2019·JAMA Oncology
DOI 10.1001/jamaoncol.2018.5080PMC PMC6439839
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Abstract

Importance: Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA). Objective: To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy. Design, Setting, and Participants: Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment. Interventions: Biweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2. Main Outcomes and Measures: Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA. Results: Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03). Conclusions and Relevance: This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02296203.

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Research works printed but not linked: 3

  1. Meazza, 2016, AKT1 and BRAF mutations in pediatric aggressive fibromatosis., Cancer Med, 5, 1204, 10.1002/cam4.2016.5.issue-6 · DOI
  2. dbSNP: short genetic variations. Bethesda, MD: National Center for Biotechnology Information, National Library of Medicine. https://www.ncbi.nlm.nih.gov/SNP/. Accessed June 15, 2018.
  3. ClinVar. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed June 15, 2018.

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Metadata

Authors
Cremolini, C., Rossini, D., Dell’Aquila, E., Lonardi, S., Conca, E., Del Re, M., Busico, A., Pietrantonio, F., Danesi, R., Aprile, G., Tamburini, E., Barone, C., Masi, G., Pantano, F., Pucci, F., Corsi, D. C., Pella, N., Bergamo, F., Rofi, E., Barbara, C., Falcone, A., & Santini, D.
Affiliations
  • University of Pisa (IT)
  • Università Campus Bio-Medico (IT)
  • Istituto Oncologico Veneto (IT)
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, Pisa, Italy
  • University of Udine (IT)
  • Ospedale Infermi di Rimini (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • Ospedale di Parma (IT)
  • Fatebenefratelli Hospital (IT)
  • Medical Oncology Unit, Presidio Ospedaliero Felice Lotti, Pontedera, Italy
Corresponding author
Falcone, Alfredo
ORCID
Venue
JAMA Oncology
Publisher
American Medical Association (AMA)
Published
2019-03-01
Volume
5
Issue
3
Pages
343
ISSN
2374-2437 (ISSN-L)
DOI
10.1001/jamaoncol.2018.5080
PMC
PMC6439839
OpenAlex
W2901178367
Cited by
424
References
38
Citations by year
2026: 36 · 2025: 48 · 2024: 75 · 2023: 66 · 2022: 72 · 2021: 61 · 2020: 47 · 2019: 18
FWCI
11.91
Type
journal article
Language
en
Open access
Locations
  • JAMA Oncology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders
  • Amgen
  • Eli Lilly and Company
  • Sanofi
  • Celgene
  • F. Hoffmann-La Roche
  • Merck KGaA
  • Eisai
  • Università Cattolica del Sacro Cuore
  • Servier
  • Ipsen
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
metastatic colorectal cancer, cetuximab, irinotecan, drug rechallenge, RAS wild-type, BRAF wild-type, acquired resistance, anti-EGFR therapy, circulating tumor DNA, liquid biopsy, third-line therapy, oxaliplatin, bevacizumab, RAS mutations, progression-free survival, overall survival, response rate, disease control rate, predictive biomarkers
MeSH terms
Cetuximab, Irinotecan, Progression-Free Survival, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Italy, Male, Middle Aged, Prospective Studies, Genes, ras, Risk Factors, Time Factors, Biomarkers, Tumor, Colorectal Neoplasms, Disease Progression, Drug Resistance, Neoplasm, Proto-Oncogene Proteins B-raf

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