BACKGROUND: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. PATIENTS AND METHODS: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. RESULTS: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. CONCLUSIONS: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. CLINICAL TRIALS REGISTRATION: NCT01183780.

Department of Clinical Oncology Aichi Cancer Center Hospital Nagoya Japan

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Oncology and Radiotherapy University Hospital Motol Prague Czech Republic

Digestive Oncology University Hospital Gasthuisberg Leuven Belgium; KU Leuven Leuven Belgium

Division of Gastrointestinal Oncology Digestive Endoscopy National Cancer Center Hospital East Chiba Japan

Laboratory for Experimental Medicine Eli Lilly and Company Indianapolis USA

Medical Oncology Department Hospital Universitario 12 de Octubre CNIO; CIBERONC Universidad Complutense Madrid Spain

Medical Oncology Prof Dr 1 Chiricuţă Institute of Oncology Cluj Napoca Romania

Medical Oncology Rocky Mountain Cancer Center US Oncology Denver USA

Medical Oncology Vall d'Hebron University Hospital and Institute of Oncology Barcelona Spain; CIBERONC Universitat Autònoma de Barcelona Barcelona Spain

Oncology Eli Lilly and Company Argentina

Oncology Eli Lilly and Company Indianapolis USA

Oncology Szent László Hospital Budapest Hungary

Oncology West Clinic Memphis USA

Ann Oncol. 2018 Mar 1;29(3):527-529. doi: 10.1093/annonc/mdy028. PubMed

Zobrazit více v PubMed

World Health Organization. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. IARC Fact Sheet. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (24 May 2017, date last accessed).

World Health Organization. Cancer Fact Sheet. February 2017. http://www.who.int/mediacentre/factsheets/fs297/en/ (24 May 2017, date last accessed).

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D.. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25(Suppl 3): iii1–iii9. PubMed

National Cancer Institute. Cancer Stat Facts: Colon and Rectum Cancer. Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/colorect.html (24 May 2017, date last accessed).

Spratlin JL, Cohen RB, Eadens M. et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28: 780–787. PubMed PMC

Tabernero J, Yoshino T, Cohn AL. et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015; 16(5): 499–508. PubMed

Obermannová R, Van Cutsem E, Yoshino T. et al. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol 2016; 27(11): 2082–2090. PubMed PMC

Fuchs CS, Tabernero J, Tomasek J. et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer 2016; 115(8): 974–982. PubMed PMC

Holzer TR, Fulford AD, Nedderman DM. et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS ONE 2013; 8(11): e80292. PubMed PMC

Freidlin B, Simon R.. Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients. Clin Cancer Res 2005; 11(21): 7872–7878. PubMed

Venook AP, Niedzwiecki D, Lenz HJ. et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA 2017; 317(23): 2392–2401. PubMed PMC

Nixon A, Sibley A, Hatch AJ. et al. Blood-based biomarkers in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI plus bevacizumab (Bev), cetuximab (Cetux), or bev plus Cetux: Results from CALGB 80405 (Alliance). J Clin Oncol 2016; 34(Suppl): Abstr 3597.

Nixon A, Sibley A, Hatch AJ. et al. Blood-based biomarkers in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI plus bevacizumab (Bev), cetuximab (Cetux), or bev plus Cetux: Results from CALGB 80405 (Alliance). 2016 ASCO Annual Meeting. Poster #294.

Tebbutt NC, Wilson K, Gebski VJ. et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol 2010; 28: 3191–3198. PubMed

Weickhardt AJ, Williams DS, Lee CK. et al. Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer. Br J Cancer 2015; 113(1): 37–45. PubMed PMC

Venook AP, Blanke CD, Niedzwiecki D. et al. Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer 2005; 5(4): 292–294. PubMed

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study

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ClinicalTrials.gov
NCT01183780