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Cetuximab rechallenge in RAS, BRAF, EGFR-ECD wild type metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies in first line: The CITRIC study
Background
Despite recent advances in the treatment of mCRC, the survival benefit obtained with third-line treatment is modest. Anti-EGFR therapy does not provide survival benefit in mCRC patients whose tumours are mutated with respect to RAS genes, and it should be only considered in RAS and BRAF wild-type patients. Unfortunately, patients with RAS wild-type mCRC eventually progress due to molecular mechanisms of acquired resistance, with RAS/BRAF mutations and EGFR extracellular domain (EGFR-ECD) mutations as the main drivers of EGFR acquired resistance. CRC dynamically adapts to external pressure exerted by anti-EGFR blockade. Acquired RAS/BRAF and EGFR ECD mutations have been shown to decrease after anti-EGFR treatment withdrawal, while tumour cells regain sensitivity to anti-EGFR treatment. This observation provides a strong rationale for the strategy of re-challenge with anti-EGFR therapy in patients previously treated with an anti-EGFR-based treatment. Several nonrandomized phase II clinical trials have demonstrated the efficacy of this strategy is in a molecularly selected population.
Trial design
This is a multicenter, randomized, open-labeled, parallel-group, phase II study to evaluate the efficacy and safety of cetuximab plus irinotecan rechallenge in the third-line setting, in comparison to investigator's choice of treatment (excluding anti-EGFR therapy), in patients with RAS, BRAF and EGFR-ECD wild-type mCRC who did benefit from cetuximab or panitumumab in the first line. RAS, BRAF V600E, and EGFR-ECD mutations will be analyzed in ctDNA using Next Generation Sequencing (NGS) panels (Colorectal Cancer kit, Oncomine, Thermofisher). The primary endpoint of the study is the overall response rate, determined according to RECIST 1.1 criteria. Main secondary endpoints include disease control rate, progression-free survival and overall survival. The sample size, calculated based on a two-sided Fisher’s exact test (alfa error 0.05, beta error 0.20), is 66 patients. It is estimated that a total of 122 patients would be required to undergo molecular screening by means of liquid biopsy. During the study it is intended to perform an extended biomarker analysis in ctDNA and tissue in order to assess the expression of potential biomarkers related to treatment resistance as an exploratory objective. Study is sponsored by Associació Per la Recerca Oncològica (APRO).
Clinical trial identification
EudraCT Number: 2020-000443-31.
Legal entity responsible for the study
Associació Per la Recerca Oncològica (APRO).
Funding
Merck KGaA.
Disclosures
F. Salva: Honoraria (self): Amgen, Merck, Sanofi. C. Fernández-Rodríguez: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Merck-Serono. V. Alonso Orduña: Advisory / Consultancy: SERVIER, MERCK, AMGEN; Travel / Accommodation / Expenses: IPSEN. D. Paez: Honoraria (self): Amgen, Sanofi, Novartis; Advisory / Consultancy: Amgen, Ipsen, Servier; Research grant / Funding (self): Merck; Travel / Accommodation / Expenses: Amgen, Merck, Roche, Lilly, Servier, Sanofi, Ipsen. P. Ribera Fernández: Speaker Bureau / Expert testimony: Merck, Sanofi ; Travel / Accommodation / Expenses: Merck, Servier, Lilly. M. Safont Aguilera: Honoraria (self): merck, amgen, servier; Advisory / Consultancy: amgen, merck, servier; Travel / Accommodation / Expenses: merck, amgen, servier. X. Hernández-Yagüe: Advisory / Consultancy: SANOFY-AVENTIS S.A. L. Layos Romero: Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Amgen, Roche, Merck. R. Garcia-Carbonero: Honoraria (self): Astra Zeneca; Honoraria (Institution): Astra Zeneca; Research grant / Funding (institution): Hospital Universitario 12 de Octubre. B. Bellosillo: Advisory / Consultancy: Amgen, Astra Zeneca, Janssen, Novartis; Speaker Bureau / Expert testimony: Astra Zeneca, Merck Serono, Biocartis, Novartis, Qiagen, ThermoFisher, Pfizer, Roche, Bristol Myers Squibb; Research grant / Funding (institution): ThermoFisher, Roche Farma, Roche Diagnostics; Travel / Accommodation / Expenses: Merck Serono; Licensing / Royalties: Biocartis. All other authors have declared no conflicts of interest.
