Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC

C. Pinto, N. Normanno, A. Orlandi, F. Fenizia, A. Damato, E. Maiello, E. Tamburini, F. Di Costanzo, G. Tonini, D. Bilancia, D. Corsi, S. Pisconti, F. Ferrau, S. Gori, B. Daniele, A. Zaniboni, H. Soto Parra, G.L. Frassinetti, R.V. Iaffaioli, A. CassataM.G. Zampino, L. Repetto, M.A. Calegari, C. Barone

Research output: Contribution to journalArticle

Abstract

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients. © 2018 Future Medicine Ltd.
Original languageEnglish
Pages (from-to)1339-1346
Number of pages8
JournalFuture Oncology
Volume14
Issue number14
DOIs
Publication statusPublished - 2018

Fingerprint

Colorectal Neoplasms
Therapeutics
Anti-Idiotypic Antibodies
Quality of Life
Medicine
Drug Therapy
Cetuximab
Population

Keywords

  • cetuximab
  • colorectal cancer
  • de-escalation therapy
  • RAS and BRAF wild-type
  • B Raf kinase
  • fluorouracil
  • folinic acid
  • irinotecan
  • antineoplastic agent
  • BRAF protein, human
  • camptothecin
  • EGFR protein, human
  • epidermal growth factor receptor
  • KRAS protein, human
  • protein p21
  • aged
  • Article
  • blood sampling
  • blood toxicity
  • BRAF gene
  • cancer growth
  • cancer survival
  • comparative study
  • controlled study
  • drug efficacy
  • drug safety
  • female
  • gene mutation
  • human
  • human tissue
  • major clinical study
  • male
  • metastatic colorectal cancer
  • multicenter study
  • multiple cycle treatment
  • oncogene ras
  • phase 3 clinical trial
  • priority journal
  • progression free survival
  • randomized controlled trial
  • skin toxicity
  • treatment duration
  • adult
  • analogs and derivatives
  • antagonists and inhibitors
  • clinical trial
  • colorectal tumor
  • disease free survival
  • dna mutational analysis
  • genetics
  • middle aged
  • mortality
  • mutation
  • pathology
  • quality of life
  • treatment outcome
  • young adult
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Camptothecin
  • Cetuximab
  • Colorectal Neoplasms
  • Disease-Free Survival
  • DNA Mutational Analysis
  • Female
  • Fluorouracil
  • Humans
  • Leucovorin
  • Male
  • Middle Aged
  • Mutation
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • Quality of Life
  • Receptor, Epidermal Growth Factor
  • Treatment Outcome
  • Young Adult

Cite this

Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC. / Pinto, C.; Normanno, N.; Orlandi, A.; Fenizia, F.; Damato, A.; Maiello, E.; Tamburini, E.; Di Costanzo, F.; Tonini, G.; Bilancia, D.; Corsi, D.; Pisconti, S.; Ferrau, F.; Gori, S.; Daniele, B.; Zaniboni, A.; Soto Parra, H.; Frassinetti, G.L.; Iaffaioli, R.V.; Cassata, A.; Zampino, M.G.; Repetto, L.; Calegari, M.A.; Barone, C.

In: Future Oncology, Vol. 14, No. 14, 2018, p. 1339-1346.

Research output: Contribution to journalArticle

Pinto, C, Normanno, N, Orlandi, A, Fenizia, F, Damato, A, Maiello, E, Tamburini, E, Di Costanzo, F, Tonini, G, Bilancia, D, Corsi, D, Pisconti, S, Ferrau, F, Gori, S, Daniele, B, Zaniboni, A, Soto Parra, H, Frassinetti, GL, Iaffaioli, RV, Cassata, A, Zampino, MG, Repetto, L, Calegari, MA & Barone, C 2018, 'Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC', Future Oncology, vol. 14, no. 14, pp. 1339-1346. https://doi.org/10.2217/fon-2017-0592
Pinto, C. ; Normanno, N. ; Orlandi, A. ; Fenizia, F. ; Damato, A. ; Maiello, E. ; Tamburini, E. ; Di Costanzo, F. ; Tonini, G. ; Bilancia, D. ; Corsi, D. ; Pisconti, S. ; Ferrau, F. ; Gori, S. ; Daniele, B. ; Zaniboni, A. ; Soto Parra, H. ; Frassinetti, G.L. ; Iaffaioli, R.V. ; Cassata, A. ; Zampino, M.G. ; Repetto, L. ; Calegari, M.A. ; Barone, C. / Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC. In: Future Oncology. 2018 ; Vol. 14, No. 14. pp. 1339-1346.
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abstract = "The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients. {\circledC} 2018 Future Medicine Ltd.",
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author = "C. Pinto and N. Normanno and A. Orlandi and F. Fenizia and A. Damato and E. Maiello and E. Tamburini and {Di Costanzo}, F. and G. Tonini and D. Bilancia and D. Corsi and S. Pisconti and F. Ferrau and S. Gori and B. Daniele and A. Zaniboni and {Soto Parra}, H. and G.L. Frassinetti and R.V. Iaffaioli and A. Cassata and M.G. Zampino and L. Repetto and M.A. Calegari and C. Barone",
note = "Export Date: 5 February 2019 Correspondence Address: Orlandi, A.; Oncology Unit, Fondazione Policlinico Universitario a GemelliItaly; email: armando.orlandi@policlinicogemelli.it Chemicals/CAS: cetuximab, 205923-56-4; fluorouracil, 51-21-8; folinic acid, 58-05-9; irinotecan, 100286-90-6; camptothecin, 7689-03-4; epidermal growth factor receptor, 79079-06-4; protein p21, 85306-28-1; BRAF protein, human; Camptothecin; Cetuximab; EGFR protein, human; Fluorouracil; KRAS protein, human; Leucovorin; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Receptor, Epidermal Growth Factor Funding details: Merck Funding details: Merck KGaA Funding text 1: The study is partially supported by an unrestricted grant provided by Merck. Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. References: Van Cutsem, E., Kohne, C.H., Hitre, E., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (2009) N. Engl. J. Med., 360, pp. 1408-1417; Van Cutsem, E., K{\"o}hne, C.H., L{\'a}ng, I., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status (2011) J. Clin. Oncol., 29 (15), pp. 2011-2019; Heinemann, V., Von Weikersthal, L.F., Decker, T., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, Phase 3 trial (2014) Lancet Oncol., 15 (10), pp. 1065-1075; Pietrantonio, F., Petrelli, F., Coinu, A., Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis (2015) Eur. J. Cancer, 51 (5), pp. 587-594; Orlandi, A., Calegari, A., Inno, A., BRAF in metastatic colorectal cancer: The future starts now (2015) Pharmacogenomics, 16 (18), pp. 2069-2081; Loupakis, F., Cremolini, C., Masi, G., Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer (2014) N. Engl. J. Med., 371 (17), pp. 1609-1618; Stintzing, S., Modest, D.P., Rossius, L., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): A post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label Phase III trial (2016) Lancet Oncol., 17 (10), pp. 1426-1434; Price, T., Kim, T.W., Li, J., Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: Randomized Phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (2016) Eur. J. Cancer, 68, pp. 51-59; De Roock, W., De Vriendt, V., Normanno, N., KRAS, BRAF, PIK3CA, and PTEN mutations: Implications for targeted therapies in metastatic colorectal cancer (2011) Lancet Oncol., 12, pp. 594-603; Ciardiello, F., Normanno, N., Maiello, E., Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next generation sequencing: Findings from the CAPRI-GOIM trial (2014) Ann. Oncol., 25 (9), pp. 1756-1761; Eisenhauer, E.A., Therasse, P., Bogaerts, J., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1. 1) (2009) Eur. J. Cancer, 45 (2), pp. 228-247; http://evs.nci.nih.gov/ftp1/CTCAE/About.html, NCI Common Terminology Criteria for Adverse Events data files (CTCAE v4. 03, minor update 2010); Tops, B.B., Normanno, N., Kurth, H., Development of a semi-conductor sequencing-based panel for genotyping of colon and lung cancer by the Onconetwork consortium (2015) BMC Cancer, 15, p. 26; Van Cutsem, E., K{\"o}hne, C.H., L{\'a}ng, I., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status (2011) J. Clin. Oncol., 29 (15), pp. 2011-2019; Van Cutsem, E., Lenz, H.J., K{\"o}hne, C.H., Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer (2015) J. Clin. Oncol., 33 (7), pp. 692-700; Rothmann, M., Li, N., Chen, G., Chi, G.Y., Temple, R., Tsou, H.H., Design and analysis of non-inferiority mortality trials in oncology (2003) Stat. Med., 22 (2), pp. 239-264",
year = "2018",
doi = "10.2217/fon-2017-0592",
language = "English",
volume = "14",
pages = "1339--1346",
journal = "Future Oncology",
issn = "1479-6694",
publisher = "Future Medicine Ltd.",
number = "14",

}

TY - JOUR

T1 - Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC

AU - Pinto, C.

AU - Normanno, N.

AU - Orlandi, A.

AU - Fenizia, F.

AU - Damato, A.

AU - Maiello, E.

AU - Tamburini, E.

AU - Di Costanzo, F.

AU - Tonini, G.

AU - Bilancia, D.

AU - Corsi, D.

AU - Pisconti, S.

AU - Ferrau, F.

AU - Gori, S.

AU - Daniele, B.

AU - Zaniboni, A.

AU - Soto Parra, H.

AU - Frassinetti, G.L.

AU - Iaffaioli, R.V.

AU - Cassata, A.

AU - Zampino, M.G.

AU - Repetto, L.

AU - Calegari, M.A.

AU - Barone, C.

N1 - Export Date: 5 February 2019 Correspondence Address: Orlandi, A.; Oncology Unit, Fondazione Policlinico Universitario a GemelliItaly; email: armando.orlandi@policlinicogemelli.it Chemicals/CAS: cetuximab, 205923-56-4; fluorouracil, 51-21-8; folinic acid, 58-05-9; irinotecan, 100286-90-6; camptothecin, 7689-03-4; epidermal growth factor receptor, 79079-06-4; protein p21, 85306-28-1; BRAF protein, human; Camptothecin; Cetuximab; EGFR protein, human; Fluorouracil; KRAS protein, human; Leucovorin; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Receptor, Epidermal Growth Factor Funding details: Merck Funding details: Merck KGaA Funding text 1: The study is partially supported by an unrestricted grant provided by Merck. Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. References: Van Cutsem, E., Kohne, C.H., Hitre, E., Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (2009) N. Engl. J. Med., 360, pp. 1408-1417; Van Cutsem, E., Köhne, C.H., Láng, I., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status (2011) J. Clin. Oncol., 29 (15), pp. 2011-2019; Heinemann, V., Von Weikersthal, L.F., Decker, T., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, Phase 3 trial (2014) Lancet Oncol., 15 (10), pp. 1065-1075; Pietrantonio, F., Petrelli, F., Coinu, A., Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis (2015) Eur. J. Cancer, 51 (5), pp. 587-594; Orlandi, A., Calegari, A., Inno, A., BRAF in metastatic colorectal cancer: The future starts now (2015) Pharmacogenomics, 16 (18), pp. 2069-2081; Loupakis, F., Cremolini, C., Masi, G., Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer (2014) N. Engl. J. Med., 371 (17), pp. 1609-1618; Stintzing, S., Modest, D.P., Rossius, L., FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): A post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label Phase III trial (2016) Lancet Oncol., 17 (10), pp. 1426-1434; Price, T., Kim, T.W., Li, J., Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: Randomized Phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (2016) Eur. J. Cancer, 68, pp. 51-59; De Roock, W., De Vriendt, V., Normanno, N., KRAS, BRAF, PIK3CA, and PTEN mutations: Implications for targeted therapies in metastatic colorectal cancer (2011) Lancet Oncol., 12, pp. 594-603; Ciardiello, F., Normanno, N., Maiello, E., Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next generation sequencing: Findings from the CAPRI-GOIM trial (2014) Ann. Oncol., 25 (9), pp. 1756-1761; Eisenhauer, E.A., Therasse, P., Bogaerts, J., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1. 1) (2009) Eur. J. Cancer, 45 (2), pp. 228-247; http://evs.nci.nih.gov/ftp1/CTCAE/About.html, NCI Common Terminology Criteria for Adverse Events data files (CTCAE v4. 03, minor update 2010); Tops, B.B., Normanno, N., Kurth, H., Development of a semi-conductor sequencing-based panel for genotyping of colon and lung cancer by the Onconetwork consortium (2015) BMC Cancer, 15, p. 26; Van Cutsem, E., Köhne, C.H., Láng, I., Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status (2011) J. Clin. Oncol., 29 (15), pp. 2011-2019; Van Cutsem, E., Lenz, H.J., Köhne, C.H., Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer (2015) J. Clin. Oncol., 33 (7), pp. 692-700; Rothmann, M., Li, N., Chen, G., Chi, G.Y., Temple, R., Tsou, H.H., Design and analysis of non-inferiority mortality trials in oncology (2003) Stat. Med., 22 (2), pp. 239-264

PY - 2018

Y1 - 2018

N2 - The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients. © 2018 Future Medicine Ltd.

AB - The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients. © 2018 Future Medicine Ltd.

KW - cetuximab

KW - colorectal cancer

KW - de-escalation therapy

KW - RAS and BRAF wild-type

KW - B Raf kinase

KW - fluorouracil

KW - folinic acid

KW - irinotecan

KW - antineoplastic agent

KW - BRAF protein, human

KW - camptothecin

KW - EGFR protein, human

KW - epidermal growth factor receptor

KW - KRAS protein, human

KW - protein p21

KW - aged

KW - Article

KW - blood sampling

KW - blood toxicity

KW - BRAF gene

KW - cancer growth

KW - cancer survival

KW - comparative study

KW - controlled study

KW - drug efficacy

KW - drug safety

KW - female

KW - gene mutation

KW - human

KW - human tissue

KW - major clinical study

KW - male

KW - metastatic colorectal cancer

KW - multicenter study

KW - multiple cycle treatment

KW - oncogene ras

KW - phase 3 clinical trial

KW - priority journal

KW - progression free survival

KW - randomized controlled trial

KW - skin toxicity

KW - treatment duration

KW - adult

KW - analogs and derivatives

KW - antagonists and inhibitors

KW - clinical trial

KW - colorectal tumor

KW - disease free survival

KW - dna mutational analysis

KW - genetics

KW - middle aged

KW - mortality

KW - mutation

KW - pathology

KW - quality of life

KW - treatment outcome

KW - young adult

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Camptothecin

KW - Cetuximab

KW - Colorectal Neoplasms

KW - Disease-Free Survival

KW - DNA Mutational Analysis

KW - Female

KW - Fluorouracil

KW - Humans

KW - Leucovorin

KW - Male

KW - Middle Aged

KW - Mutation

KW - Proto-Oncogene Proteins B-raf

KW - Proto-Oncogene Proteins p21(ras)

KW - Quality of Life

KW - Receptor, Epidermal Growth Factor

KW - Treatment Outcome

KW - Young Adult

U2 - 10.2217/fon-2017-0592

DO - 10.2217/fon-2017-0592

M3 - Article

VL - 14

SP - 1339

EP - 1346

JO - Future Oncology

JF - Future Oncology

SN - 1479-6694

IS - 14

ER -