Skip to main content

Advertisement

SpringerLink
Log in

Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial

  • Original Research
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) investigated the efficacy and safety of weekly and every 2 weeks cetuximab maintenance therapy in this setting. Patients were treated with platinum-based chemotherapy plus cetuximab, and those progression-free after four to six cycles were randomized to every 2 weeks (500 mg/m2) or weekly (250 mg/m2) cetuximab maintenance. Randomization was stratified for tumor histology and response status. The primary endpoint for a regimen would be reached if the lower boundary of the 95 % confidence interval (CI) for the 1-year survival rate exceeded 55 %. A planned 480 patients were to be randomized. However, enrollment was curtailed following a negative opinion from the European Medicines Agency with regard to the use of cetuximab in this setting. After combination therapy, 311/583 (53.3 %) patients without progression were randomized to maintenance therapy: 157 to every 2 weeks cetuximab and 154 to weekly cetuximab. Baseline characteristics were balanced between these groups and exposure to cetuximab was similar. The 1-year survival rate was 62.8 % (95 % CI, 54.7–70.0) for every 2 weeks cetuximab and 64.4 % (95 % CI, 56.2–71.4) for weekly cetuximab. Safety profiles were similar, manageable, and in line with expectations. Therefore, in patients with advanced NSCLC who were progression-free after four to six cycles of first-line chemotherapy plus cetuximab, weekly and every 2 weeks cetuximab maintenance therapy were associated with similar survival outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O’Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U (2009) Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373(9674):1525–1531. doi:10.1016/S0140-6736(09)60569-9

    Article  CAS  PubMed  Google Scholar 

  2. Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D (2010) Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 28(6):911–917. doi:10.1200/JCO.2009.21.9618

    Article  CAS  PubMed  Google Scholar 

  3. Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA (2007) Randomized phase II study of gemcitabine plus cisplatin or carboplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non-small-cell lung cancer. J Clin Oncol 25(36):5777–5784. doi:10.1200/JCO.2007.13.0856

    Article  CAS  PubMed  Google Scholar 

  4. Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, Pfeifer W, O’Byrne KJ, Welte T, Kolb R, Pirker R, Chemaissani A, Perol M, Ranson MR, Ellis PA, Pilz K, Reck M (2008) Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 19(2):362–369. doi:10.1093/annonc/mdm474

    Article  CAS  PubMed  Google Scholar 

  5. Chen P, Wang L, Liu B, Zhang HZ, Liu HC, Zou Z (2011) EGFR-targeted therapies combined with chemotherapy for treating advanced non-small-cell lung cancer: a meta-analysis. Eur J Clin Pharmacol 67(3):235–243. doi:10.1007/s00228-010-0965-4

    Article  CAS  PubMed  Google Scholar 

  6. Ibrahim EM, Abouelkhair KM, Al-Masri OA, Chaudry NC, Kazkaz GA (2011) Cetuximab-based therapy is effective in chemotherapy-naive patients with advanced and metastatic non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Lung 189(3):193–198. doi:10.1007/s00408-011-9286-3

    Article  CAS  PubMed  Google Scholar 

  7. Lin H, Jiang J, Liang X, Zhou X, Huang R (2010) Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer 70:57–62. doi:10.1016/j.lungcan.2010.01.009

    Article  PubMed  Google Scholar 

  8. Thatcher N, Lynch TJ, Butts CA, Rosell R, Shepherd FA, Pujol J-L, Vansteenkiste J, Emig M, Groos J, Pirker R (2009) Cetuximab plus platinum-based chemotherapy as 1st-line treatment in patients with non-small cell lung cancer (NSCLC): a meta-analysis of randomized phase II/III trials. J Thorac Oncol 4(9):S297, abstr A293.297

    Google Scholar 

  9. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671. doi:10.1200/JCO.2008.20.8397

    Article  CAS  PubMed  Google Scholar 

  10. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417. doi:10.1056/NEJMoa0805019

    Article  PubMed  Google Scholar 

  11. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127. doi:10.1056/NEJMoa0802656

    Article  CAS  PubMed  Google Scholar 

  12. Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Rosello S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A (2010) Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol 21(7):1537–1545. doi:10.1093/annonc/mdp549

    Article  CAS  PubMed  Google Scholar 

  13. Martin-Martorell P, Rosello S, Rodriguez-Braun E, Chirivella I, Bosch A, Cervantes A (2008) Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer 99(3):455–458. doi:10.1038/sj.bjc.6604530

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Pfeiffer P, Nielsen D, Bjerregaard J, Qvortrup C, Yilmaz M, Jensen B (2008) Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol 19(6):1141–1145. doi:10.1093/annonc/mdn020

    Article  CAS  PubMed  Google Scholar 

  15. Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X, Vlassak S, Schlichting M, Ciardiello F (2012) Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol 30(23):2861–2868. doi:10.1200/JCO.2011.40.9243

    Article  PubMed  Google Scholar 

  16. Brodowicz T, Ciuleanu TE, Radosavljevic D, Shacham-Shmueli E, Vrbanec D, Plate S, Mrsic-Krmpotic Z, Dank M, Purkalne G, Messinger D, Zielinski CC (2013) FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study. Ann Oncol 24(7):1769–1777. doi:10.1093/annonc/mdt116

    Article  CAS  PubMed  Google Scholar 

  17. (2002) In: Sobin LH, Wittekind C (eds) TNM classification of malignant tumours, sixth edition. Wiley-Liss, New York, pp 99–103

  18. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG, European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92(3):205–216. doi:10.1093/jnci/92.3.205

    Article  CAS  PubMed  Google Scholar 

  19. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezinek I, Klingelschmitt G, Klughammer B, Giaccone G (2010) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11(6):521–529. doi:10.1016/S1470-2045(10)70112-1

    Article  CAS  PubMed  Google Scholar 

  20. Perol M, Chouaid C, Perol D, Barlesi F, Gervais R, Westeel V, Crequit J, Lena H, Vergnenegre A, Zalcman G, Monnet I, Le Caer H, Fournel P, Falchero L, Poudenx M, Vaylet F, Segura-Ferlay C, Devouassoux-Shisheboran M, Taron M, Milleron B (2012) Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 30(28):3516–3524. doi:10.1200/JCO.2011.39.9782

    Article  CAS  PubMed  Google Scholar 

  21. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440. doi:10.1016/S0140-6736(09)61497-5

    Article  CAS  PubMed  Google Scholar 

  22. Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2013) PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 31(23):2895–2902. doi:10.1200/JCO.2012.47.1102

    Article  CAS  PubMed  Google Scholar 

  23. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikstrom A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ (2013) Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 31(24):3004–3011. doi:10.1200/JCO.2012.42.3749

    Article  CAS  PubMed  Google Scholar 

  24. Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt WE, Paz-Ares L, Storkel S, Schumacher KM, von Heydebreck A, Celik I, O’Byrne KJ (2012) EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 13(1):33–42. doi:10.1016/S1470-2045(11)70318-7

    Article  CAS  PubMed  Google Scholar 

  25. Belani CP, Schreeder MT, Steis RG, Guidice RA, Marsland TA, Butler EH, Ramalingam SS (2008) Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer 113(9):2512–2517. doi:10.1002/cncr.23902

    Article  CAS  PubMed  Google Scholar 

  26. Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, Atkins JN, Dakhil SR, Albain KS, Kim ES, Redman M, Crowley JJ, Gandara DR (2010) Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. J Clin Oncol 28(31):4747–4754. doi:10.1200/JCO.2009.27.9356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Robert F, Blumenschein G, Herbst RS, Fossella FV, Tseng J, Saleh MN, Needle M (2005) Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol 23(36):9089–9096. doi:10.1200/JCO.2004.00.1438

    Article  CAS  PubMed  Google Scholar 

  28. Socinski MA, Saleh MN, Trent DF, Dobbs TW, Zehngebot LM, Levine MA, Bordoni R, Stella PJ (2009) A randomized, phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small-cell lung cancer (NSCLC). Ann Oncol 20(6):1068–1073. doi:10.1093/annonc/mdn745

    Article  CAS  PubMed  Google Scholar 

  29. Thienelt CD, Bunn PA Jr, Hanna N, Rosenberg A, Needle MN, Long ME, Gustafson DL, Kelly K (2005) Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol 23(34):8786–8793. doi:10.1200/JCO.2005.03.1997

    Article  PubMed  Google Scholar 

  30. Redman MW, Crowley JJ, Herbst RS, Hirsch FR, Gandara DR (2012) Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819. Clin Cancer Res: J Am Assoc Cancer Res 18(15):4004–4012. doi:10.1158/1078-0432.CCR-12-0167

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The NEXT trial was sponsored by Merck KGaA, Darmstadt, Germany. The authors would like to thank the patients, investigators, co-investigators, and the study teams at each of the participating centers and at Merck KGaA. Medical writing services were provided by Cancer Communications & Consultancy Ltd, Knutsford, UK, and funded by Merck KGaA, Darmstadt, Germany.

Conflict of interest

DFH received personal fees for advisory boards and/or lectures from Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, and Bristol-Myers Squibb and travel and registration costs for meeting attendance from Merck KGaA. OM received personal fees from Boehringer Ingelheim, GlaxoSmithKline, and Medison and a research grant from Roche. BS and RE are compensated employees of Merck KGaA and RE holds shares in the company. UG declared a consultant/advisory relationship with Merck KGaA. Other authors declared no conflict of interest in relation to the work under consideration.

Author information

Authors and Affiliations

  1. LungenClinic Grosshansdorf, Woehrendamm 80, 22927, Grosshansdorf, Germany

    David F. Heigener & Ulrich Gatzemeier

  2. Instituto do Cancer—Arnaldo Vieira de Carvalho, São Paulo, Brazil

    José Rodrigues Pereira

  3. Hospital General Vall d’Hebron, Barcelona, Spain

    Enriqueta Felip

  4. F.D. Roosevelt Faculty Hospital, Banská Bystrica, Slovakia

    Juraj Mazal

  5. Russian Cancer Research Centre, Moscow, Russian Federation

    Lyudmila Manzyuk

  6. National Cancer Centre Singapore, Singapore, Singapore

    Eng Huat Tan

  7. Tel Aviv Medical Center, Tel Aviv, Israel

    Ofer Merimsky

  8. Merck KGaA, Darmstadt, Germany

    Barbara Sarholz & Regina Esser

Authors
  1. David F. Heigener
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José Rodrigues Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enriqueta Felip
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juraj Mazal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lyudmila Manzyuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eng Huat Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ofer Merimsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Barbara Sarholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Regina Esser
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ulrich Gatzemeier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David F. Heigener.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 192 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heigener, D.F., Pereira, J.R., Felip, E. et al. Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial. Targ Oncol 10, 255–265 (2015). https://doi.org/10.1007/s11523-014-0336-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-014-0336-7

Keywords

Search

Navigation