Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 3, pp 539–548 | Cite as

A randomized phase II trial of ERCC1 and RRM1 mRNA expression-based chemotherapy versus docetaxel/carboplatin in advanced non-small cell lung cancer

  • Su Jin Heo
  • Inkyung Jung
  • Choong-kun Lee
  • Jee Hung Kim
  • Sun Min Lim
  • Yong Wha Moon
  • Hyo Sup Shim
  • Jaeheon Jeong
  • Joo-Hang Kim
  • Hye Ryun KimEmail author
  • Byoung Chul ChoEmail author
Original Article

Abstract

Objectives

To evaluate whether the selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients.

Materials and methods

Eligible patients were randomly assigned 1:1 to the experimental and control arms; the experimental arm received gemcitabine/carboplatin (GC) if ERCC1 and RRM1 expression was low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received DC.

Results

This study was prematurely terminated after the futility analysis of 43 progression-free survival (PFS) events. A total of 55 patients (n = 26 in the experimental arm, n = 29 in the control arm) were evaluable for efficacy and toxicity. Nineteen (73.1 %) patients were assigned to receive GC, 0 (0.0 %) to GV, 4 (15.4 %) to DC, and 3 (11.5 %) to DV in the experimental arm. The overall response rates were 42.3 and 48.3 % in the experimental and control arms, respectively, which were not statistically different (P = 0.657). The median PFS was 5.2 months in the experimental arm and 5.4 months in the control arm (P = 0.286). The median overall survival was 17.4 months in the experimental arm and 12.6 months in the control arm (P = 0.638). The occurrence of grade 3 or higher neutropenia (69.2 vs. 93.1 %, P = 0.035) and febrile neutropenia (3.8 vs. 24.1 %, P = 0.054) was more common in the control arm.

Conclusion

ERCC1 and RRM1 mRNA expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

Keywords

ERCC1 RRM1 mRNA expression Chemotherapy Non-small cell lung cancer 

Notes

Acknowledgments

This study was supported partly by Sanofi-Aventis Korea Ltd. and Sandoz Korea. This study was supported in part by the National Research Foundation of Korea (NRF) funded by the Korea government (MEST) (2012R1A2A2A01046927 to B.C.Cho) and by Korea Ministry of Environment (MOE) as “the Environmental Health Action Program” (2015001350002 to H.R. Kim).

Compliance with ethical standards

Conflict of interest

No conflict of interest exists in the submission of this article.

Supplementary material

280_2016_2968_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 20 kb)

References

  1. 1.
    Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R, Ajani UA, Kohler B, Edwards BK (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100(23):1672–1694. doi: 10.1093/jnci/djn389 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12(8):735–742. doi: 10.1016/s1470-2045(11)70184-x CrossRefPubMedGoogle Scholar
  3. 3.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11(2):121–128. doi: 10.1016/s1470-2045(09)70364-x CrossRefPubMedGoogle Scholar
  4. 4.
    Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703. doi: 10.1056/NEJMoa1006448 PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Kim HR, Lim SM, Kim HJ, Hwang SK, Park JK, Shin E, Bae MK, Ou SH, Wang J, Jewell SS, Kang DR, Soo RA, Haack H, Kim JH, Shim HS, Cho BC (2013) The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. Ann Oncol 24(9):2364–2370. doi: 10.1093/annonc/mdt220 CrossRefPubMedGoogle Scholar
  6. 6.
    Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346(2):92–98. doi: 10.1056/NEJMoa011954 CrossRefPubMedGoogle Scholar
  7. 7.
    Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19(13):3210–3218PubMedGoogle Scholar
  8. 8.
    Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP (2003) Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 21(16):3016–3024. doi: 10.1200/jco.2003.12.046 CrossRefPubMedGoogle Scholar
  9. 9.
    Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F (2003) Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21(16):3025–3034. doi: 10.1200/jco.2003.06.099 CrossRefPubMedGoogle Scholar
  10. 10.
    Volker M, Mone MJ, Karmakar P, van Hoffen A, Schul W, Vermeulen W, Hoeijmakers JH, van Driel R, van Zeeland AA, Mullenders LH (2001) Sequential assembly of the nucleotide excision repair factors in vivo. Mol Cell 8(1):213–224CrossRefPubMedGoogle Scholar
  11. 11.
    Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355(10):983–991. doi: 10.1056/NEJMoa060570 CrossRefPubMedGoogle Scholar
  12. 12.
    Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, Cardenal F, Sanchez JM, Gumerlock PH, Taron M, Sanchez JJ, Danenberg KD, Danenberg PV, Rosell R (2002) Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 8(7):2286–2291PubMedGoogle Scholar
  13. 13.
    Roth JA, Carlson JJ (2011) Prognostic role of ERCC1 in advanced non-small-cell lung cancer: a systematic review and meta-analysis. Clin Lung Cancer 12(6):393–401. doi: 10.1016/j.cllc.2011.04.005 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Friboulet L, Barrios-Gonzales D, Commo F, Olaussen KA, Vagner S, Adam J, Goubar A, Dorvault N, Lazar V, Job B, Besse B, Validire P, Girard P, Lacroix L, Hasmats J, Dufour F, Andre F, Soria JC (2011) Molecular characteristics of ERCC1-negative versus ERCC1-positive tumors in resected NSCLC. Clin Cancer Res 17(17):5562–5572. doi: 10.1158/1078-0432.CCR-11-0790 CrossRefPubMedGoogle Scholar
  15. 15.
    Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, Gadgeel S, Zhao X, Schreiber F, Brahmer J, Chiappori A, Tanvetyanon T, Pinder-Schenck M, Gray J, Haura E, Antonia S, Fischer JR (2013) Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 31(19):2404–2412. doi: 10.1200/jco.2012.46.9783 PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O’Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J, Peng G, Monberg MJ, Bepler G (2009) Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol 27(34):5808–5815. doi: 10.1200/jco.2009.21.9766 PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Vinolas N, Paz-Ares L, Lopez-Vivanco G, Munoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R (2007) Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol 25(19):2747–2754. doi: 10.1200/JCO.2006.09.7915 CrossRefPubMedGoogle Scholar
  18. 18.
    Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA (2004) An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res 64(11):3761–3766. doi: 10.1158/0008-5472.can-03-3363 CrossRefPubMedGoogle Scholar
  19. 19.
    Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, Provencio M, Isla D, Taron M, Diz P, Artal A (2004) Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 10(4):1318–1325CrossRefPubMedGoogle Scholar
  20. 20.
    Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, Simon G (2006) RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 24(29):4731–4737. doi: 10.1200/jco.2006.06.1101 CrossRefPubMedGoogle Scholar
  21. 21.
    Lee JJ, Maeng CH, Baek SK, Kim GY, Yoo JH, Choi CW, Kim YH, Kwak YT, Kim DH, Lee YK, Kim JB, Kim SY (2010) The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Lung Cancer 70(2):205–210. doi: 10.1016/j.lungcan.2010.02.005 CrossRefPubMedGoogle Scholar
  22. 22.
    Gong W, Zhang X, Wu J, Chen L, Li L, Sun J, Lv Y, Wei X, Du Y, Jin H, Dong J (2012) RRM1 expression and clinical outcome of gemcitabine-containing chemotherapy for advanced non-small-cell lung cancer: a meta-analysis. Lung Cancer 75(3):374–380. doi: 10.1016/j.lungcan.2011.08.003 CrossRefPubMedGoogle Scholar
  23. 23.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi: 10.1016/j.ejca.2008.10.026 CrossRefPubMedGoogle Scholar
  24. 24.
    Simon G, Sharma A, Li X, Hazelton T, Walsh F, Williams C, Chiappori A, Haura E, Tanvetyanon T, Antonia S, Cantor A, Bepler G (2007) Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 25(19):2741–2746. doi: 10.1200/jco.2006.08.2099 CrossRefPubMedGoogle Scholar
  25. 25.
    Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G (2007) DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 356(8):800–808. doi: 10.1056/NEJMoa065411 CrossRefPubMedGoogle Scholar
  26. 26.
    Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, Cambieri A, Selvaggi G, Saviozzi S, Calogero R, Papotti M, Scagliotti GV (2006) ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 17(12):1818–1825. doi: 10.1093/annonc/mdl300 CrossRefPubMedGoogle Scholar
  27. 27.
    Sijbers AM, van der Spek PJ, Odijk H, van den Berg J, van Duin M, Westerveld A, Jaspers NG, Bootsma D, Hoeijmakers JH (1996) Mutational analysis of the human nucleotide excision repair gene ERCC1. Nucl Acids Res 24(17):3370–3380PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Friboulet L, Olaussen KA, Pignon JP, Shepherd FA, Tsao MS, Graziano S, Kratzke R, Douillard JY, Seymour L, Pirker R, Filipits M, Andre F, Solary E, Ponsonnailles F, Robin A, Stoclin A, Dorvault N, Commo F, Adam J, Vanhecke E, Saulnier P, Thomale J, Le Chevalier T, Dunant A, Rousseau V, Le Teuff G, Brambilla E, Soria JC (2013) ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med 368(12):1101–1110. doi: 10.1056/NEJMoa1214271 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Treat J, Scagliotti GV, Peng G, Monberg MJ, Obasaju CK, Socinski MA (2012) Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): a combined analysis of three phase 3 trials. Lung Cancer 76(2):222–227. doi: 10.1016/j.lungcan.2011.10.021 CrossRefPubMedGoogle Scholar
  30. 30.
    Thomas A, Liu SV, Subramaniam DS, Giaccone G (2015) Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol. doi: 10.1038/nrclinonc.2015.90 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Su Jin Heo
    • 1
  • Inkyung Jung
    • 2
  • Choong-kun Lee
    • 1
  • Jee Hung Kim
    • 1
  • Sun Min Lim
    • 1
  • Yong Wha Moon
    • 1
  • Hyo Sup Shim
    • 3
  • Jaeheon Jeong
    • 4
  • Joo-Hang Kim
    • 1
  • Hye Ryun Kim
    • 1
    Email author
  • Byoung Chul Cho
    • 1
    Email author
  1. 1.Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer CenterYonsei University College of MedicineSeoulKorea
  2. 2.Department of Biostatistics and Medical InformaticsYonsei University College of MedicineSeoulKorea
  3. 3.Department of PathologyYonsei University College of MedicineSeoulKorea
  4. 4.Division of Medical Oncology and Hematology, Department of Internal Medicine, School of MedicineKyunghee UniversitySeoulKorea

Personalised recommendations