Erlotinib treatment after platinum-based therapy in elderly patients with non-small-cell lung cancer in routine clinical practice - results from the ElderTac study

Wolfgang M Brueckl, H Jost Achenbach, Joachim H Ficker, Wolfgang Schuette, Wolfgang M Brueckl, H Jost Achenbach, Joachim H Ficker, Wolfgang Schuette

Abstract

Background: In this prospective non-interventional study, the effectiveness and tolerability of erlotinib in elderly patients with non-small-cell lung cancer (NSCLC) after ≥1 platinum-based chemotherapy were assessed.

Methods: A total of 385 patients ≥65 years of age with advanced NSCLC receiving erlotinib were observed over 12 months. The primary endpoint was the 1-year overall survival (OS) rate.

Results: Patients were predominantly Caucasian (99.2%), a mean of 73 years old; 24.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Most common tumor histologies were adenocarcinoma (64.9%) and squamous cell carcinoma (22.3%). Of 119 patients tested, 15.1% had an activating epidermal growth factor receptor gene (EGFR) mutation. The 1-year OS rate was 31% (95% CI 25-36) with a median OS of 7.1 months (95% CI 6.0-7.9). OS was significantly better in females than males (p = 0.0258) and in patients with an EGFR mutation compared to EGFR wild-type patients (p = 0.0004). OS was not affected by age (p = 0.3436) and ECOG PS (p = 0.5364). Patients with squamous NSCLC tended to live longer than patients with non-squamous EGFR wild-type tumors (median OS: 8.6 vs 5.5 months). Cough and dyspnea improved during the observation period. The erlotinib safety profile was comparable to that in previous studies with rash (45.2%) and diarrhea (22.6%) being the most frequently reported adverse events.

Conclusions: Erlotinib represents a suitable palliative treatment option in further therapy lines for elderly patients with advanced NSCLC. The results obtained under real-life conditions add to our understanding of the benefits and risks of erlotinib in routine clinical practice.

Trial registration: BfArM ( https://www.bfarm.de ; ML23023); ClinicalTrials.gov (NCT01535729; 20 Feb 2012).

Keywords: Aged; Epidermal growth factor receptor; Non-small-cell lung carcinoma; Second line; Tyrosine kinase inhibitor.

Conflict of interest statement

Ethics approval and consent to participate

All participating patients provided written informed consent. The study was approved by the ethics committee of the Friedrich-Alexander-Universitaet Erlangen-Nuernberg (no. 4441).

Consent for publication

Not applicable.

Competing interests

WMB received lecture and consultancy fees from Astra Zeneca, Boehringer Ingelheim, BMS, Lilly, MSD and Roche Pharma. JHF received lecture and consultancy fees from AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Pharma. WS declares receiving payments for lectures and consultancy from Roche Pharma. HJA received lecture and consultancy fees, as well as travel support from Bristol-Myers-Squibb, Boehringer Ingelheim, Grifols, Insmed, Lilly, Novartis, PneumRx, and Roche Pharma.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves on 1-year overall survival in erlotinib-treated patients. a) Overall survival in the whole study population according to prespecified age group. b) Overall survival in patients with squamous carcinoma, patients with non-squamous EGFR wild-type carcinoma and patients with EGFR activating mutations. c) Overall survival according to age group (< 75 vs ≥75 years) in patients with squamous carcinoma and in patients with non-squamous EGFR wild-type carcinoma. CI, confidence interval; EGFR, epidermal growth factor receptor gene; HR, hazard ratio; NSCLC, non-small-cell lung cancer; OS, overall survival; WT, wild-type.
Fig. 2
Fig. 2
Occurrence of symptoms during the study period. Percentage of patients with mild, moderate and severe dyspnea (a) and cough (b) at baseline and 6, 9 and 12 months. Percentages were based on patients remaining in the study at the respective timepoints

References

    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi: 10.3322/caac.21262.
    1. American Cancer Society: . Accessed 19 Mar 2018.
    1. SEER Cancer Statistics: . Accessed 2 Dec 2015.
    1. Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32(4):669–692. doi: 10.1016/j.ccm.2011.08.005.
    1. Chang JS, Chen LT, Shan YS, Lin SF, Hsiao SY, Tsai CR, Yu SJ, Tsai HJ. Comprehensive analysis of the incidence and survival patterns of lung Cancer by Histologies, including rare subtypes, in the era of molecular medicine and targeted therapy: a nation-wide Cancer registry-based study from Taiwan. Medicine (Baltimore) 2015;94(24):e969. doi: 10.1097/MD.0000000000000969.
    1. Jimenez Massa AE, Alonso Sardon M, Gomez Gomez FP. Lung cancer: how does it appear in our hospital? Rev Clin Esp. 2009;209(3):110–117. doi: 10.1016/S0014-2565(09)70876-8.
    1. Kukulj S, Popovic F, Budimir B, Drpa G, Serdarevic M, Polic-Vizintin M. Smoking behaviors and lung cancer epidemiology: a cohort study. Psychiatr Danub. 2014;26(Suppl 3):485–489.
    1. Missaoui N, Hmissa S, Landolsi H, Korbi S, Joma W, Anjorin A, Ben Abdelkrim S, Beizig N, Mokni M. Lung cancer in Central Tunisia: epidemiology and clinicopathological features. Asian Pac J Cancer Prev. 2011;12(9):2305–2309.
    1. Novaes FT, Cataneo DC, Ruiz Junior RL, Defaveri J, Michelin OC, Cataneo AJ. Lung cancer: histology, staging, treatment and survival. J Bras Pneumol. 2008;34(8):595–600. doi: 10.1590/S1806-37132008000800009.
    1. Olszewski AJ, Ali S, Witherby SM. Disparate survival trends in histologic subtypes of metastatic non-small cell lung cancer: a population-based analysis. Am J Cancer Res. 2015;5(7):2229–2240.
    1. Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese PP, Larussi T, Mucilli F, Mezzetti A, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005;23(4):857–865. doi: 10.1200/JCO.2005.08.043.
    1. Sugio K, Uramoto H, Ono K, Oyama T, Hanagiri T, Sugaya M, Ichiki Y, So T, Nakata S, Morita M, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer. 2006;94(6):896–903. doi: 10.1038/sj.bjc.6603040.
    1. Varghese AM, Sima CS, Chaft JE, Johnson ML, Riely GJ, Ladanyi M, Kris MG. Lungs don't forget: comparison of the KRAS and EGFR mutation profile and survival of collegiate smokers and never smokers with advanced lung cancers. J Thorac Oncol. 2013;8(1):123–125. doi: 10.1097/JTO.0b013e31827914ea.
    1. Lopes GL, Vattimo EF, Castro Junior G. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer. J Bras Pneumol. 2015;41(4):365–375. doi: 10.1590/S1806-37132015000004531.
    1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–137. doi: 10.1038/35052073.
    1. Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, Kerr K, Popat S, Reck M, Senan S, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v1–v27. doi: 10.1093/annonc/mdw326.
    1. Brueckl WM. Treatment choice in EGFR-mutant non-small-cell lung cancer. Lancet Oncol. 2017; 10.1016/S1470-2045(17)30684-8. [Epub ahead of print]
    1. Tarceva® . Last updated 12. 2017. Summary of product characteristics.
    1. Gridelli C, Maione P, Rossi A, Ferrara ML, Castaldo V, Palazzolo G, Mazzeo N. Treatment of advanced non-small-cell lung cancer in the elderly. Lung Cancer. 2009;66(3):282–286. doi: 10.1016/j.lungcan.2009.08.006.
    1. Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA. Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada clinical trials group study BR.21. J Clin Oncol. 2008;26(14):2350–2357. doi: 10.1200/JCO.2007.15.2280.
    1. Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ, Housman MG, Escarce JJ. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21(7):1383–1389. doi: 10.1200/JCO.2003.08.010.
    1. Vora N, Reckamp KL. Non-small cell lung cancer in the elderly: defining treatment options. Semin Oncol. 2008;35(6):590–596. doi: 10.1053/j.seminoncol.2008.08.009.
    1. Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, Kotsakis A, Papakotoulas P, Rapti A, Agelidou M, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic oncology research group (HORG) randomized phase 3 study. Cancer. 2013;119(15):2754–2764. doi: 10.1002/cncr.28132.
    1. Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13(3):300–308. doi: 10.1016/S1470-2045(11)70385-0.
    1. Reck M, van Zandwijk N, Gridelli C, Baliko Z, Rischin D, Allan S, Krzakowski M, Heigener D. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva lung Cancer survival treatment study. J Thorac Oncol. 2010;5(10):1616–1622. doi: 10.1097/JTO.0b013e3181f1c7b0.
    1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123–132. doi: 10.1056/NEJMoa050753.
    1. Chen YM, Tsai CM, Fan WC, Shih JF, Liu SH, Wu CH, Chou TY, Lee YC, Perng RP, Whang-Peng J. Phase II randomized trial of erlotinib or vinorelbine in chemonaive, advanced, non-small cell lung cancer patients aged 70 years or older. J Thorac Oncol. 2012;7(2):412–418. doi: 10.1097/JTO.0b013e31823a39e8.
    1. Jackman DM, Yeap BY, Lindeman NI, Fidias P, Rabin MS, Temel J, Skarin AT, Meyerson M, Holmes AJ, Borras AM et al: Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol 2007, 25(7):760–766.
    1. Merimsky O, Cheng CK, Au JS, von Pawel J, Reck M. Efficacy and safety of first-line erlotinib in elderly patients with advanced non-small cell lung cancer. Oncol Rep. 2012;28(2):721–727. doi: 10.3892/or.2012.1824.
    1. Stinchcombe TE, Peterman AH, Lee CB, Moore DT, Beaumont JL, Bradford DS, Bakri K, Taylor M, Crane JM, Schwartz G et al.: A randomized phase II trial of first-line treatment with gemcitabine, erlotinib, or gemcitabine and erlotinib in elderly patients (age >/=70 years) with stage IIIB/IV non-small cell lung cancer. J Thorac Oncol 2011, 6(9):1569–1577.
    1. Yoshioka H, Komuta K, Imamura F, Kudoh S, Seki A, Fukuoka M. Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer. 2014;86(2):201–206. doi: 10.1016/j.lungcan.2014.09.015.
    1. Yamada K, Azuma K, Takeshita M, Uchino J, Nishida C, Suetsugu T, Kondo A, Harada T, Eida H, Kishimoto J, et al. Phase II trial of Erlotinib in elderly patients with previously treated non-small cell lung Cancer: results of the lung oncology Group in Kyushu (LOGiK-0802) Anticancer Res. 2016;36(6):2881–2887.
    1. Miyawaki M, Naoki K, Yoda S, Nakayama S, Satomi R, Sato T, Ikemura S, Ohgino K, Ishioka K, Arai D, et al. Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio lung oncology group study 001 (KLOG001) Mol Clin Oncol. 2017;6(3):409–414. doi: 10.3892/mco.2017.1154.
    1. Soo RA, Kawaguchi T, Loh M, Ou SH, Shieh MP, Cho BC, Mok TS, Soong R. Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol. 2012;8(4):451–462. doi: 10.2217/fon.12.25.
    1. Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, Ayoub J, Lago S, de Albuquerque Ribeiro R, Gerogianni A, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada clinical trials group study BR.21. J Clin Oncol. 2006;24(24):3831–3837. doi: 10.1200/JCO.2006.05.8073.
    1. Cioffi P, Marotta V, Fanizza C, Giglioni A, Natoli C, Petrelli F, Grappasonni I. Effectiveness and response predictive factors of erlotinib in a non-small cell lung cancer unselected European population previously treated: a retrospective, observational, multicentric study. J Oncol Pharm Pract. 2013;19(3):246–253. doi: 10.1177/1078155212465994.
    1. Van Meerbeeck J, Galdermans D, Bustin F, De Vos L, Lechat I, Abraham I. Survival outcomes in patients with advanced non-small cell lung cancer treated with erlotinib: expanded access programme data from Belgium (the TRUST study) Eur J Cancer Care (Engl) 2014;23(3):370–379. doi: 10.1111/ecc.12146.
    1. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–246. doi: 10.1016/S1470-2045(11)70393-X.
    1. Vale CL, Burdett S, Fisher DJ, Navani N, Parmar MK, Copas AJ, Tierney JF. Should Tyrosine Kinase Inhibitors Be Considered for Advanced Non-Small-Cell Lung Cancer Patients With Wild Type EGFR? Two Systematic Reviews and Meta-Analyses of Randomized Trials. Clin Lung Cancer. 2015;16(3):173–182.e174. doi: 10.1016/j.cllc.2014.11.007.
    1. Osarogiagbon RU, Cappuzzo F, Ciuleanu T, Leon L, Klughammer B. Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials. Transl Lung Cancer Res. 2015;4(4):465–474.
    1. Jazieh AR, Al Sudairy R, Abu-Shraie N, Al Suwairi W, Ferwana M, Murad MH. Erlotinib in wild type epidermal growth factor receptor non-small cell lung cancer: a systematic review. Ann Thorac Med. 2013;8(4):204–208. doi: 10.4103/1817-1737.118503.
    1. Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14(10):981–988. doi: 10.1016/S1470-2045(13)70310-3.
    1. Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: docetaxel and Erlotinib lung Cancer trial (DELTA) J Clin Oncol. 2014;32(18):1902–1908. doi: 10.1200/JCO.2013.52.4694.
    1. Hirsch FR, Varella-Garcia M, Bunn PA, Jr, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21(20):3798–3807. doi: 10.1200/JCO.2003.11.069.
    1. The Cancer Genome Atlas Research Network Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–525. doi: 10.1038/nature11404.
    1. Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Balint B, Losonczy G, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763–774. doi: 10.1016/S1470-2045(15)00021-2.
    1. Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Goker E, Georgoulias V, Li W, Isla D, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897–907. doi: 10.1016/S1470-2045(15)00006-6.
    1. Gambale E, Carella C, Amerio P, Buttitta F, Patea RL, Natoli C, De Tursi M. Extraordinary and prolonged erlotinib-induced clinical response in a patient with EGFR wild-type squamous lung cancer in third-line therapy: a case report. Int Med Case Rep J. 2017;10:173–175. doi: 10.2147/IMCRJ.S134944.
    1. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–265. doi: 10.1016/S0140-6736(16)32517-X.
    1. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375(19):1823–1833. doi: 10.1056/NEJMoa1606774.
    1. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–1550. doi: 10.1016/S0140-6736(15)01281-7.
    1. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung Cancer. N Engl J Med. 2015;373(2):123–135. doi: 10.1056/NEJMoa1504627.
    1. Masago K, Fujita S, Togashi Y, Kim YH, Hatachi Y, Fukuhara A, Nagai H, Sakamori Y, Mio T, Mishima M. Clinicopathologic factors affecting the progression-free survival of patients with advanced non-small-cell lung cancer after gefitinib therapy. Clin Lung Cancer. 2011;12(1):56–61. doi: 10.3816/CLC.2011.n.008.
    1. Bertram M, Petersen V, Heßling J, Tessen HW, Münz M, Jänicke M, Spring L. N M: EGFR mutation testing and treatment with tyrosin-kinase inhibitors in patients with metastatic non-small cell lung cancer treated by office based medical oncologists in Germany - data from the clinical registry on lung cancer (TLK) Oncol Res Treat. 2015;38(suppl 5):V886.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться