Predictive and prognostic factors in second- and third-line erlotinib treatment in NSCLC patients with known status of the EGFR gene

Krawczyk,Paweł; Kowalski,Dariusz  M.; Wojas Krawczyk,Kamila; Szczyrek,Michał; Mlak,Radosław; Rolski,Andrzej; Szudy,Aneta; Kieszko,Robert; Winiarczyk,Kinga; Milanowski,Janusz; Krzakowski,Maciej

doi:10.3892/or.2013.2553

Predictive and prognostic factors in second- and third-line erlotinib treatment in NSCLC patients with known status of the EGFR gene

Authors:
- Paweł Krawczyk
- Dariusz M. Kowalski
- Kamila Wojas Krawczyk
- Michał Szczyrek
- Radosław Mlak
- Andrzej Rolski
- Aneta Szudy
- Robert Kieszko
- Kinga Winiarczyk
- Janusz Milanowski
- Maciej Krzakowski
View Affiliations

Affiliations: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland, Department of Lung Cancer and Chest Tumours, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
Published online on: June 19, 2013 https://doi.org/10.3892/or.2013.2553
Pages: 1463-1472

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Erlotinib is a reversible tyrosine kinase inhibitor of epidermal growth factor receptor (TKI EGFR). In Poland, as of July 2012, it is used in the treatment only of patients with non-small cell lung cancer (NSCLC) and with EGFR mutation gene after standard chemotherapy failure. The effectiveness of erlotinib in second- or third-line treatment of NSCLC patients without EGFR activating mutation gene remains debatable. Clinical trial results indicated that TKI EGFR showed an efficacy of 70‑80% in patients with EGFR mutations, while the clinical response to treatment among unselected Caucasian patients is only 10%. The present study was conducted in a group of 71 patients with inoperable, locally advanced or metastatic NSCLC treated with erlotinib as the second- or third-line therapy. Molecular tests (examination of EGFR mutation and gene amplification) were carried out retrospectively. Objective response rate, overall survival (OS) and progression-free survival (PFS) were calculated. Effects of clinical and molecular factors including the presence of EGFR mutations, EGFR gene amplification, patient performance status, rash, smoking status, time from diagnosis to start of therapy, weight loss and the serum LDH levels were analyzed. An objective response in the form of partial response occurred in only 5 patients (7%), who carried EGFR gene mutation. Median time to PFS for the entire group of patients was 1.5 months and median OS was 10 months. The strongest factors increasing the risk of progression in patients treated with erlotinib were the absence of activating mutations in the EGFR gene (6‑fold increased risk) and no treatment‑related rash (4.5‑fold increased risk). The most important factors affecting the risk of early mortality were poor performance status (HR 37.344; P>0.0001), no treatment-related rash (HR 14.9348; P=0.0002) and a short response time on the first-line chemotherapy (HR 9.519; P=0.0445).

View Figures

View References

1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	D'Addario G, Früh M, Reck M, Baumann P, Klepetko W and Felip E: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21:v116–v119. 2010. View Article : Google Scholar
3	Dancey J and Sausville EA: Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov. 2:296–313. 2003. View Article : Google Scholar : PubMed/NCBI
4	Cohen MH, Johnson JR, Chen YF, Sridhara R and Pazdur R: FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 10:461–466. 2005. View Article : Google Scholar : PubMed/NCBI
5	Shepherd FA, Rodrigues PJ, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 353:123–132. 2005. View Article : Google Scholar : PubMed/NCBI
6	Herbst RS, Prager D, Hermann R, et al: TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 23:5892–5899. 2005. View Article : Google Scholar
7	Petrelli F, Borgonovo K, Cabiddu M, Lonati V and Barni S: Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer. 78:8–15. 2012. View Article : Google Scholar : PubMed/NCBI
8	Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 353:133–144. 2005. View Article : Google Scholar : PubMed/NCBI
9	Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non small- cell lung cancer. J Clin Oncol. 23:6829–6837. 2005. View Article : Google Scholar : PubMed/NCBI
10	Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 Trial). J Clin Oncol. 21:2237–2246. 2003. View Article : Google Scholar : PubMed/NCBI
11	Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD 1839 (‘Iressa’) in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol. 21:292a2002.
12	Kim ES, Hirsh V, Mok T, et al: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 372:1809–1818. 2008. View Article : Google Scholar : PubMed/NCBI
13	Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 366:1527–1537. 2005. View Article : Google Scholar
14	Reck M, van Zandwijk N, Gridelli C, et al: 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. 5:1616–1622. 2010. View Article : Google Scholar : PubMed/NCBI
15	Ciuleanu T, Stelmakh L, Cicenas S, et al: 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. 13:300–308. 2012. View Article : Google Scholar : PubMed/NCBI
16	Taron M, Ichinose Y, Rosell R, et al: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res. 11:5878–5885. 2005. View Article : Google Scholar
17	Endo K, Konishi A, Sasaki H, et al: Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay. Lung Cancer. 50:375–384. 2005. View Article : Google Scholar : PubMed/NCBI
18	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar
19	Fukuoka M, Wu YL, Thongprasert S, et al: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 29:2866–2874. 2011. View Article : Google Scholar
20	Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
21	Mitsudomi T, Morita S, Yatabe Y, et al: 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. 11:121–128. 2010. View Article : Google Scholar
22	Han JY, Park K, Kim SW, et al: First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 30:1122–1128. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zhou C, Wu YL, Chen G, et al: 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. 12:735–742. 2011.PubMed/NCBI
24	Rosell R, Carcereny E, Gervais R, 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 phace 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
25	Rosell R, Moran T, Quertalt C, et al: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 361:958–967. 2009. View Article : Google Scholar : PubMed/NCBI
26	Gao H, Ding X, Wei D, et al: Erlotinib in patients with advanced non-small-cell lung cancer: a meta-analysis. Trans Lung Cancer Res. 1:129–144. 2012.PubMed/NCBI