Erlotinib for Patients with EGFR Wild-Type Metastatic NSCLC: a Retrospective Biomarkers Analysis
- 96 Downloads
Erlotinib is approved for the treatment of patients with EGFR mutation positive, metastatic NSCLC. It is also approved as second/third line therapy for EGFR mutation negative patients, but in this setting the benefit of erlotinib is modest and there is no validated biomarker for selecting EGFR wild-type patients who may benefit the most from the treatment. We retrospectively assessed EGFR and K-RAS mutational status, and EGFR, c-MET and IGF1-R expression in tumor samples of 72 patients with metastatic NSCLC treated with erlotinib after at least one prior line of chemotherapy, from 2008 to 2012. We analyzed the association between biomarkers and outcome (RR, PFS, and OS). EGFR mutated patients achieved a better RR (56% vs 8%, p = .002), PFS (10 vs 3 months, HR 0.53, p = 0.48) and OS (20 vs 6 months, HR 0.55, p = .07), compared to EGFR wild-type patients. Among 63 EGFR wild-type patients, those with EGFR high-expression had a better outcome in terms of RR (40% vs 2%, p = .002), PFS (7.5 vs 2 months, HR 0.45, p = .007) and OS (30 vs 5 months, HR 0.34, p < .001) compared to patients with EGFR intermediate or low/negative-expression. IGF1-R expression, c-MET expression and K-RAS mutational status did not significantly affect the outcome; however, no patients with K-RAS mutation or c-MET high-expression achieved an objective response. In patients with metastatic, chemo-refractory EGFR wild-type NSCLC, EGFR high-expression may represent a positive predictor of activity for erlotinib, whereas K-RAS mutation and c-MET high-expression may predict lack of activity. These findings deserve further prospective evaluation.
KeywordsEGFR wild-type NSCLC Erlotinib K-RAS mutation IGF1-R expression C-MET expression
Compliance with Ethical Standards
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
For this type of study formal consent is not required.
Conflict of Interest
All authors declare that they do not have any conflict of interest.
- 9.Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al (2012) 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 13:239–246. https://doi.org/10.1016/S1470-2045(11)70393-X CrossRefGoogle Scholar
- 13.Rossi S, D'Argento E, Basso M, Strippoli A, Dadduzio V, Cerchiaro E et al (2015) Different EGFR gene mutations in exon 18, 19 and 21 as prognostic and predictive markers in NSCLC: a single institution analysis. Mol Diagn Ther 20:55–63. https://doi.org/10.1007/s40291-015-0176-x CrossRefGoogle Scholar
- 14.Natalicchio MI, Improta G, Zupa A, Cursio OE, Stampone E, Possidente L et al (2014) Pyrosequencing evaluation of low-frequency KRAS mutant alleles for EGF receptor therapy selection in metastatic colorectal carcinoma. Future Oncol 10:713–723. https://doi.org/10.2217/fon.13.233 CrossRefGoogle Scholar
- 17.Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM et al (2003) 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 21:3798–3807. https://doi.org/10.1200/JCO.2003.11.069 CrossRefGoogle Scholar
- 18.Coudert B, Ciuleanu T, Park K, Wu YL, Giaccone G, Brugger W et al (2012) Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann Oncol 23:388–394. https://doi.org/10.1093/annonc/mdr125 CrossRefGoogle Scholar
- 19.Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E et al (2013) 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. 14:981–988. https://doi.org/10.1016/S1470-2045(13)70310-3 CrossRefGoogle Scholar
- 21.Zer A, Leighl NB (2014) Second-line therapy in non-small-cell lung cancer: the DELTA between different genotypes widens. J Clin Oncol 32:1874–1881Google Scholar
- 23.Parra HS, Cavina R, Latteri F, Zucali PA, Campagnoli E, Morenghi E et al (2004) Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer 91:208–212. https://doi.org/10.1038/sj.bjc.6601923 CrossRefGoogle Scholar
- 25.Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J et al (2017) KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep 7:39721. https://doi.org/10.1038/srep39721 CrossRefGoogle Scholar
- 26.Cserepes M, Ostoros G, Lohinai Z, Raso E, Barbai T, Timar J et al (2014) Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer 50:1819–1828. https://doi.org/10.1016/j.ejca.2014.04.001 CrossRefGoogle Scholar
- 27.Califano R, Landi L, Cappuzzo F (2012) Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. Drugs 72(Suppl 1):28–36. https://doi.org/10.2165/1163012-S0-000000000-00000 CrossRefGoogle Scholar
- 29.Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N et al (2008) Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada clinical trials group study BR.21. J Clin Oncol 26:4268–4275. https://doi.org/10.1200/JCO.2007.14.8924 CrossRefGoogle Scholar
- 30.Del Re M, Tiseo M, Bordi P, D'Incecco A, Camerini A, Petrini I et al (2017) Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget 8:13611–13619. https://doi.org/10.18632/oncotarget.6957 Google Scholar
- 31.Dziadziuszko R, Wynes MW, Singh S, Asuncion BR, Ranger-Moore J, Konopa K et al (2012) Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer. J Thorac Oncol 7:340–347. https://doi.org/10.1097/JTO.0b013e318240ca0d CrossRefGoogle Scholar