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Targeted Therapies for Locally Advanced or Metastatic Squamous Cell Carcinoma of the Lung

  • Lung Cancer (HA Wakelee, Section Editor)
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Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Most patients with squamous cell carcinoma (SCC) present with advanced or metastatic disease at the time of diagnosis. Given the low prevalence of oncogenic driver mutations in SCC, I do not routinely perform molecular testing. The times that I perform molecular testing in SCC are for patients with SCC and a light or never smoking history, adenosquamous histology, or when the histological diagnosis is not definitive. For patients with a good performance status and adequate organ function, a platinum doublet is the standard therapy, and I generally use carboplatin and gemcitabine or carboplatin and paclitaxel. In the second-line setting for patients who are chemotherapy candidates, I will use docetaxel on a weekly or every three week schedule. Erlotinib is a treatment option in the third-line setting. My preference is for patients to participate in clinical trials because the development of novel therapies for patients with SCC has been slow compared with nonsquamous non-small cell lung cancer. Ongoing investigations into the genomics of SCC will hopefully identify driver mutations or alterations in pathways essential for oncogenesis and tumor growth and will lead to the development of targeted therapies. The complexity of the genomics of SCC will make the development of targeted therapies challenging.

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References and Recommended Reading

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  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  3. Travis WD, Lubin J, Ries L, et al. United States lung carcinoma incidence trends: declining for most histologic types among males, increasing among females. Cancer. 1996;77:2464–70.

    Article  PubMed  CAS  Google Scholar 

  4. Kenfield SA, Wei EK, Stampfer MJ, et al. Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control. 2008;17:198–204.

    Article  PubMed  CAS  Google Scholar 

  5. Ito H, Matsuo K, Tanaka H, et al. Nonfilter and filter cigarette consumption and the incidence of lung cancer by histological type in Japan and the United States: analysis of 30-year data from population-based cancer registries. Int J Cancer. 2011;128:1918–28.

    Article  PubMed  CAS  Google Scholar 

  6. Benhamou S, Benhamou E, Tirmarche M, et al. Lung cancer and use of cigarettes: a French case–control study. J Natl Cancer Inst. 1985;74:1169–75.

    PubMed  CAS  Google Scholar 

  7. Wynder EL, Muscat JE. The changing epidemiology of smoking and lung cancer histology. Environ Health Perspect. 1995;103 Suppl 8:143–8.

    Article  PubMed  Google Scholar 

  8. Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995. J Toxicol Environ Health. 1997;50:307–64.

    Article  PubMed  CAS  Google Scholar 

  9. Rosado-de-Christenson ML, Templeton PA, Moran CA. Bronchogenic carcinoma: radiologic-pathologic correlation. Radiographics. 1994;14:429–46. quiz 447–8.

    Article  PubMed  CAS  Google Scholar 

  10. Wistuba II. Histologic evaluation of bronchial squamous lesions: any role in lung cancer risk assessment? Clin Cancer Res. 2005;11:1358–60.

    Article  PubMed  CAS  Google Scholar 

  11. Grilley-Olson JE, Hayes DN, Moore DT, et al. Validation of interobserver agreement in lung cancer assessment: hematoxylin-eosin diagnostic reproducibility for non-small cell lung cancer: the 2004 World Health Organization classification and therapeutically relevant subsets. Arch Pathol Lab Med. 2013;137:32–40.

    Article  PubMed  Google Scholar 

  12. Bishop JA, Teruya-Feldstein J, Westra WH, et al. p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012;25:405–15. This publication describes the p63 immunohistiochemistry test that will be more specific for the diagnosis of squamous cell carcinoma which is increasingly important related to treatment options and the need for additional molecular testing.

    Article  PubMed  CAS  Google Scholar 

  13. Pelosi G, Fabbri A, Bianchi F, et al. DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol. 2012;7:281–90.

    Article  PubMed  Google Scholar 

  14. Nobre AR, Albergaria A, Schmitt F. p40: a p63 isoform useful for lung cancer diagnosis - a review of the physiological and pathological role of p63. Acta Cytol. 2013;57:1–8.

    Article  PubMed  CAS  Google Scholar 

  15. Travis WD, Bramilla E, Muller-Hermelink A, et al. World Health Organization classification of tumors. Pathology and genetics of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: IARC Press; 2004.

    Google Scholar 

  16. Moro-Sibilot D, Lantuejoul S, Diab S, et al. Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis. Eur Respir J. 2008;31:854–9.

    Article  PubMed  CAS  Google Scholar 

  17. Wilkerson MD, Yin X, Hoadley KA, et al. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types. Clin Cancer Res. 2010;16:4864–75.

    Article  PubMed  CAS  Google Scholar 

  18. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  PubMed  CAS  Google Scholar 

  19. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.

    Article  PubMed  CAS  Google Scholar 

  20. 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 phase 3 trial. Lancet Oncol. 2012;13:239–46.

    Article  PubMed  CAS  Google Scholar 

  21. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25. The most comprehensive evaluation of genomics of squamous cell carcinoma to date, and many of the molecular alterations identified will be the target of future drug development.

    Google Scholar 

  22. Paik PK, Hasanovic A, Wang L, et al. Multiplex testing for driver mutations in squamous cell carcinomas of the lung. J Clin Oncol. 2012;30:abstract 7505

    Google Scholar 

  23. Drilon A, Rekhtman N, Ladanyi M, et al. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13:e418–26.

    Article  PubMed  CAS  Google Scholar 

  24. Chen S, Xu Y, Chen Y, et al. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells. PLoS One. 2012;7:e36326.

    Article  PubMed  CAS  Google Scholar 

  25. Hussenet T, du Manoir S. SOX2 in squamous cell carcinoma: amplifying a pleiotropic oncogene along carcinogenesis. Cell Cycle. 2010;9:1480–6.

    Article  PubMed  CAS  Google Scholar 

  26. Hussenet T, Dali S, Exinger J, et al. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One. 2010;5:e8960.

    Article  PubMed  Google Scholar 

  27. Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2:305–16.

    Article  PubMed  CAS  Google Scholar 

  28. Su X, Chakravarti D, Flores ER. p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer. 2013;13:136–43.

    Article  PubMed  CAS  Google Scholar 

  29. Bass AJ, Watanabe H, Mermel CH, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41:1238–42.

    Article  PubMed  CAS  Google Scholar 

  30. Yuan P, Kadara H, Behrens C, et al. Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One. 2010;5:e9112.

    Article  PubMed  Google Scholar 

  31. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2:62ra93.

    Article  PubMed  CAS  Google Scholar 

  32. Dutt A, Ramos AH, Hammerman PS, et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One. 2011;6:e20351.

    Article  PubMed  CAS  Google Scholar 

  33. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78–89.

    Article  PubMed  CAS  Google Scholar 

  34. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–51.

    Article  PubMed  CAS  Google Scholar 

  35. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009;14:253–63.

    Article  PubMed  CAS  Google Scholar 

  36. Di Maio M, Perrone F, Chiodini P, et al. Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2007;25:1377–82.

    Article  PubMed  Google Scholar 

  37. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.

    Article  PubMed  CAS  Google Scholar 

  38. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.

    Article  PubMed  CAS  Google Scholar 

  39. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21:1804–9.

    Article  PubMed  CAS  Google Scholar 

  40. Hainsworth JD, Fang L, Huang JE, et al. BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer. J Thorac Oncol. 2011;6:109–14.

    Article  PubMed  Google Scholar 

  41. Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:650–6.

    Article  PubMed  CAS  Google Scholar 

  42. Gatzemeier U, Blumenschein G, Fosella F, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol (Ann Meet Proc). 2006;24:7002.

    Google Scholar 

  43. Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:1835–42.

    Article  PubMed  CAS  Google Scholar 

  44. Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012;30:2829–36.

    Article  PubMed  CAS  Google Scholar 

  45. Reck M, Kaiser R, Mellemgaard A, et al. Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol. 2013;31:abstract LBA801.

  46. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525–31.

    Article  PubMed  CAS  Google Scholar 

  47. Pirker R, Pereira JR, von Pawel J, et al. 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. 2012;13:33–42.

    Article  PubMed  CAS  Google Scholar 

  48. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306–11.

    Article  PubMed  CAS  Google Scholar 

  49. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol. 2004;22:1103–9.

    Article  PubMed  CAS  Google Scholar 

  50. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

    Article  PubMed  CAS  Google Scholar 

  51. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  PubMed  CAS  Google Scholar 

  52. Chou TY, Chiu CH, Li LH, et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res. 2005;11:3750–7.

    Article  PubMed  CAS  Google Scholar 

  53. Park SH, Ha SY, Lee JI, et al. Epidermal growth factor receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung. J Korean Med Sci. 2009;24:448–52.

    Article  PubMed  CAS  Google Scholar 

  54. Pallis AG, Voutsina A, Kalikaki A, et al. 'Classical' but not 'other' mutations of EGFR kinase domain are associated with clinical outcome in gefitinib-treated patients with non-small cell lung cancer. Br J Cancer. 2007;97:1560–6.

    Article  PubMed  CAS  Google Scholar 

  55. Miyamae Y, Shimizu K, Hirato J, et al. Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep. 2011;25:921–8.

    PubMed  CAS  Google Scholar 

  56. Kim KS, Jeong JY, Kim YC, et al. Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res. 2005;11:2244–51.

    Article  PubMed  CAS  Google Scholar 

  57. Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 2012;18:1167–76. This study provides an estimate of the rate of EGFR and KRAS mutations in patients with a definitive diagnosis of squamous cell carcinoma by immunohistiochemistry.

    Article  PubMed  CAS  Google Scholar 

  58. Zhu CQ, da Cunha SG, Ding K, et al. 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. 2008;26:4268–75.

    Article  PubMed  CAS  Google Scholar 

  59. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010;28:744–52.

    Article  PubMed  CAS  Google Scholar 

  60. Hirsch FR, Varella-Garcia M, Bunn Jr PA, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol. 2006;24:5034–42.

    Article  PubMed  CAS  Google Scholar 

  61. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.

    Article  PubMed  CAS  Google Scholar 

  62. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521–9.

    Article  PubMed  CAS  Google Scholar 

  63. Clinicaltrials.gov-accessed 7/11/2013

  64. http://newsroom.lilly.com/releasedetail.cfm?releaseid=784772-accessed 8/17/2013

  65. http://en.sanofi.com/Images/33127_20130603_rdupdate_en.pdf-accessed 7/13/2013.

  66. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  PubMed  CAS  Google Scholar 

  67. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. One of the trials that investigated immunotherapy as a treatment for non-small cell lung cancer and demonstrates responses in patients with squamous cell cancer. It also investigated PD-L1 expression as potential biomarker. This agent is being investigated in phase II and III trials in patients with squamous cell carcinoma.

    Article  PubMed  CAS  Google Scholar 

  68. Brahmer JR, Horn L, Antonia SJ, et al. Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31:abstract 8030. One of the trials that investigated immunotherapy as a treatment for non-small cell lung cancer and demonstrates responses in patients with squamous cell cancer.

  69. Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31:abstract 8008.

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Thomas E. Stinchcombe declares that he has no conflict of interest.

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Stinchcombe, T.E. Targeted Therapies for Locally Advanced or Metastatic Squamous Cell Carcinoma of the Lung. Curr. Treat. Options in Oncol. 14, 568–579 (2013). https://doi.org/10.1007/s11864-013-0256-2

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