Squamous NSCLC

Squamous NSCLC Pathophysiology and Treatment Overview

NSCLC is a heterogenous disease. Squamous cell lung cancer (sqCLC) is an aggressive histological type of NSCLC representing about 25-30 % of NSCLC cases. The estimated median survival time of advanced or metastatic sqCLC is around 9-11 months. Patients with sqCLC tend to be older in age, presenting one of the many challenges associated with treatment of sqCLC. Traditional therapies used for NSCLC, such as bevacizumab and pemetrexed lack efficacy or are contraindicated for use in sqCLC. Furthermore, because patients are older in age when diagnosed, comorbidities and toxicity issues are prevalent in this patient cohort.1

Metastatic sqCLC is considered a difficult-to-treat form of lung cancer and until recently treatment options remain limited with platinum doublets being the standard of care. Since 2012, monoclonal antibodies targeting angiogenesis (i.e ramcirumab) or epidermal growth factor receptor (EGFR) (i.e. necitumumab) and immune checkpoints inhibitors (i.e. nivolumab and pembrolizumab) have emerged as novel treatment options.

Prior to initiation of treatment for advanced NSCLC, molecular testing for EGFR mutations, ALK rearrangements and other oncogenic drivers is recommended in order to select treatment with the corresponding tyrosine kinase inhibitors. These gene arrangements are only observed in about 7-10% of patients with sqCLC (with EGFR overexpression being more prevalent) and it is reported that molecular testing for these patients is rarerly done apart from patients with minimal to no tobacco use/exposure. First-line treatment for advanced or metastatic sqCLC includes a platinum analog with either gemcitabine or a taxane derivative as the standard of care.2

Anti-EGFR strategies

Overexpression of the EGFR protein is more common in sqCLC than in nonsquamous NSCLC with EGFR amplification occurring in 7% to 10% of sqCLC tumors. Necitumumab (an anti-EGFR monoclonal antibody) in combination with gemcitabine and cisplatin has been the first biologic to be FDA-approved for first-line treatment of people with metastatic sqCLC, based on significant improvements in overall survival versus with gemcitabine-cisplatin alone.3

Immunotherapy in sqCLC

Activated T-cells and B-cells express a receptor, PD-1, that responds to immunosuppressive PD-1 ligands expressed by tumor or stromal cells2,3. Inhibition of this interaction has been thought to enhance T-cell responses and antitumor activity and currently immunotherapy options2,3. The anti–PD-1 agent nivolumab has been FDA-approved for second-line treatment of advanced sqCLC were based on the results of the phase III Checkmate 017.4  Pembrolizumab (anti-PD-1) gained FDA approval as second line treatment in patients with advanced sqCLC with PD-L1 tumor expression.5

Angiogenesis Inhibitors

Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor 2, gained approval in both Europe and the United States for second line treatment of metastatic or advanced NSCLC. The challenge of targeting angiogenesis in patients with sqCLC involves the heighted risk of pulmonary hemorrhage, rendering agents such as bevazicumab contraindicated in these patients. The REVEL study demonstrated that ramucirumab plus docetaxel improved median overall survival versus docetaxel alone in the overall population and in the sqCLC subgroup with no increased toxicity in sqCLC compared to non-squamous lung cancer patients. 5

Other Agents

The EGFR TKI afatinib has been recently FDA-approved for second-line advanced sqCLC based on superiority over erlotinib for disease control rate, progression-free survival and overall survival.6

Challenges associated with sqCLC1:

  • Older age at diagnosis
  • Central location of most squamous tumors near blood vessels pose treatment challenges such as bleeding and hemoptysis leading to a contraindication for some therapeutic agents
  • Smoking and comorbidities
  • Genetic heterogeneity among patients with sqCLC

Resources and Additional Reading:

  1. Langer CJ, Obasaju C, Bunn P, et al. Incremental Innovation and Progress in Advanced Squamous Cell lung cancer: Status and Future Impact of Treatment. Journal of Thoracic Oncology. 2016. Vol 11, No 12: 2066-2081
  2. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell lung cancer. Version 5, 2017. Available at: https://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
  3. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plusgemcitabine 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 2015;16:763–774.
  4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135
  5. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity and Immune Correlates of Anti-PD-1 Antibody in Cancer. NEJM. 2012. 366;26. Doi: 10.1056/NEJMoa1200690
  6. Soria, J.C., Felip, E., Cobo, M. 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;16:897–907.
  7. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. NEJM. 2015;372:2018–2028.
  8. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–673
  9. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 Ligands and Other Features of the Tumor Immune Microenvironment with Response to Anti-PD-1 Therapy. Clinical Cancer Research. 2014;20(19)
  10. Choi M, Kadara H, Shang L, et al. Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Annals of Oncology. 2017, 28 (1):83-89. Doi: https://doi.org/10.1093/annonc/mdw437
  11. Kim BR, Van de Laar E, Cabanero M, Tarumi S, Hasenoeder S, Wang D, et al. SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis. PLoS Biol. 2016. 14(11): e1002581. https://doi.org/10.1371/journal.pbio.1002581
  12. Le T, Sailors J, Oliver DH, Mayer M, Hoskin S, Gerber DE. Histologic transformation of EGFR mutant lung adenocarcinoma without exposure to EGFR inhibition. lung cancer. Vol 105, pages 14-16. https://doi.org/10.1016/j.lungcan.2017.01.005
  13. Baumeister SH, Gordon JF, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annual Review of Immunology. Vol 34: 539-573. Doi: 10.1146/annurev-immunol-032414-112049
  14. Li Y, Wi-long W. Immunotherapy for small-cell lung cancer. Lancet Oncology; London. 2016. Pages 846-847