Few treatment options are available for advanced squamous cell carcinoma of the lung, which accounts for 20–30% of cases of non-small-cell lung cancer,1 especially after failure of first-line platinum-based doublet chemotherapy.2 Despite the identification of specific molecular aberrations (eg, FGFR1 amplification, PIK3K3 abnormalities, DDR2 mutations),3 progress in squamous cell carcinoma lags behind adenocarcinoma, particularly with regard to approved drugs targeting oncogenic drivers. Furthermore, drugs approved for the treatment of adenocarcinoma are contraindicated in patients with squamous cell carcinoma either because of safety concerns (bevacizumab)4 or reduced efficacy (pemetrexed).5 Consequently, until recently, erlotinib (an EGFR tyrosine kinase inhibitor) and docetaxel were the only approved second-line treatments for squamous cell carcinoma.2 In December, 2014, the US Food and Drug Administration approved ramucirumab, an anti-VEGFR-2 antibody, in combination with docetaxel, for the treatment of metastatic non-small-cell lung cancer and in March, 2015, approved nivolumab, an immune checkpoint inhibitor, for treatment of patients with metastatic squamous non-small-cell lung cancer, who progressed during or after platinum-based chemotherapy. Although the trial that led to the approval of ramucirumab enrolled patients with non-squamous and squamous histology,6 the nivolumab trials enrolled only patients with squamous cell carcinoma.7, 8
Research in context
Evidence before this study
We systematically reviewed PubMed up to March 17, 2015, and trials presented as abstracts at the American Society of Clinical Oncology and the European Society for Medical Oncology annual meetings. We used the search terms “phase 2” or “phase 3” and “squamous cell carcinoma” and “lung”, and reviewed reports and presentations of phase 2 and 3 trials investigating anti-cancer drugs (chemotherapy or targeted therapies) that included patients with squamous cell carcinoma of the lung who had progressed on or after platinum treatment. Based on this review, we confirmed that there is an unmet medical need for patients in this setting, with few (although increasing) efficacious treatment options. At the time the trial was started, only two drugs had been approved in this setting: erlotinib and docetaxel. During the trial, ramucirumab (plus docetaxel) and nivolumab were approved.
Added value of this study
This study shows that afatinib has clinical efficacy as second-line treatment for patients with squamous cell carcinoma of the lung. Afatinib reduced the risk of death compared with erlotinib and also improved progression-free survival, health-related quality-of-life outcomes, and symptom control.
Implications of all the available evidence
These data support the addition of afatinib to the armamentarium of treatments for this difficult-to-treat population. Further research is needed to define the role of afatinib in squamous cell carcinoma of the lung in relation to nivolumab, ramucirumab, and other emerging treatments. In this context, afatinib has the advantage of oral administration as monotherapy and a well-defined manageable adverse event profile. Further ongoing biomarker analysis might identify subgroups of patients with squamous cell carcinoma of the lung who are most likely to benefit from afatinib treatment.
Molecular data suggest a role for overexpression or gene amplification of EGFR in the pathobiology of squamous cell carcinoma. Several studies9, 10 suggest that EGFR overexpression is more common in squamous tumours (up to 82% of cases) than in adenocarcinomas. Although EGFR expression does not seem to be a reliable predictor of responsiveness to EGFR inhibitors in non-small-cell lung cancer (all histological subtypes),11 this feature might explain the sensitivity of some patients with squamous cell carcinoma of the lung to EGFR-targeted treatments despite having few (<5%) EGFR-activating mutations.12 For example, second-line treatment with erlotinib significantly improves survival compared with placebo in patients with squamous cell carcinoma of the lung.13, 14 This observation, along with the lack of myelosuppression, positions erlotinib as a viable treatment option for a population that has many comorbidities. The rationale for targeting EGFR in patients with squamous cell carcinoma of the lung is supported by trials15, 16 showing an improvement in overall survival when the anti-EGFR monoclonal antibodies cetuximab or necitumumab were added to first-line platinum doublet chemotherapy compared with doublet chemotherapy only. In addition to EGFR, other members of the ErbB family, including HER2,17, 18, 19 HER3,20 and HER4,20 as well as their cognate ligand NRG1,21 have been implicated in the pathogenesis of squamous cell carcinoma.
Afatinib is an irreversible ErbB-family inhibitor that, by contrast with EGFR tyrosine kinase inhibitors, selectively blocks signalling from all homodimers and heterodimers formed by EGFR, HER2, HER3, and HER4.22 It improved first-line progression-free survival compared with chemotherapy in two large phase 3 trials in patients with EGFR mutation-positive advanced lung adenocarcinoma, as well as improving overall survival in patients with the EGFR del19 mutation.23, 24, 25 Afatinib has a well-defined safety profile and is associated with class-related gastrointestinal (diarrhoea, stomatitis) and cutaneous (rash or acne) adverse events.23, 24, 26 These adverse events are generally manageable, with 6–8% of patients in phase 3 trials discontinuing treatment because of adverse events.23, 24, 26 We hypothesised that, on the basis of its broader mechanism of action and encouraging activity in patients with squamous histology cancers,27, 28 afatinib would improve efficacy compared with erlotinib (the only tyrosine kinase inhibitor approved in this setting) in a randomised trial of pretreated patients with squamous cell carcinoma of the lung.