This section considers the characteristic features of advanced, metastatic squamous cell carcinoma (SqCC) of the lung and the challenges faced in its clinical management. Current therapy options are discussed as well as clinical questions that remain in the treatment and management of SqCC of the lung.
What is it about the biology of SqCC of the lung that makes it difficult to treat?
SqCCs of the lung are genetically complex and characterised by high mutation rates – only malignant melanomas exhibit a higher accumulation of genetic abnormalities.1,2 One study revealed a mean of 360 exon mutations, 165 rearrangements and 323 segments of copy-number alterations per SqCC lung tumour.2 However, mutations that are common and targetable in adenocarcinoma tumours, such as epidermal growth factor receptor (EGFR) and KRAS, were found to be rare.1
Lung tumours of SqCC histology are usually centrally located and within the main airways, possibly due to an association with smoking.3,4 As a result, patients can be more prone to symptoms such as dyspnoea, cough, obstructive pneumonia and haemoptysis.3,4 The latter symptom in particular prevents the use of some of the anti-angiogenic agents commonly used to treat patients with adenocarcinoma non-small cell lung cancer (NSCLC), such as bevacizumab.3,4
What makes the clinical management of SqCC of the lung such a challenge?
Unlike NSCLC of adenocarcinoma histology, there is a lack of druggable oncogene targets in SqCC of the lung; recurrent alterations in kinase genes do not appear to be common core genomic events.5 Consequently, until recently, first-line systemic therapy options for the treatment of patients with SqCC of the lung remained limited to platinum-based doublet chemotherapy, with modest survival outcomes.5 Despite new classes of agents receiving approval for the first-line treatment of SqCC of the lung in recent years,6,7 novel treatment options are still needed.
The genetic complexity of SqCC lung tumours, largely associated with tobacco carcinogenesis, complicates approaches to treatment.5 Additionally, there tends to be a higher incidence of comorbidities, such as chronic pulmonary obstructive disease (COPD).8,9
Which targets have been investigated for the treatment of SqCC of the lung?
Overexpression and gene amplification of the EGFR protein is common in SqCC lung tumours, with overexpression being more frequently observed than in non-squamous NSCLC tumours.10,11 Other members of the ErbB Family are also overexpressed in SqCC of the lung, notably HER2 and HER3.4,12,13 EGFR activating mutations and gene mutations of other ErbB Family members have been identified in SqCC lung tumours, but are less common.5,14–16
There is evidence that immune escape may play a role in the development of SqCC of the lung, and two key immune pathways have been investigated: the programmed death receptor-1/programmed death-ligand 1 (PD-L1) pathway and the cytotoxic T-lymphocyte antigen-4/cluster of differentiation 28 (CTLA-4/CD28) pathway.4,17 Three immune checkpoint inhibitors that target the first pathway have recently been approved for use in many countries, including in the US and Europe: nivolumab, pembrolizumab and atezolizumab (currently approved in the US only).6,7,14
The fibroblast growth factor receptor (FGFR) family of kinases has been extensively studied as potential druggable targets in SqCC of the lung.5 Focal amplification of FGFR1, recurrent activating mutations of FGFR2 and FGFR3, and FGFR1/3 fusion events are frequent, and studies have reported FGFR1 amplifications in 10–15% of SqCC tumours.5,18 However, clinical data have indicated that only a minority of patients with FGFR1 amplification would derive benefit from FGFR inhibitors, and feedback-loop mediated resistance mechanisms may further reduce the effectiveness of drugs that target this pathway.5
Research by the Cancer Genome Atlas Research Network also identified further recurrent genomic alterations that are currently under investigation as potential drug targets, including the phosphoinositide 3-kinase (PI3K) and mesenchymal-epithelial transition (MET) pathways.1,4,19
What recent advances have been made in the treatment of SqCC of the lung?
In 2016, the anti-EGFR monoclonal antibody necitumumab, in combination with first-line chemotherapy, became the first new therapy to be approved for treatment-naïve patients with SqCC of the lung in 15 years.6,20,21 Patients who receive PD-L1 biomarker testing of tumour specimens and have PD-L1 expression ≥50% can be treated with the recently approved immune checkpoint inhibitor pembrolizumab, while the recommended first-line treatment for patients with PD-L1 expression <50% is still platinum-based chemotherapy.6,7,14 Further advances have also been made in the second-line setting, with approvals in Europe and/or the US for the ErbB Family blocker afatinib,* as well as immune checkpoint inhibitors nivolumab (regardless of PD-L1 expression), pembrolizumab (for patients with PD-L1 expression ≥1%) and atezolizumab (currently in the US only and not dependent upon PD-L1 expression).6,7 These join the EGFR inhibitor erlotinib, the anti-angiogenic agent ramucirumab in combination with docetaxel, and docetaxel alone as approved, though not always recommended, second-line therapies for SqCC of the lung.6,7
With these significant advances, clinicians now have multiple treatment options across the different lines of therapy.
What are the current clinical questions in SqCC of the lung?
With advances finally being made in the treatment of patients with advanced, metastatic SqCC of the lung, the treatment paradigm has shifted considerably in the past year from mainly chemotherapy-based regimens to the inclusion of targeted therapies and immunotherapies.22 Diagnosis is guided by biopsies, as well as immunohistochemistry for small samples, to identify histology, but there is scope for further biomarker analyses to guide personalised treatment.6,22 Molecular EGFR testing is generally not recommended unless patients are non-smokers or former light smokers (<15 pack‑years).6 With regard to immunotherapies, the predictive and prognostic value of PD-L1 expression remains to be fully determined.2,22
For patients with SqCC of the lung, screening for individual biomarker-driven studies is time consuming and requires considerable tissue sampling, often with a low chance of subsequent trial enrolment.23 Research is ongoing to identify ways in which patients can be allocated to the most appropriate targeted treatments, such as the Lung Master Protocol (Lung-MAP) trial in which next-generation sequencing is being used to place patients in specific biomarker sub-studies.23
Despite significant shifts in the treatment paradigm over the past year, as well as continuing research into potential new therapies, an unmet need remains for patients with SqCC of the lung. The optimal sequence in which to administer chemotherapy, immunotherapies and targeted therapies, either as single agents or combined, and on an individualised basis for each patient, remains an unanswered question for clinicians.4,21
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*Afatinib is approved in more than 80 markets including the EU, Japan, Taiwan, and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list please see here. Registration conditions differ internationally; please refer to locally approved prescribing information.