Squamous cell carcinoma NSCLC in focus

Characteristics of SqCC of the lung

SqCCs of the lung are genetically complex and characterized by high mutation rates – only malignant melanomas exhibit a higher accumulation of genetic abnormalities.¹ One study revealed a mean of 360 exon mutations, 165 rearrangements and 323 segments of copy-number alterations per SqCC lung tumor.¹ However, mutations that are common and targetable in adenocarcinoma non-small cell lung cancer (NSCLC), such as epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS), are rare in SqCC.^1,2

Lung tumors of SqCC histology are usually centrally located and found 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 dyspnea, cough, obstructive pneumonia and hemoptysis.^3,4 Hemoptysis in particular prevents the use of some of the anti-angiogenic agents commonly used to treat patients with adenocarcinoma NSCLC.⁴

Challenges involved in the clinical management of SqCC of the lung

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 were 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.

Additional challenges in treating SqCC lung tumors arise from their genetic complexity, and the high incidence of comorbidities such as chronic pulmonary obstructive disease.^5,8,9

Molecular targets investigated in SqCC of the lung

EGFR gene amplification and overexpression is common in SqCC lung tumors, with overexpression being more frequently observed than in non-squamous NSCLC tumors.^10,11 Other members of the ErbB Family are also overexpressed in SqCC of the lung, notably human epidermal growth factor receptor 2 (HER2) and HER3.^4,12,13 EGFR activating mutations and gene mutations of other ErbB family members have been identified in SqCC lung tumors, but are less common.^5,14–16

Immune escape may play a role in the development of SqCC of the lung. Two key immune pathways have been investigated: the programmed cell death receptor-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway and the cytotoxic T-lymphocyte antigen-4 (CTLA-4)/cluster of differentiation 28 (CD28) pathway.^4,17 Pembrolizumab, nivolumab, ipilimumab and atezolizumab are immune checkpoint inhibitors that might be considered for the treatment of SqCC of the lung, depending on PD-L1 expression levels, patient suitability and local approval status.^6,7

The fibroblast growth factor receptor (FGFR) family of kinases has been extensively studied as potential druggable targets in SqCC of the lung.^5,18 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 tumors.^5,19 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

Another area of interest is cell cycle inhibition, given the frequency of alterations in G1/S checkpoint proteins in SqCC tumors.¹⁸ Clinical trials with cyclin-dependent kinase (CDK) inhibitors in patients with SqCC of the lung are ongoing.

Research by the Cancer Genome Atlas Research Network has also identified a wide range of recurrent genomic alterations that are currently under investigation as potential drug targets, including the phosphoinositide 3-kinase (PI3K) and mesenchymal-epithelial transition (MET) pathways.^1,4,20

Few NSCLC tumors (and even fewer SqCC tumors) have neurotrophic receptor tyrosine kinase (NTRK) gene fusions.²¹ The recent approval of agents that target NTRK fusion-positive solid tumors (larotrectinib and entrectinib) might open a new therapeutic avenue for SqCC patients, although future studies are warranted.^22,23

Recent advances 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.^5,24,25 However, the use of necitumumab has not been widely adopted as a standard of care, due to the lack of a clinically meaningful improvement in overall survival (OS) or progression-free survival (PFS).⁶

In contrast, immunotherapies (either alone or in combination with chemotherapy) are now recommended in the first-line setting – their use may be guided by factors such as PD-L1 expression level, patient suitability, treatment availability and local approval status; platinum-based chemotherapy combinations also remain an option in this setting.^6,7,18

In the second-line setting, options for SqCC include the ErbB family blocker afatinib,* the EGFR inhibitor erlotinib, the anti-angiogenic agent ramucirumab in combination with docetaxel, and docetaxel alone; several immunotherapies are also approved in this setting.^6,7

With these significant advances, clinicians now have multiple treatment options across the different lines of therapy.

Current clinical questions in SqCC of the lung

The treatment paradigm for advanced, metastatic SqCC of the lung has shifted considerably from chemotherapy-based regimens towards immunotherapies and chemo-immunotherapy regimens.^6,7 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 personalized treatment.^5,26 Molecular testing is generally not recommended unless patients are non-smokers or former/light smokers (<15 pack‑years), in which case, treatment with driver mutation-targeted agents may be suitable.⁶ The best approach to predicting benefit with immunotherapies (based on PD-L1 expression, tumor mutational burden or other molecular markers) is yet to be determined.

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 enrollment.^27,28 Research is ongoing to identify ways in which patients can be allocated to the most appropriate targeted treatments:

• The ALCHEMIST trial is evaluating adjuvant therapies based on biomarkers in high-risk resected NSCLC patients (patients with squamous cell histology are eligible for the immunotherapy trial)²⁹
• The ongoing National Lung Matrix trial used next-generation sequencing (NGS) to stratify NSCLC patients to eight different drugs, although current outcomes showed no success for patients with SqCC³⁰
• The Lung Master Protocol (Lung-MAP) trial was recently completed and used NGS to place SqCC patients in specific biomarker sub-studies^27,28

Despite significant shifts in the treatment paradigm for SqCC of the lung, as well as continuing research into potential new therapies, an unmet need remains for patients with this disease. The optimal sequence in which to administer immunotherapies, chemotherapy and targeted therapies, either as single agents or in combination regimens and on an individualized basis for each patient, remains an unanswered question for clinicians.^4,25