Overview

NSCLC is the most frequently occurring histologic subtype of lung cancer and accounts for >85% of all lung cancers.^5-7 NSCLC can be further categorized into squamous (SQ) cell carcinoma and non-squamous (NSQ) NSCLC, which includes adenocarcinoma, defined by the type of cancerous cells and the unique growth and spread of the malignancy: ^{2,8-10, 39}

• Adenocarcinoma: Cancer that begins in the cells that line the alveoli and make substances such as mucus, represents ~40-50% of NSCLC 
• Squamous cell carcinoma (also called epidermoid carcinoma), represents ~25%-30% of NSCLC
• Large cell (undifferentiated) carcinoma: Cancer that may begin in several types of large cells, represents ~5-10% of NSCLC
• Other less common subtypes of NSCLC: adenosquamous carcinoma, sarcomatoid carcinoma, neuroendocrine tumors

Mechanism of Disease

Squamous NSCLC arise centrally in thin, flat squamous cells within the large bronchi and are usually associated with smoking.¹⁰

Non-squamous NSCLC:¹

• Adenocarcinomas arise in the peripheral epithelial tissue and primarily have a lepidic, acinar, papillary, or mucinous morphology.⁸ Approximately 75% of adenocarcinomas are associated with smoking.¹⁰
• Large cell carcinomas lack morphologic or immunohistochemistry evidence of clear lineage.^2,8
• Adenosquamous carcinomas are tumors with mixed adenocarcinoma and squamous cell carcinoma components, each being at least 10% of the tumor.^2,8

Development involves a multistep process that includes multiple genetic and epigenetic alterations, particularly activation of growth-promoting pathways and inhibition of tumor-suppressing pathways.^2,11-13

• The most common targetable genomic alterations in lung adenocarcinoma are KRAS- and EGFR-activating mutations followed by ALK and ROS1 rearrangements, BRAF mutations, MET exon 14 skipping mutations and MET amplifications, RET gene fusions, and HER2 mutations. NTRK and NRG1 gene fusions rarely occur in NSCLC.⁴⁰

Dysregulation of DNA repair is also associated with platinum resistance in NSCLC.^14,15

• Significantly correlates with the relative risk of death in patients with NSCLC who are treated with chemotherapy

Diagnosis & Staging

All NSCLC should be classified into specific pathologic subtypes based on the specific histologic and genetic characteristics of the patient's tumor using the 2015 WHO Guidelines.⁸ In the era of personalized medicine and targeted therapies, this can determine eligibility for certain types of molecular testing and therapeutic strategies.⁸ International guidelines recommend testing patients with NSCLC for select immune and molecular biomarkers (genomic alterations) that may have a predictive or prognostic value.^{2,39, 40}

Challenges in Treatment

Most patients (>65%) present with Stage III or IV disease at diagnosis,¹⁶ which is a strong predictor of poor prognosis, with 5-year survival rates of 36% for Stage IIIA, ≤26% for Stages IIIB/IIIC, and ≤10% for Stage IV. ¹⁷

• Advanced lung cancer patients typically have poor performance status at diagnosis and cannot tolerate aggressive chemotherapy.¹⁸
• Choice of treatment is often driven by biomarkers associated with the patient's specific tumor biology.

Squamous and non-squamous histologies may react differently to similar therapies.

Some therapies may have different safety profiles and clinical outcomes depending on the histologic subtype of NSCLC present.

Predicting who will respond to immunotherapy targeting PD-1 and PD-L1 has proven to be difficult, and there remains a need to discover new predictive immunotherapy biomarkers.²

At least one third of patients with NSCLC have genomic alterations that will influence treatment selection. These patients should receive first-line therapy targeting the oncogene such as EGFR tyrosine kinase inhibitors (TKIs), ALK inhibitors, ROS1 inhibitors, BRAF inhibitors, KRAS inhibitors, and MET kinase inhibitors.^2,39

In patients with no known actionable mutations, single-agent immunotherapy is recommended as first-line therapy, if PD-L1 expression is high (≥50%).^2,39 For those with low (<50%) or negative (<1%) levels of PD-L1 expression, immunotherapy plus chemotherapy or chemotherapy alone are recommended.^2,41

For these patients that do not harbor a targetable biomarker, strategies to improve the efficacy of chemotherapy is an unmet need.^32,35 Combination therapies also hold promise to address the unmet need of treatment for patients unfit or resistant/refractory to current treatment options for NSCLC.³⁶