Non-Small Cell Lung Cancer

The most lethal cancer worldwide — epidemiology, driver mutations, presentation, and evolving targeted and immunotherapy strategies by stage

Key Points

• Lung cancer is the leading cause of cancer death in both men and women in the US; NSCLC accounts for ~85% of lung cancers.
• Tobacco smoking is responsible for ~85% of lung cancer cases; never-smokers account for ~15% and more frequently harbor actionable driver mutations.
• Adenocarcinoma is now the most common NSCLC subtype, overtaking squamous cell carcinoma; it most frequently harbors targetable alterations (EGFR, ALK, ROS1, KRAS G12C, MET, BRAF, NTRK, RET).
• Molecular profiling (comprehensive NGS) is mandatory for all newly diagnosed non-squamous advanced NSCLC before initiating systemic therapy.
• Early-stage (I–II) NSCLC is treated with surgery ± adjuvant therapy; osimertinib is approved adjuvant therapy for EGFR-mutated resected stage IB–IIIA.
• Stage III (unresectable) is treated with concurrent chemoradiation followed by durvalumab (PACIFIC trial) — the first regimen to improve OS in stage III NSCLC.
• Stage IV NSCLC is increasingly treated with matched targeted therapy for driver mutations or pembrolizumab for high PD-L1 tumors, with dramatically improved survival compared to chemotherapy alone.

Epidemiology & Incidence

Lung cancer is the second most commonly diagnosed cancer in the US but the leading cause of cancer mortality, claiming more lives annually than breast, prostate, and colorectal cancers combined. In 2024, approximately 234,580 new cases and 125,070 deaths were projected. The global burden is even larger: lung cancer is the most common cancer diagnosis and cause of cancer death worldwide, particularly in regions with high smoking prevalence. Incidence has declined significantly among men (reflecting earlier peak in smoking rates) but has been slower to decline among women. The improving trends…

Genetic Predispositions & Risk Factors

Cigarette smoking is the dominant risk factor, accounting for ~85% of lung cancer cases. Relative risk for current smokers versus never-smokers is 10–30×, depending on intensity and duration. Risk declines after cessation but never returns to baseline. Second-hand smoke exposure increases risk ~20–30%. Radon gas — a naturally occurring radioactive gas — is the second leading cause of lung cancer and the leading cause among never-smokers. It causes ~21,000 deaths annually in the US. Occupational exposures include asbestos (synergistic with smoking — relative risk >50× for combined exposure),…

Clinical Presentation

Most lung cancers are asymptomatic until locally advanced or metastatic, which accounts for the poor stage at diagnosis (only ~16% are detected at localized stage). When symptoms occur, they relate to intrathoracic tumor growth, regional invasion, or distant metastases. Primary tumor symptoms: • Persistent or worsening cough (most common — present in ~75%) • Hemoptysis — ranges from blood-streaked sputum to massive hemorrhage • Dyspnea — from endobronchial obstruction, pleural effusion, or lymphangitic spread • Chest pain — typically dull, aching; pleuritic if pleural involvement •…

Staging Overview

NSCLC is staged using the AJCC 8th Edition TNM system: Stage IA1–IA3: T1 (≤3 cm) N0 M0 — subdivided by size Stage IB: T2a (>3–4 cm) N0 M0 Stage IIA: T2b (>4–5 cm) N0 M0 Stage IIB: T3 (>5–7 cm, or chest wall/pericardium/phrenic nerve involvement) N0 M0; or T1–2 N1 M0 Stage IIIA: T3 N1, T1–3 N2, T4 N0–1 M0 Stage IIIB: T1–2 N3, T3–4 N2 M0 Stage IIIC: T3–4 N3 M0 Stage IVA: M1a–b (contralateral lung nodule, pleural/pericardial effusion, single extrathoracic metastasis) Stage IVB: M1c (multiple extrathoracic metastases) Essential workup: CT chest + upper abdomen, PET/CT (for stage I–III to detect…

Stage I–II Treatment

Surgical resection is the standard curative treatment for stage I and II NSCLC. Lobectomy with systematic mediastinal lymph node sampling/dissection is the preferred anatomic resection. Anatomic segmentectomy is acceptable for stage IA1 tumors ≤2 cm with peripheral location (JCOG0802 trial supports oncologic equivalence); wedge resection carries higher local recurrence risk and is reserved for poor surgical candidates. Minimally invasive approaches (VATS or robotic) have largely replaced open thoracotomy at experienced centers with equivalent oncologic outcomes and faster recovery.…

Stage III Treatment

Stage III NSCLC is heterogeneous — roughly half are potentially resectable (stage IIIA selected) and half are unresectable (stage IIIB–C and bulky IIIA). This requires multidisciplinary tumor board review. Resectable stage IIIA (selected): Surgery after neoadjuvant chemoimmunotherapy (nivolumab + chemo, CheckMate 816) or induction chemoradiation, followed by adjuvant therapy. Pneumonectomy should be avoided where possible due to mortality risk. Unresectable stage III: The PACIFIC trial established concurrent chemoradiation (2 platinum-based doublets × 2 cycles + thoracic RT 60–66 Gy)…

Stage IV (Metastatic) Treatment

Treatment selection for stage IV NSCLC is driven entirely by molecular and immunologic biomarkers — empiric chemotherapy without biomarker testing is now substandard care. Driver mutation present (non-squamous or squamous with confirmed mutation): • EGFR exon 19del or L858R: Osimertinib (FLAURA trial) — 1st-line; median PFS 18.9 months. Amivantamab + lazertinib for osimertinib-resistant EGFR-mutated (MARIPOSA-2). EGFR exon 20 insertions: amivantamab or mobocertinib. • ALK: Alectinib or brigatinib 1st-line; lorlatinib for ALK+ resistance or CNS-predominant disease. • ROS1: Entrectinib or…