Lung Cancer (NSCLC) Therapies

RET Fusion — Selective RET Inhibitor

Manufacturer: Eli Lilly | Mechanism: Highly selective RET kinase inhibitor | Key Publication: Drilon et al. NEJM 2020 ↗

Epidemiology & Impact

Lung cancer remains the leading cause of cancer death worldwide, responsible for approximately 1.8 million deaths annually. In the United States, an estimated 234,580 new cases and 125,070 deaths are projected for 2024. While overall incidence has declined due to reduced smoking rates, lung cancer in never-smokers now accounts for 10-20% of all cases and is increasingly recognized as a molecularly distinct entity enriched for actionable driver mutations. The five-year survival rate has improved from 17% to 25% over the past decade, driven by targeted therapy and immunotherapy advances.

Molecular Biology & Biomarkers

Molecular profiling has become the cornerstone of NSCLC management. Next-generation sequencing at diagnosis is now standard of care, testing for EGFR mutations (15-30% of adenocarcinomas), ALK rearrangements (3-7%), ROS1 fusions (1-2%), BRAF V600E (2-4%), KRAS G12C (13%), MET exon 14 skipping (3-4%), RET fusions (1-2%), NTRK fusions (<1%), HER2 mutations (2-3%), and NRG1 fusions (<1%). PD-L1 tumor proportion score guides immunotherapy decisions. Liquid biopsy (ctDNA) has emerged as a complementary diagnostic tool for monitoring treatment response and detecting resistance mutations early.

Evolving Treatment Landscape

The NSCLC therapeutic landscape now includes over 40 FDA-approved agents. For EGFR-mutated disease, osimertinib is the dominant first-line agent, with combinations pushing outcomes further. Third-generation ALK inhibitors like lorlatinib extend PFS beyond 5 years. KRAS G12C inhibitors have opened a previously undruggable target. For patients without driver mutations, pembrolizumab-based regimens remain first-line standard. The perioperative space is evolving with neoadjuvant chemoimmunotherapy and adjuvant targeted therapy changing surgical paradigms.