Non-small cell lung cancer (NSCLC) management has undergone a paradigm shift with the integration of molecular diagnostics and targeted therapies. Current guidelines emphasise the importance of biomarker-driven approaches for effective treatment selection, ensuring personalised care for patients. This article reviews the molecular guidelines and highlights a few emerging trials and therapies shaping the future of NSCLC treatment.
Molecular Diagnostics in NSCLC
Guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend comprehensive molecular testing for all advanced NSCLC patients at diagnosis. Key biomarkers include EGFR mutations (common in adenocarcinoma subtypes), ALK and ROS1 rearrangements, MET exon 14 skipping mutations, NTRK fusions, RET and BRAF alterations, and KRAS G12C mutations.
PD-L1 expression testing remains critical for stratifying patients for immunotherapy-based regimens. Next-generation sequencing (NGS) is the preferred approach to capture multiple biomarkers efficiently, particularly in regions with high EGFR mutation prevalence.
Implementing reflex biomarker testing—initiating molecular assays alongside diagnostic biopsies—minimises delays and ensures timely initiation of targeted treatments. While individual testing remains an option in certain cases, NGS offers a more comprehensive, cost-effective strategy in the long term.
Treatment Strategies Based on Current Guidelines
Targeted Therapies
For EGFR mutations, first-line therapies include osimertinib (a third-generation EGFR TKI), while earlier-generation inhibitors like gefitinib or afatinib remain viable options depending on availability and accessibility. For ALK and ROS1 rearrangements, ALK inhibitors such as lorlatinib, alectinib and brigatinib are preferred over the first-generation crizotinib due to their superior efficacy and ability to penetrate the central nervous system. Similarly, ROS1-positive tumours show strong responses to targeted agents like entrectinib or lorlatinib. Emerging therapies are also broadening the landscape of NSCLC treatment, with novel agents like sotorasib targeting KRAS G12C mutations and selpercatinib addressing RET rearrangements, providing promising options for mutations that were previously challenging to treat.
Immunotherapy
Immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab have transformed advanced NSCLC care. Current protocols recommend PD-L1 expression as a primary determinant of ICI use, with combination regimens (ICIs plus chemotherapy) demonstrating robust efficacy irrespective of PD-L1 levels.
Emerging Trials and Future Directions
Adjuvant and Early-Stage Therapies: The ADAURA trial demonstrated the efficacy of osimertinib as adjuvant therapy in resected EGFR-mutant NSCLC, signalling a shift toward molecular therapies in earlier stages.
Novel Combinations: Ongoing studies explore combinations of ICIs with anti-angiogenic agents or dual immunotherapy, aiming to overcome resistance mechanisms and improve the durability of responses.
Tumor-Agnostic Treatments: Therapies targeting NTRK fusions and high tumour mutational burden (TMB) represent significant advances, offering options across cancer types. Comprehensive Molecular Profiling Tests, such as the Somatic Advantage 500 from Strand Life Sciences cover important fusion genes along with TMB, allowing for faster identification of these biomarkers for tumor-agnostic treatments.
Current molecular guidelines underscore the necessity of comprehensive biomarker profiling and tailored treatment strategies to optimise outcomes in NSCLC. Advances in targeted therapies and immunotherapy continue to expand the therapeutic arsenal. Incorporating robust diagnostic protocols, timely access to treatments, and novel clinical insights will drive improved care delivery and patient outcomes in NSCLC globally.
