Developments in advanced / metastatic NSCLC treatment 

Targeting driver mutations in NSCLC

One of the most significant advances in the treatment of advanced/metastatic NSCLC has been the identification and targeting of driver mutations.^6,7 Several molecular drivers have been identified that represent strong predictive biomarkers and serve as therapeutic targets. Guidelines suggest that all patients with advanced adenocarcinoma should be tested for the presence of oncogenic drivers that can be therapeutically targeted. This includes broad molecular profiling of EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, and HER2 genes. Testing for these biomarkers is now considered mandatory in many countries.^6,7 Tyrosine kinase inhibitors (TKIs) that target EGFR mutations or ALK rearrangement are considered the standard of care in the first-line treatment of patients whose tumors bear these mutations, which occur most frequently in non-squamous NSCLC.^6,7

HER2-targeted therapies for NSCLC

Approximately 3% of non-squamous NSCLCs are driven by mutations in the HER2 gene.⁸ While chemotherapy and/or immunotherapy remain the first-line standard of care for patients with HER2-mutated NSCLC, HER2-targeted therapies are being studied in later lines of therapy with variable success.^7,9,10

NSCLC lacking targetable driver mutations

For NSCLC without driver mutations, recent advances in various treatment lines have included agents that inhibit angiogenesis, as well as immunotherapies that target the programmed cell death receptor 1 (PD-1) or programmed cell death ligand 1 (PD-L1).^7,11 In recent treatment guidelines, anti-PD-1 and anti-PD-L1 have become the preferred first-line therapy for patients with tumors that are PD-L1 positive ≥50% and have no other targetable driver mutations.^7,11 Combinations of chemotherapy with anti-PD-1 or anti-PD-L1 are recommended for those with tumors that are PD-L1 positive ≥1% to 49%.^7,11

While progress has been made in treatment options and the ability to customize therapy to some, there is still much room for improvement. Although EGFR- and ALK-targeted therapies are effective, a proportion of patients with adenocarcinoma and the large majority of patients with squamous disease do not have tumors that bear these driver mutations.^6,7 In addition, while immunotherapy has been widely utilized, not all tumors respond to this class of treatment and almost all patients eventually relapse.¹³ Further research is needed to clearly identify which patient subgroups will benefit most from novel treatments such as immunotherapies, and what the optimal treatment options are when these novel treatments fail.