New Targets Beyond EGFR, ALK and ROS1
Liam Chong Kin, Department of Medicine, Faculty of Medicine, University of Malaya

The treatment landscape for advanced non-small cell lung cancer (NSCLC) continues to evolve at an impressive pace with the addition of newer generations of drugs for existing targets such as EGFR, ALK and ROS1 alterations, as well as new and emerging targets. To provide optimal care for patients, comprehensive next-generation sequencing (NGS)-based biomarker testing that identifies variants across hundreds of genes in one seamless workflow is the most effective method for identifying as many actionable driver gene alterations as possible. The activating genetic alterations to be tested have expanded beyond EGFR, ALK and ROS1 to include BRAFV600E, MET, RET, NTRK, KRASG12C, EGFR exon 20 insertion and HER2. In non-squamous NSCLC, exclusionary testing, involving upfront testing for EGFR and ALK followed by targeted NGS for the other less common actionable genomic alterations is the most efficient and cost-saving strategy. For advanced squamous NSCLC, molecular testing should be considered in patients who are never-smokers, those with mixed histology or small biopsy specimens. A reflex molecular test standing order allows molecular testing on confirmation of a NSCLC histology resulting in a short turnaround time, avoiding the need for individual test requests and to conserve tissue.
There is an expanding list of approved targeted therapies for BRAFV600E mutations (dabrafenib plus trametinib), NTRK fusions (entrectinib and larotrectinib), MET exon 14 skipping mutations (capmatinib and tepotinib), RET fusion (selpercatinib and pralsetinib), KRAS G12C mutation (sotorasib and adagrasib after platinum-based chemotherapy), and EGFR exon 20 insertion mutations (amivantamab and mobocertinib after platinum-based chemotherapy).