ATS 2026: Lung Cancer Management Advances in Targeted Therapy

Lung cancer remains a leading cause of cancer-related mortality globally, with NSCLC accounting for approximately 85% of all cases.¹ Historically, treatment relied on surgery, radiation, and cytotoxic chemotherapy. However, the understanding of lung cancer biology has evolved, revealing numerous oncogenic drivers that can be targeted therapeutically. This shift towards precision medicine has been a central theme in oncology, with significant progress presented at ATS 2026. The conference underscored the importance of identifying specific molecular alterations, such as mutations in EGFR, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, and MET exon 14 skipping alterations, which dictate treatment selection and prognosis.²

Current State of Targeted Therapies in NSCLC

The ATS 2026 presentations reinforced the established role of targeted therapies in NSCLC. For patients with EGFR-mutated NSCLC, third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have demonstrated superior efficacy. For instance, in the FLAURA trial, osimertinib showed a median progression-free survival (PFS) of 18.9 months compared to 10.2 months with standard EGFR-TKIs (HR 0.46, 95% CI 0.37-0.57, p < 0.001) in the first-line setting.³ This data supports its continued use as a preferred initial treatment for these patients. Similarly, for ALK-positive NSCLC, next-generation ALK inhibitors such as alectinib have shown improved outcomes. The ALEX trial reported a median PFS of 34.8 months for alectinib versus 10.9 months for crizotinib (HR 0.32, 95% CI 0.23-0.44, p < 0.001), establishing alectinib as a standard first-line option.⁴

Beyond these well-established targets, ATS 2026 highlighted advancements in therapies for less common but equally critical alterations. For patients with ROS1-positive NSCLC, entrectinib and crizotinib remain viable options, with entrectinib demonstrating an objective response rate (ORR) of 77% (95% CI 62-88) and a median PFS of 19.0 months (95% CI 12.2-not estimable) in a pooled analysis of phase 1/2 trials.⁵ For BRAF V600E mutations, the combination of dabrafenib and trametinib has shown an ORR of 64% and a median PFS of 10.9 months.⁶

Emerging data presented at ATS 2026 also focused on MET exon 14 skipping mutations and KRAS G12C mutations. Capmatinib and tepotinib have received approval for MET exon 14 skipping NSCLC, with capmatinib showing an ORR of 68% in treatment-naïve patients and 41% in previously treated patients.⁷ For KRAS G12C mutations, sotorasib and adagrasib represent a new class of targeted agents. Sotorasib demonstrated an ORR of 36% and a median PFS of 6.8 months in previously treated patients with KRAS G12C-mutated NSCLC.⁸ These developments underscore the rapid expansion of actionable targets and available therapies.

The conference also addressed resistance mechanisms to targeted therapies and strategies to overcome them. Sequential use of different generations of TKIs, combination therapies, and the role of liquid biopsies for monitoring treatment response and detecting resistance mutations were discussed. The integration of immunotherapy with targeted therapy in specific contexts, particularly for patients with co-occurring driver mutations and high PD-L1 expression, was also a topic of interest, though definitive guidelines for such combinations are still evolving.⁹

Limitations in current practice include the accessibility and turnaround time of comprehensive molecular testing, which can delay initiation of optimal therapy. Furthermore, the cost-effectiveness of these advanced therapies remains a consideration for healthcare systems globally. Future research is directed towards identifying novel targets, developing therapies for currently undruggable mutations, and understanding the optimal sequencing and combination of existing treatments to prolong patient survival and improve quality of life.