The management of non-small cell lung cancer (NSCLC) is evolving as new biomarkers and therapeutic strategies emerge. During the 20th Annual New York Lung Cancers Symposium on November 15, 2025, Dr. Soo-Ryum (Stewart) Yang highlighted significant advancements in biomarker testing, which now extends beyond traditional genomic markers to include protein-based and computationally derived indicators. As the field progresses, the integration of these new tools is essential for optimizing patient treatment.
Dr. Yang, an assistant attending pathologist and co-director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center in New York, outlined four key trends reshaping NSCLC management. These include the increasing use of protein-based immunohistochemistry (IHC) biomarkers for antibody-drug conjugates (ADCs), insights into tumor suppressor gene actionability, the application of synthetic lethality in treatment, and advancements in computational pathology.
Despite the promise of these developments, the challenge of tissue scarcity remains a pressing issue. Dr. Yang emphasized the need for multiplex IHC and the integration of broad-panel next-generation sequencing (NGS) with artificial intelligence (AI) to enhance personalized therapy delivery for a wider range of NSCLC patients.
The shift towards protein expression analysis marks a significant departure from the traditional focus on genetic mutations. Pathologists are now measuring protein expression levels to identify actionable biomarkers. Dr. Yang underscored two critical protein biomarkers for NSCLC: HER2 and c-MET overexpression. These biomarkers offer distinct pathways for treatment and differ significantly from their genetic counterparts. For instance, HER2 overexpression is detected in up to 20% of patients, with the highest level (IHC 3+) found in approximately 3% of cases. This overexpression does not necessarily correlate with HER2 mutation status, indicating the complexity of tumor biology.
The approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC, is supported by the results of the phase 2 DESTINY-Lung01 study (NCT03505710). Dr. Yang advocated for applying gastric cancer HER2 scoring guidelines to NSCLC testing, aiming to refine treatment approaches.
Similarly, c-MET overexpression is prevalent in NSCLC, with an actionable c-MET-high status—defined as over 50% of tumor cells exhibiting 3+ staining—occurring in up to 17% of EGFR wild-type cases. The FDA granted accelerated approval to telisotuzumab vedotin-tllv (teliso-V; Emrelis) for this patient population, based on the phase 2 LUMINOSITY trial (NCT03539536). Dr. Yang noted the integration of HER2 and c-MET IHC screening poses significant challenges to current diagnostic workflows, suggesting a flexible, standardized approach tailored to institutional capabilities.
Several promising biomarkers are under investigation that could refine personalized treatment protocols for NSCLC. KRAS mutations, particularly in lung adenocarcinomas, occur in up to 40% of cases, with the KRAS G12C mutation being the most prevalent. Dr. Yang explained that KRAS G12D mutations, associated with lower tumor mutational burden and poor response to chemoimmunotherapy, present particular challenges. Targeted therapies for KRAS G12C, including sotorasib (Lumakras) and adagrasib (Krazati), are already established, while new agents targeting KRAS G12D, such as zoldonrasib (RMC-9805), demonstrate promising efficacy in early trials.
The impact of STK11 and KEAP1 mutations, found in up to 20% of lung cancers, also warrants attention. These mutations often co-occur with KRAS mutations and create immunosuppressive environments, leading to resistance to immunotherapy. Analysis of the phase 3 POSEIDON trial (NCT03164616) indicates potential strategies to overcome this resistance by combining PD-L1 inhibitors with CTLA-4 inhibitors, enhancing progression-free survival and overall survival.
Dr. Yang also discussed the role of MTAP deletions in lung cancer, which occur in up to 18% of cases. These deletions create metabolic vulnerabilities that can be targeted therapeutically. Detection methods for MTAP include NGS and IHC, with each having specific advantages and challenges.
Another area of exploration is TROP2, a cell surface protein that is being targeted by ADCs like datopotamab deruxtecan-dlnk (Dato-DXd; Datroway). While the phase 3 TROPION-Lung01 study (NCT04656652) indicated benefits over traditional chemotherapy, the lack of biomarker enrichment raises questions about patient selection. Researchers are investigating AI-driven approaches to enhance predictive accuracy by quantifying TROP2 expression more effectively.
As the landscape of NSCLC management continues to expand, Dr. Yang concluded that it is crucial to explore multiplex IHC testing alongside existing molecular markers and NGS. The integration of these advanced diagnostic tools will be pivotal in shaping the future of personalized lung cancer therapy.
