The management of non-small cell lung cancer (NSCLC) is evolving rapidly, shifting from traditional genomic assessments to a broader array of protein-based and computationally derived biomarkers. This change is largely fueled by the approval of new therapies, especially antibody-drug conjugates (ADCs), and an enhanced understanding of therapeutic resistance. Dr. Soo-Ryum (Stewart) Yang, an assistant attending pathologist and co-director of Clinical Biomarker Development at the Memorial Sloan Kettering Cancer Center in New York, discussed these advancements during his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025.
Dr. Yang identified four key trends shaping the future of NSCLC management: the rise of protein-based immunohistochemistry (IHC) biomarkers, the actionability of tumor suppressor genes, the therapeutic potential of synthetic lethality, and advancements in computational pathology. These developments highlight the increasing importance of protein expression levels in cancer treatment decisions, moving beyond mere genetic mutations.
One of the most prominent shifts is the use of IHC testing to guide ADC treatment, which is a departure from the traditional reliance on genetic markers. Yang emphasized the significance of two essential biomarkers: HER2 and c-MET. The former can be overexpressed in up to 20% of NSCLC patients, with the highest levels (IHC 3+) found in approximately 3%. Importantly, there is no direct correlation between HER2 mutation status and its overexpression, a distinction that may lead to new treatment options.
The FDA’s recent approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients with prior treatments, was supported by the phase 2 DESTINY-Lung01 study, which used HER2 scoring guidelines from gastric cancer. Yang advocates for applying these same guidelines to NSCLC.
Similarly, c-MET overexpression is prevalent in NSCLC, with a significant proportion of patients exhibiting actionable c-MET-high status. Yang reported that up to 17% of EGFR wild-type cases show more than 50% of tumor cells with 3+ staining. Notably, c-MET overexpression is distinct from MET exon 14 skipping mutations and MET amplification, which complicates treatment paradigms.
In May 2025, the FDA granted accelerated approval to telisotuzumab vedotin-tllv (teliso-V; Emrelis) for patients with c-MET overexpression, bolstered by data from the phase 2 LUMINOSITY trial. Yang pointed out the integration of HER2 and c-MET IHC screening poses challenges for current diagnostic workflows, suggesting a need for flexible approaches that can adapt to various practice settings.
The landscape of biomarkers continues to expand, with promising candidates under investigation that could refine personalized treatment for NSCLC. Dr. Yang highlighted that mutations in KRAS genes occur in up to 40% of lung adenocarcinomas, with specific mutations like G12C being the most common. These mutations are associated with distinct clinical features and responses to treatment, creating unique challenges in patient management.
KRAS G12C-targeted therapies, such as sotorasib (Lumakras) and adagrasib (Krazati), are already established in clinical use. Emerging therapies targeting other KRAS mutations, including multi-RAS inhibitors, are currently in clinical trials. For instance, zoldonrasib (RMC-9805), a KRAS G12D inhibitor, demonstrated an overall response rate of 61% in a phase 1 study.
Dr. Yang also discussed the role of tumor suppressor genes STK11 and KEAP1, which mutate in up to 20% of lung cancers and often coexist with KRAS mutations. These mutations are linked to a poor response to immunotherapy, making them critical targets in treatment strategies. Results from the phase 3 POSEIDON trial suggest that combining a CTLA-4 inhibitor with PD-L1 inhibitors and chemotherapy may improve outcomes for patients with these mutations.
The concept of synthetic lethality is gaining traction, especially concerning MTAP deletions, which occur in 18% of lung cancers. Yang noted that the loss of MTAP impairs the purine salvage pathway, creating a vulnerability that can be targeted therapeutically. Detection of MTAP deletions can be achieved through next-generation sequencing (NGS) or IHC, although both methods have their own challenges.
Yang highlighted the potential of TROP2 as a target for ADC development. The anti-TROP2 ADC datopotamab deruxtecan-dlnk (Dato-DXd) showed a progression-free survival benefit in phase 3 trials, though it lacked a statistically significant overall survival advantage. To enhance predictive capabilities, an AI-driven method was developed to measure TROP2 expression more accurately, which could lead to improved treatment outcomes.
As the field progresses, Dr. Yang emphasized the necessity for a comprehensive approach to biomarker testing that encompasses protein analysis, AI insights, and innovative therapies. He concluded that the coming years will see broad-panel NGS and IHC testing, along with AI integration, becoming pivotal in the fight against lung cancer. The ongoing advancements in biomarker research are paving the way for personalized medicine, aiming to benefit a larger segment of the NSCLC population.
