The management of non-small cell lung cancer (NSCLC) is evolving significantly, with a shift from traditional genomic testing to a broader array of protein-based and computational biomarkers. This transformation is largely influenced by recent advancements in therapies, particularly antibody-drug conjugates (ADCs), and a deeper understanding of treatment resistance, as detailed by Soo-Ryum Yang, MD, during his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025.
In his address, Yang, who serves as an assistant attending pathologist and co-director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center in New York, highlighted four key trends reshaping NSCLC management. These include the increasing reliance on protein-based immunohistochemistry (IHC) biomarkers for ADCs, the actionable insights from tumor suppressor genes, the therapeutic potential of synthetic lethality, and the rise of computational pathology.
One of the central challenges in this evolving landscape is the scarcity of tissue samples, necessitating the development of multiplex IHC techniques and the integration of broad-panel next-generation sequencing (NGS) and artificial intelligence (AI). These innovations aim to enhance personalized therapies for a wider range of NSCLC patients.
Yang emphasized a pivotal shift in focus from mutational analysis to measuring protein expression levels. This shift has the potential to unveil new treatment avenues for patients. For instance, while PD-L1 IHC testing has been established for guiding checkpoint inhibitor therapy, it is now also being utilized to inform ADC treatment decisions. Yang identified two essential protein biomarkers in NSCLC: HER2 and c-MET. Notably, HER2 overexpression occurs in up to 20% of patients, with the highest expression level (IHC 3+) seen in approximately 3%. Yang pointed out that there is no direct correlation between HER2 mutation status and its overexpression.
The FDA recently approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients who have undergone prior treatment. This approval was based on data from the phase 2 DESTINY-Lung01 study (NCT03505710) and suggests that gastric cancer scoring guidelines should be adapted for use in NSCLC.
On the other hand, c-MET overexpression is prevalent in NSCLC. Yang reported that an actionable c-MET-high status, defined as over 50% of tumor cells showing 3+ staining, is observed in up to 17% of EGFR wild-type cases. The FDA granted accelerated approval to telisotuzumab vedotin-tllv (teliso-V; Emrelis) for this patient demographic, supported by findings from the phase 2 LUMINOSITY trial (NCT03539536).
The integration of HER2 and c-MET IHC screening presents significant challenges in diagnostic processes. Yang proposed that there is no one-size-fits-all solution; instead, a flexible approach with standardized options can help institutions tailor their workflows based on multidisciplinary insights and available resources.
Several promising biomarkers are currently under investigation that could further refine personalized treatment for NSCLC patients. One notable example is KRAS mutations, which are found in up to 40% of lung adenocarcinomas. Within this category, mutations in codons G12, G13, and Q61 are significant, with the KRAS G12C mutation being the most prevalent.
Yang explained that KRAS G12D mutations, often linked to a history of light or non-smoking, present unique challenges due to their correlation with a lower tumor mutational burden and lower PD-L1 expression, which can hinder responses to chemoimmunotherapy. Targeted therapies for KRAS G12C, including sotorasib (Lumakras) and adagrasib (Krazati), are already established, with ongoing clinical trials exploring therapies targeting other KRAS mutations.
The mutations in tumor suppressor genes such as STK11 and KEAP1, which occur in up to 20% of lung cancers, often co-occur with KRAS mutations. These alterations create an immunosuppressive tumor microenvironment, contributing to primary resistance against immunotherapy. Yang cited data from the phase 3 POSEIDON trial (NCT03164616), highlighting that combining a CTLA-4 inhibitor with PD-L1 inhibitors and chemotherapy improved progression-free survival and overall survival in patients with these mutations.
Effective detection of STK11 and KEAP1 mutations necessitates broad-panel NGS, as PCR methods are inadequate. Yang also discussed the role of MTAP deletions, which affect the purine salvage pathway and occur in up to 18% of lung cancers. These deletions are associated with poorer outcomes, especially in immunotherapy contexts, and are emerging as therapeutic targets.
Yang proposed a diagnostic workflow that begins with NGS for initial screening, followed by confirmatory IHC in cases where MTAP status is ambiguous, particularly in low-purity samples. He acknowledged ongoing concerns regarding tissue availability, stressing the need for adequate samples to conduct an expanding array of biomarker tests.
The exploration of TROP2, a cell surface protein widely expressed in NSCLC, is also garnering attention for ADC development. The phase 3 TROPION-Lung01 study (NCT04656652) showcased a progression-free survival advantage for datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) compared to docetaxel, although it did not demonstrate a statistically significant overall survival benefit.
To enhance predictive accuracy, Yang described the development of an AI-driven approach involving computational pathology. This method scans IHC slides and employs AI algorithms to quantify TROP2 staining, offering a more nuanced understanding of its role in treatment response. Although preliminary findings are promising, Yang emphasized the need for prospective validation in larger cohorts.
The advancements in lung cancer management reflect a significant shift towards a more comprehensive approach that integrates protein analysis, AI insights, and innovative therapeutic strategies like synthetic lethality. Yang concluded by asserting the importance of exploring multiplex IHC methodologies akin to those used in molecular markers and NGS. He anticipates that in the coming years, broad-panel NGS, IHC, and AI will form the cornerstone of comprehensive biomarker testing in lung cancer, ultimately enhancing personalized medicine for a wider patient population.
