The management of non-small cell lung cancer (NSCLC) is evolving rapidly, with a shift towards innovative biomarker testing that incorporates protein-based and computationally derived markers. This transformation reflects recent advancements in therapy and a deeper understanding of cancer resistance mechanisms, as highlighted by Dr. Soo-Ryum (Stewart) Yang at the 20th Annual New York Lung Cancers Symposium on November 15, 2025.
Yang, who serves as an assistant attending pathologist and co-director of Clinical Biomarker Development at the Memorial Sloan Kettering Cancer Center in New York, outlined several key trends that are reshaping NSCLC diagnostics. These include the rise of protein-based immunohistochemistry (IHC) biomarkers for antibody-drug conjugates (ADCs), the actionable nature of tumor suppressor genes, the therapeutic potential of synthetic lethality, and the integration of computational pathology.
The increasing focus on protein expression levels marks a significant departure from traditional genomic testing. Pathologists are now assessing the intensity of protein expression rather than simply identifying mutated genes. This approach allows for a broader range of treatment options. While PD-L1 IHC testing has long been a standard for guiding checkpoint inhibitor therapy, Yang emphasized the importance of IHC testing for ADCs as well.
He identified two critical protein biomarkers for NSCLC: HER2 and c-MET. HER2 overexpression occurs in up to 20% of patients, with the highest levels (IHC 3+) detected in about 3%. Importantly, Yang noted that there is no direct correlation between HER2 mutation status and overexpression. In contrast, c-MET overexpression is also prevalent, with actionable c-MET-high status found in up to 17% of EGFR wild-type cases.
The approval of the drug fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients who have undergone previous treatments, was supported by the phase 2 DESTINY-Lung01 study (NCT03505710). This study utilized HER2 scoring guidelines previously established for gastric cancer, which Yang advocates should also be applied to NSCLC testing.
Addressing the challenges within current diagnostic workflows, Yang proposed two primary strategies for integrating HER2 and c-MET IHC screening. He emphasized the need for a flexible approach that allows institutions to develop optimized workflows based on their unique resources and multidisciplinary input.
The landscape of NSCLC biomarkers is expanding, with several promising candidates under investigation. For example, mutations in KRAS are present in up to 40% of lung adenocarcinomas, with specific mutations such as KRAS G12C being the most common. Yang pointed out that KRAS G12D mutations, often associated with a history of light or non-smoking, correlate with lower tumor mutational burden and reduced PD-L1 expression, leading to poorer responses to treatment.
Established therapies targeting KRAS G12C include sotorasib (Lumakras) and adagrasib (Krazati), while ongoing clinical trials are exploring developments in multi-RAS and RAS(ON) inhibitors. Yang highlighted the efficacy of zoldonrasib (RMC-9805), a KRAS G12D inhibitor, which demonstrated an overall response rate of 61% in a phase 1 study (NCT06040541).
Additionally, mutations in tumor suppressor genes such as STK11 and KEAP1 occur in up to 20% of lung cancers and are often co-mutated with KRAS. These mutations contribute to an immunosuppressive tumor microenvironment, leading to primary resistance to immunotherapy. Yang referenced the phase 3 POSEIDON trial (NCT03164616), which indicated that combining a CTLA-4 inhibitor with a PD-L1 inhibitor and chemotherapy could enhance treatment efficacy for patients with these mutations.
Yang also discussed the significance of MTAP deletions in lung cancers, which affect up to 18% of patients and are associated with poor outcomes. He emphasized the importance of detecting MTAP deletions using broad-panel next-generation sequencing (NGS) and the potential for PRMT5 inhibitors as therapeutic targets.
Emerging biomarkers such as TROP2 are also gaining attention. The anti-TROP2 ADC, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), is being evaluated as a second-line treatment. Although the phase 3 TROPION-Lung01 study (NCT04656652) demonstrated a progression-free survival benefit with Dato-DXd over docetaxel, Yang noted the need for further investigation into the biomarker’s predictive capabilities.
To enhance predictive power, researchers are utilizing AI-driven methods in computational pathology. This approach involves scanning IHC slides and employing algorithms to analyze TROP2 staining, ultimately generating a quantitative score that can be correlated with treatment response.
Yang concluded that the integration of multiplex IHC testing, broad-panel NGS, and AI will form the foundation of comprehensive biomarker testing in lung cancer in the coming years. Despite the advancements, he acknowledged ongoing challenges related to tissue availability for testing and emphasized the need for innovative solutions to meet the growing demand for personalized treatment options in NSCLC.
