New Insights in NSCLC Management Emerges at Lung Cancer Symposium

The field of biomarker testing in non–small cell lung cancer (NSCLC) is evolving significantly, as highlighted by Dr. Soo-Ryum Yang during his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025. This transformation moves beyond traditional genomic markers, incorporating a range of protein-based and computationally derived markers that reflect a deeper understanding of therapeutic responses and resistance.

Dr. Yang, who serves as an assistant attending pathologist and co-director of Clinical Biomarker Development at the Memorial Sloan Kettering Cancer Center, outlined four key trends influencing the landscape of NSCLC management. These include the utilization of protein-based immunohistochemistry (IHC) biomarkers for antibody-drug conjugates (ADCs), the therapeutic implications of tumor suppressor genes, the advancement of synthetic lethality approaches, and the integration of computational pathology in diagnostics.

The ongoing scarcity of tissue samples poses a significant challenge. To address this, there is a critical need for multiplex IHC development and the integration of broad panel next-generation sequencing (NGS) coupled with artificial intelligence (AI). Such advancements aim to enhance personalized therapy delivery to a wider NSCLC patient demographic.

Dr. Yang emphasized that the expression levels of specific proteins on cancer cells are emerging as crucial actionable biomarkers. For instance, while PD-L1 IHC testing has guided checkpoint inhibitor therapies, it is now increasingly utilized for ADCs. He identified two essential protein biomarkers in NSCLC: HER2 and c-MET overexpression.

HER2 overexpression occurs in up to 20% of NSCLC patients, with the highest expression levels (IHC 3+) present in approximately 3% of cases. Notably, there is a lack of correlation between HER2 mutation status and overexpression, a distinction that is vital for treatment determination. The FDA’s recent approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients previously treated, was supported by the findings from the phase 2 DESTINY-Lung01 study. Dr. Yang advocated for applying gastric cancer HER2 scoring guidelines to NSCLC testing.

c-MET overexpression is also prevalent in NSCLC, with actionable c-MET-high status—characterized by over 50% of tumor cells exhibiting 3+ staining—found in nearly 17% of EGFR wild-type cases. The recent FDA approval of telisotuzumab vedotin-tllv (teliso-V; Emrelis) for this patient population was backed by data from the phase 2 LUMINOSITY trial.

Dr. Yang proposed two primary strategies to navigate the integration challenges of HER2 and c-MET IHC screening into current diagnostic workflows. He stressed the importance of a flexible approach that allows institutions to optimize their workflows based on both multidisciplinary input and available resources.

Several promising biomarkers are currently under investigation, which could refine personalized treatment strategies for NSCLC patients. Dr. Yang noted that KRAS mutations occur in up to 40% of lung adenocarcinomas, with specific mutations such as G12C being the most common. KRAS G12D mutations, often associated with a history of light or non-smoking, present unique challenges, correlating with poorer responses to chemoimmunotherapy.

Targeted therapies for KRAS G12C, including sotorasib (Lumakras) and adagrasib (Krazati), are already established. Furthermore, ongoing clinical trials are exploring additional targeted therapies beyond G12C-directed agents, like multi-RAS and RAS(ON) inhibitors. Among these, zoldonrasib (RMC-9805), a KRAS G12D inhibitor, has shown an overall response rate of 61% in early studies.

Dr. Yang also discussed the implications of mutations in tumor suppressor genes such as STK11 and KEAP1, found in up to 20% of lung cancers. These mutations often coexist with KRAS mutations and contribute to an immunosuppressive environment, leading to resistance against immunotherapy. Analysis of the phase 3 POSEIDON trial suggests that combining a CTLA-4 inhibitor with PD-L1 inhibitors and chemotherapy might enhance outcomes for patients harboring these mutations.

The exploration of synthetic lethality was another focal point of Dr. Yang’s presentation. He explained the potential of targeting metabolic vulnerabilities in cancer cells with MTAP deletions, which occur in about 18% of lung cancers. This deletion can impair enzyme activity, creating a therapeutic opportunity through targeted inhibition strategies.

Dr. Yang also highlighted the potential of TROP2, a cell surface protein widely expressed in NSCLC, as a target for ADC development. The phase 3 TROPION-Lung01 study indicated a progression-free survival benefit with the anti-TROP2 ADC, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), although no statistically significant overall survival advantage was observed.

To enhance predictive power for TROP2, an AI-driven method employing computational pathology was developed. This innovative approach scans IHC slides to measure TROP2 expression, translating findings into actionable insights. While this method shows promise, Dr. Yang underscored the need for prospective validation and raised concerns regarding its proprietary nature, which may hinder broader accessibility.

As the toolkit for lung cancer management expands, the emphasis is shifting from a narrow focus on genomics to a more comprehensive approach incorporating protein analysis, AI-driven insights, and novel therapeutic strategies. Dr. Yang concluded by urging the exploration of multiplex IHC methodologies, akin to previous advancements in molecular markers and NGS, to further enhance biomarker testing in lung cancer. The integration of broad-panel NGS and IHC, alongside AI, is set to become foundational in the evolving landscape of NSCLC management.