The management of non-small cell lung cancer (NSCLC) is evolving significantly, with a shift from traditional genomic testing to a broader range of protein-based and computationally derived biomarkers. This transformation is largely influenced by the approval of innovative therapies, particularly antibody-drug conjugates (ADCs), as well as a deeper understanding of therapeutic resistance and vulnerabilities.
During his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025, Soo-Ryum (Stewart) Yang, MD, an assistant attending pathologist and co-director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center, outlined four key trends shaping this landscape. These include the rise of protein-based immunohistochemistry (IHC) biomarkers for ADCs, the actionable nature of tumor suppressor genes, the therapeutic potential of synthetic lethality, and the integration of computational pathology into diagnostic processes.
One of the pressing challenges in NSCLC management is the scarcity of tissue samples. Yang emphasized the urgent need for multiplex IHC development and the integration of broad panel next-generation sequencing (NGS) combined with artificial intelligence (AI) to provide personalized therapies to a larger segment of NSCLC patients.
As the understanding of cancer biology deepens, the focus is shifting from merely analyzing genetic mutations to assessing the protein expression levels on cancer cells. This approach can reveal critical, actionable biomarkers. While PD-L1 IHC testing has been established for guiding checkpoint inhibitor therapies, IHC testing is now being adapted for ADC applications.
Yang identified two essential protein biomarkers for NSCLC: HER2 and c-MET overexpression. He noted that HER2 overexpression is observed in up to 20% of patients, with a significant subset (3%) exhibiting the highest level (IHC 3+). Importantly, there is no direct correlation between HER2 mutation status and its overexpression, which poses unique considerations for treatment strategies.
The recent FDA approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients who have previously received treatment, was supported by the phase 2 DESTINY-Lung01 study (NCT03505710). Yang advocated for applying gastric cancer HER2 scoring guidelines to NSCLC testing.
Furthermore, c-MET overexpression is prevalent in NSCLC, with an actionable status found in up to 17% of EGFR wild-type cases. The FDA granted accelerated approval to telisotuzumab vedotin (teliso-V; Emrelis) in this patient population, based on findings from the phase 2 LUMINOSITY trial (NCT03539536). Yang proposed that integrating HER2 and c-MET IHC screening presents significant challenges to current diagnostic workflows, suggesting a flexible approach tailored to institutional capabilities.
As research advances, several promising biomarkers may soon be incorporated into standard care protocols. KRAS mutations, prevalent in up to 40% of lung adenocarcinomas, are of particular interest. Yang detailed various KRAS mutations, including the most common KRAS G12C, and highlighted their association with specific patient characteristics and treatment responses. Targeted therapies for KRAS G12C, such as sotorasib (Lumakras) and adagrasib (Krazati), have emerged as approved options, while ongoing trials are exploring therapies targeting other KRAS mutations, including zoldonrasib (RMC-9805) for KRAS G12D.
Yang also pointed out the relevance of STK11 and KEAP1 mutations, which occur in up to 20% of lung cancers. These mutations contribute to an immunosuppressive environment, leading to resistance against single-agent PD-1/PD-L1 inhibitors. The phase 3 POSEIDON trial (NCT03164616) suggests that combining a CTLA-4 inhibitor with PD-L1 therapy and chemotherapy could enhance treatment outcomes for patients harboring these mutations.
The discussion also touched on the role of MTAP deletions in lung cancer. Yang described how these deletions create a metabolic vulnerability that may be exploited through synthetic lethality strategies. MTAP deletions occur in up to 18% of lung cancers and are associated with poor immunotherapy responses, making them an emerging therapeutic target.
Yang proposed a diagnostic workflow that begins with NGS screening, followed by IHC confirmation for cases where MTAP status is unclear. He underscored the ongoing challenge of tissue availability, noting the need for comprehensive testing for an expanding list of biomarkers.
In the evolving field of NSCLC treatment, TROP2 has emerged as a promising target for ADC development. The phase 3 TROPION-Lung01 study (NCT04656652) demonstrated progression-free survival benefits with the anti-TROP2 ADC, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), although overall survival benefits were not statistically significant.
To enhance predictive capabilities, Yang discussed the application of AI-driven methods in computational pathology. This innovative approach involves scanning IHC slides to quantify TROP2 staining, potentially improving response rate predictions. However, he highlighted the need for prospective validation and raised concerns regarding accessibility due to the proprietary nature of the current digital pathology ecosystem.
The advancements in NSCLC management, moving beyond a sole focus on genomics, are paving the way for a more comprehensive approach that includes protein analysis, AI-driven insights, and novel therapeutic strategies. This evolution is making personalized medicine more accessible to a broader range of lung cancer patients. Yang concluded, “We’re at a point where we should be starting to explore the feasibility of multiplex IHC similar to what we did with molecular markers and NGS.” In the coming years, broad-panel NGS and IHC, combined with AI, are expected to become foundational elements of comprehensive biomarker testing in lung cancer.
