Advancements in biomarker testing for non-small cell lung cancer (NSCLC) are reshaping treatment strategies, moving beyond traditional genomic analyses to incorporate innovative protein-based and computational markers. This evolution is largely driven by the approval of new therapies, particularly antibody-drug conjugates (ADCs), and a deeper understanding of how tumors develop resistance. Insights were shared by Soo-Ryum (Stewart) Yang, MD, during his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025.
Yang, an assistant attending pathologist and co-director of Clinical Biomarker Development at the Memorial Sloan Kettering Cancer Center, highlighted four significant trends in the field: the rise of protein-based immunohistochemistry (IHC) biomarkers for ADCs, the actionability of tumor suppressor genes, the therapeutic potential of synthetic lethality, and the integration of computational pathology.
The ongoing challenge of tissue scarcity necessitates the development of multiplex IHC techniques alongside broad panel next-generation sequencing (NGS). This approach aims to deliver personalized therapies to a wider NSCLC patient population. Traditionally, cancer treatment focused on genetic mutations, but now the expression levels of surface proteins are gaining recognition as critical biomarkers. Pathologists are shifting their focus from identifying mutated genes to measuring protein expression intensity, which may unlock new treatment avenues.
Yang emphasized two essential protein biomarkers: HER2 and c-MET. HER2 overexpression occurs in approximately 20% of NSCLC cases, with the highest expression level (IHC 3+) found in about 3% of patients. Importantly, Yang pointed out that there is no correlation between HER2 mutation status and 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 supported by findings from the phase 2 DESTINY-Lung01 study (NCT03505710), which applied HER2 scoring guidelines used previously for gastric cancer.
Similarly, c-MET overexpression is prevalent in NSCLC and can be actionable. Yang reported that an actionable c-MET–high status, defined as over 50% of tumor cells exhibiting 3+ staining, is present 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 data from the phase 2 LUMINOSITY trial (NCT03539536).
Despite these advancements, integrating HER2 and c-MET IHC screening into current diagnostic workflows poses challenges. Yang proposed a flexible approach that would allow institutions to create optimized workflows based on their specific resources and multidisciplinary input.
In addition, several promising biomarkers are under investigation for their potential to enhance personalized treatment for NSCLC patients. For example, KRAS mutations are found in up to 40% of lung adenocarcinomas. The most common mutation, KRAS G12C, is followed by G12V and G12D mutations. Yang noted that KRAS G12D mutations are typically associated with a lower tumor mutational burden and poorer responses to chemoimmunotherapy, posing challenges for treatment.
Therapies targeting KRAS G12C, such as sotorasib (Lumakras) and adagrasib (Krazati), have been established and approved. Moreover, research is progressing on inhibitors for KRAS G12D mutations, such as zoldonrasib (RMC-9805), which showed an overall response rate of 61% in a phase 1 study (NCT06040541).
Yang elaborated on the roles of tumor suppressor genes like STK11 and KEAP1, mutated in up to 20% of lung cancers and often co-mutated with KRAS. These mutations create an immunosuppressive environment, leading to resistance against immunotherapy. The phase 3 POSEIDON trial (NCT03164616) suggests that combining a CTLA-4 inhibitor with a PD-L1 inhibitor and chemotherapy may improve outcomes for these patients.
Moreover, MTAP deletions, which occur in up to 18% of lung cancers, represent another emerging therapeutic target. They create a vulnerability that can be exploited through a two-hit therapeutic strategy, potentially leading to selective cancer cell death. Yang discussed the importance of utilizing NGS to detect MTAP deletions, as it requires no additional tissue when included in the panel.
Yang also highlighted the potential of TROP2, a surface protein expressed in NSCLC, as a target for ADC development. The phase 3 TROPION-Lung01 study (NCT04656652) indicated a progression-free survival benefit with datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) compared to docetaxel, although no significant overall survival benefit was found. To enhance predictive power, researchers are developing AI-driven methods using computational pathology to assess TROP2 staining and predict treatment response.
In conclusion, advancements in biomarker testing for NSCLC are significantly expanding the arsenal of treatment options, moving beyond a focus on genomics to include protein analysis and AI-driven insights. These innovations are paving the way towards personalized medicine for a broader range of lung cancer patients. Yang called for further exploration of multiplex IHC and emphasized the need for comprehensive biomarker testing that incorporates broad-panel NGS, IHC, and AI technologies to meet the growing demands of the field.
