The management of non-small cell lung cancer (NSCLC) is evolving, as recent advancements in biomarker testing shift the focus beyond traditional genomic drivers. During his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025, Dr. Soo-Ryum (Stewart) Yang, assistant attending pathologist and co-director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center, highlighted significant trends in the field. The rise of protein-based biomarkers, particularly in the context of antibody-drug conjugates (ADCs), is reshaping treatment strategies.
Dr. Yang identified four pivotal trends: the increasing importance of protein-based immunohistochemistry (IHC) biomarkers, the actionable potential of tumor suppressor genes, the therapeutic applications of synthetic lethality, and the integration of computational pathology. Despite these advancements, he noted ongoing challenges, particularly the scarcity of tissue samples. This underscores the urgent need for multiplex IHC and broad-panel next-generation sequencing (NGS) to expand access to personalized therapies for NSCLC patients.
Traditionally, the focus has been on identifying mutated genes within cancer cells. Now, the measurement of protein expression levels is emerging as a critical avenue for treatment options. PD-L1 IHC testing has already proven pivotal in guiding checkpoint inhibitor therapy, and it is now expanding to inform ADC usage. Dr. Yang emphasized two crucial protein biomarkers in NSCLC: HER2 and c-MET overexpression.
HER2 overexpression occurs in up to 20% of NSCLC cases, with the most significant levels (IHC 3+) found in about 3% of patients. It is important to note that there is no correlation between HER2 mutation status and its overexpression. The approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients who have previously been treated, was backed by the phase 2 DESTINY-Lung01 study (NCT03505710). Dr. Yang advocates applying gastric cancer HER2 scoring guidelines to NSCLC testing.
In addition, c-MET overexpression is prevalent in NSCLC, with an actionable c-MET-high status—defined as over 50% of tumor cells exhibiting 3+ staining—detected in up to 17% of EGFR wild-type cases. The FDA’s accelerated approval of telisotuzumab vedotin-tllv (teliso-V; Emrelis) for this population was supported by the phase 2 LUMINOSITY trial (NCT03539536). Dr. Yang pointed out that integrating HER2 and c-MET IHC screening presents considerable challenges to current diagnostic workflows.
To address these challenges, he proposed a flexible approach that includes standardized options, enabling institutions to create optimized workflows tailored to their resources and multidisciplinary input. The search for additional promising biomarkers continues, with several under investigation that could refine personalized treatment for NSCLC patients.
KRAS mutations are significant, occurring in up to 40% of lung adenocarcinomas. The most common mutation is KRAS G12C, followed by KRAS G12V and KRAS G12D. Dr. Yang explained that KRAS G12D mutations are associated with a history of never or light smoking, lower tumor mutational burden, and poorer responses to chemoimmunotherapy. Existing therapies targeting KRAS G12C, such as sotorasib (Lumakras) and adagrasib (Krazati), have gained approval, while new targeted therapies are in clinical trials. For example, zoldonrasib (RMC-9805), a KRAS G12D inhibitor, reported an overall response rate of 61% in a phase 1 study (NCT06040541).
Dr. Yang noted that mutations in the tumor suppressor genes STK11 and KEAP1 occur in up to 20% of lung cancers, often in conjunction with KRAS mutations. These mutations contribute to an immunosuppressive tumor microenvironment, leading to resistance to immunotherapy. Analysis of the phase 3 POSEIDON trial (NCT03164616) suggests that combining a CTLA-4 inhibitor with a PD-L1 inhibitor and chemotherapy may enhance treatment efficacy in patients with these mutations.
MTAP, another significant gene, plays a key role in the purine salvage pathway. Its deletion in cancer cells creates a metabolic vulnerability that can be targeted through therapeutic inhibition. This “first hit” can be exploited by a “second hit,” leading to selective cancer cell death—a strategy known as synthetic lethality. MTAP deletions are observed in up to 18% of lung cancers and are associated with poor outcomes.
Detection methods include NGS, which can identify homozygous deletions of the MTAP gene, and IHC, which detects loss of MTAP protein expression. Dr. Yang proposed a diagnostic workflow that uses NGS for initial screening, followed by confirmatory IHC in cases where MTAP status is ambiguous.
The exploration of TROP2, a cell surface protein commonly expressed in NSCLC, represents another frontier in treatment development. The ADC datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) is being evaluated as a second-line treatment. While the phase 3 TROPION-Lung01 study (NCT04656652) indicated a progression-free survival benefit over docetaxel, it did not show a statistically significant overall survival advantage.
To enhance predictive capabilities, investigators developed an AI-driven method utilizing computational pathology. This approach measures TROP2 staining in tumor cells, generating a quantitative score that could help predict treatment responses. Although promising, Dr. Yang emphasized the need for prospective validation in independent cohorts.
The advancements in lung cancer management reflect a shift toward a comprehensive approach that integrates protein analysis, AI insights, and innovative strategies like synthetic lethality. These developments are paving the way for personalized medicine to benefit a broader range of lung cancer patients. Dr. Yang concluded, “We are 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.” He believes that broad-panel NGS and IHC, combined with AI, will become foundational elements of biomarker testing in lung cancer over the next few years.
