Significant advancements in the management of non-small cell lung cancer (NSCLC) are emerging, driven by a shift towards advanced biomarker testing. This evolution moves beyond traditional genomic analysis to include protein-based and computationally derived markers. Dr. Soo-Ryum (Stewart) Yang, a prominent pathologist at Memorial Sloan Kettering Cancer Center, discussed these developments during his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025.
Dr. Yang highlighted four key trends shaping this new landscape: the rise of protein-based immunohistochemistry (IHC) biomarkers for antibody-drug conjugates (ADCs), the actionable nature of tumor suppressor genes, the therapeutic implications of synthetic lethality, and the integration of computational pathology. As the approval of innovative therapies progresses, addressing the ongoing challenge of tissue scarcity remains critical. This underscores the necessity for multiplex IHC and comprehensive next-generation sequencing (NGS) technologies, alongside artificial intelligence, to enhance personalized treatment options for a broader NSCLC patient demographic.
The focus is shifting from merely identifying mutated genes to measuring protein expression levels on the surface of cancer cells. This new approach can unlock diverse treatment avenues for patients. Dr. Yang noted that while PD-L1 IHC testing is established for guiding checkpoint inhibitor therapy, it is increasingly employed to direct ADC usage. He emphasized the importance of two “must-test” biomarkers in NSCLC: HER2 and c-MET overexpression.
HER2 overexpression appears in up to 20% of NSCLC patients, with the most intense expression (IHC 3+) noted in approximately 3%. Dr. Yang clarified that there is no direct correlation between HER2 mutation status and overexpression. It is common for high-level gene amplification to present with IHC 3+ staining, but not all 3+ cases are driven by amplification. The FDA’s approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC cases previously treated, was based on the phase 2 DESTINY-Lung01 study.
c-MET overexpression is prevalent in NSCLC, with actionable c-MET-high status—defined as over 50% of tumor cells showing 3+ staining—occurring in up to 17% of EGFR wild-type cases. Like HER2, c-MET can coexist with other driver mutations yet remains a distinct biomarker from MET exon 14 skipping mutations and MET amplification. The FDA granted accelerated approval to telisotuzumab vedotin-tllv (teliso-V; Emrelis) for this patient population based on findings from the phase 2 LUMINOSITY trial.
The integration of HER2 and c-MET IHC screening poses challenges to current diagnostic workflows. Dr. Yang proposed a flexible strategy, allowing healthcare institutions to tailor their approaches based on available resources and multidisciplinary input. This adaptability is essential as several promising biomarkers are under investigation, potentially refining personalized treatment for NSCLC further.
KRAS mutations, occurring in up to 40% of lung adenocarcinomas, predominantly affect codons G12, G13, and Q61. The KRAS G12C mutation is the most frequently observed, followed by G12V and G12D mutations. Dr. Yang noted that KRAS G12D mutations correlate with a lighter smoking history, a lower tumor mutational burden, and reduced PD-L1 expression, complicating treatment responses. Established KRAS G12C-targeted therapies, including sotorasib (Lumakras) and adagrasib (Krazati), are being supplemented by ongoing trials exploring multi-RAS and RAS(ON) inhibitors, such as zoldonrasib (RMC-9805), which showed a 61% overall response rate in preliminary studies.
Dr. Yang also addressed the role of tumor suppressor gene mutations, specifically STK11 and KEAP1, which are present in up to 20% of lung cancers. These mutations often coexist with KRAS mutations and contribute to an immunosuppressive tumor microenvironment, leading to resistance against immunotherapy. Analysis of the phase 3 POSEIDON trial indicated that combining a CTLA-4 inhibitor with PD-L1 inhibitors and chemotherapy could improve patient outcomes.
The exploration of MTAP deletions, which occur in up to 18% of lung cancers, reveals another layer of complexity. These deletions impair the activity of the enzyme PRMT5, creating a unique therapeutic vulnerability. Emerging clinical trial data suggest promising opportunities for PRMT5 inhibitors in treating MTAP-deleted lung cancers.
Lastly, TROP2, a protein expressed on the surface of NSCLC cells, is gaining attention as a target for ADC development. The phase 3 TROPION-Lung01 study revealed a progression-free survival benefit with the ADC datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) compared to docetaxel. However, no statistically significant overall survival benefit was found, prompting further investigation of predictive biomarkers.
Dr. Yang emphasized the importance of applying artificial intelligence to enhance the predictive power of biomarker testing. An AI-driven method measuring TROP2 staining could yield significant insights into treatment responses. However, the current reliance on proprietary digital pathology ecosystems raises concerns regarding accessibility and broader implementation.
The developments in biomarker testing are paving the way for a comprehensive approach to lung cancer management, moving beyond a sole focus on genomics. Dr. Yang concluded that broad-panel NGS and IHC, coupled with artificial intelligence, will be integral to advancing personalized medicine in NSCLC. As the field continues to evolve, the integration of these technologies could profoundly impact the treatment landscape, bringing hope to a larger segment of the lung cancer population.
