Advancements in NSCLC Management Focus on Protein Biomarkers

The management of non-small cell lung cancer (NSCLC) is evolving, with new strategies emphasizing protein-based biomarkers and computational methods. During his presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025, Soo-Ryum (Stewart) Yang, MD, outlined these significant shifts in biomarker testing. Yang, who serves as an assistant attending pathologist and co-director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center in New York, highlighted key trends that could enhance treatment options for patients.

Yang noted a surge in the utilization of protein-based immunohistochemistry (IHC) biomarkers, particularly in the context of antibody-drug conjugates (ADCs). He identified the importance of assessing tumor suppressor genes, exploring synthetic lethality in therapeutic applications, and integrating computational pathology into diagnostic processes. A primary concern remains the scarcity of tissue samples, which underscores the necessity for multiplex IHC and comprehensive next-generation sequencing (NGS) to broaden access to personalized therapies for a larger NSCLC patient population.

The focus is shifting from solely genetic mutations to the expression levels of specific proteins on cancer cells. This approach allows pathologists to identify actionable biomarkers that could lead to new treatment avenues. For instance, while PD-L1 testing has been well established for guiding checkpoint inhibitor therapies, it is now also being adapted for use with ADCs. Yang emphasized the critical role of two protein biomarkers in NSCLC: HER2 and c-MET overexpression.

HER2 overexpression is prevalent in approximately 20% of NSCLC patients, with the highest expression levels, classified as IHC 3+, found in about 3% of cases. Yang pointed out that there is no direct correlation between HER2 mutation status and its overexpression. He explained that while most high-level gene amplifications would typically exhibit IHC 3+ staining, not all cases with this level of expression are driven by gene amplification.

The FDA’s recent approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients who have undergone prior treatment, was bolstered by findings from the phase 2 DESTINY-Lung01 study (NCT03505710). Yang suggested that the HER2 scoring guidelines established for gastric cancer should now be applied to NSCLC testing.

Similarly, c-MET overexpression is identified in up to 17% of EGFR wild-type cases. Yang reported that an actionable c-MET-high status, defined by over 50% of tumor cells exhibiting 3+ staining, is significant in the treatment landscape. The FDA granted accelerated approval to telisotuzumab vedotin-tllv (teliso-V; Emrelis) in this patient demographic, based on data from the phase 2 LUMINOSITY trial (NCT03539536).

As Yang highlighted the integration of HER2 and c-MET IHC screening, he acknowledged the challenges posed to existing diagnostic workflows. He advocated for a flexible strategy that permits institutions to tailor their processes based on available resources and multidisciplinary collaboration. The ongoing investigation of promising biomarkers may soon refine the standard of care for NSCLC patients.

Mutations in KRAS are found in up to 40% of lung adenocarcinomas, with specific mutations in codons G12, G13, and Q61. The KRAS G12C mutation is the most frequent, followed by G12V and G12D mutations. Yang explained that KRAS G12D mutations are often associated with patients having a lighter smoking history and correlate with poor responses to chemoimmunotherapy.

Targeted therapies for KRAS G12C, such as sotorasib (Lumakras) and adagrasib (Krazati), are already established, with ongoing clinical trials exploring further options for various KRAS mutations. For instance, the KRAS G12D inhibitor zoldonrasib (RMC-9805) demonstrated a 61% overall response rate in early studies (NCT06040541), while the multi-RAS inhibitor daraxonrasib (RMC-6236) shows promise in treating KRAS G12V mutations.

Yang also discussed the role of tumor suppressor gene mutations, specifically in STK11 and KEAP1, which can occur in up to 20% of lung cancers and often co-occur with KRAS mutations. These mutations can create an immunosuppressive environment, leading to resistance against immunotherapy. Data from the phase 3 POSEIDON trial (NCT03164616) indicates that combining CTLA-4 inhibitors with PD-L1 inhibitors and chemotherapy can enhance progression-free survival and overall survival for patients with these mutations.

The role of MTAP deletions, occurring in up to 18% of lung cancers, is also emerging as a significant area of research. Yang described how therapeutic strategies exploiting these deletions could lead to selective cancer cell death through synthetic lethality. Detection methods include NGS, which can identify homozygous deletion of the MTAP gene, and IHC, which assesses protein expression levels.

Yang proposed a diagnostic workflow that utilizes NGS for initial screenings, followed by confirmatory IHC testing in cases with ambiguous MTAP status. He underscored the ongoing challenge of tissue availability, stressing that the expanding list of biomarkers requires careful management of biopsies.

The role of TROP2, a cell surface protein widely expressed in NSCLC, is also being explored for ADC development. The phase 3 TROPION-Lung01 study (NCT04656652) evaluated datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) as a second-line treatment. While the study demonstrated benefits in progression-free survival, the overall survival results were not statistically significant.

In an innovative approach, Yang discussed an AI-driven method that employs computational pathology to measure TROP2 expression quantitatively. This method, which converts optical density measurements into a continuous score, showed promise in predicting patient response rates. Nonetheless, Yang cautioned that this approach requires further validation and broader accessibility beyond proprietary systems.

The advancements in NSCLC management mark a significant shift towards a more comprehensive and personalized approach to treatment. Yang concluded that integrating multiplex IHC, broad-panel NGS, and AI-driven insights will be pivotal in the future of biomarker testing for lung cancer, ultimately benefiting a wider range of patients.