The management of non-small cell lung cancer (NSCLC) is evolving as researchers and clinicians increasingly recognize the importance of new biomarkers that extend beyond traditional genomic analysis. During a presentation at the 20th Annual New York Lung Cancers Symposium on November 15, 2025, Dr. Soo-Ryum (Stewart) Yang, an assistant attending pathologist at Memorial Sloan Kettering Cancer Center, highlighted critical trends that are shaping the future of NSCLC treatment.
Dr. Yang emphasized four emerging trends that are transforming biomarker testing: the growing significance of protein-based immunohistochemistry (IHC) biomarkers, the actionability of tumor suppressor genes, the therapeutic potential of synthetic lethality, and the integration of computational pathology. Despite these advancements, he acknowledged a persistent challenge: the scarcity of tissue samples, underscoring the urgent need for multiplex IHC and broad panel next-generation sequencing (NGS) to enhance personalized treatment for NSCLC patients.
Traditionally, biomarker testing focused on genetic mutations within cancer cells. However, the expression levels of specific proteins on a cancer cell’s surface are now recognized as critical, actionable biomarkers. Dr. Yang pointed out that instead of solely searching for mutated genes, pathologists are increasingly measuring the intensity of protein expression, which can significantly broaden treatment options for patients.
Among the notable biomarkers discussed, Dr. Yang highlighted two essential proteins: HER2 and c-MET. While IHC testing for PD-L1 has guided checkpoint inhibitor therapy, it is now also instrumental in determining the use of antibody-drug conjugates (ADCs). HER2 overexpression is noted in up to 20% of NSCLC cases, with the highest expression level (IHC 3+) found in approximately 3% of patients. Importantly, there is no correlation between HER2 mutation status and overexpression, which Dr. Yang stressed is crucial for treatment decisions.
The FDA’s approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive solid tumors, including NSCLC patients with prior treatment, was backed by the phase 2 DESTINY-Lung01 study. Dr. Yang advocated for the application of gastric cancer HER2 scoring guidelines to NSCLC testing as a standard practice.
In addition, c-MET overexpression frequently occurs in NSCLC. 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 group based on data from the phase 2 LUMINOSITY trial. Dr. Yang noted that the integration of HER2 and c-MET IHC screening into diagnostic workflows poses significant challenges, advocating for a flexible approach that considers institutional resources and multidisciplinary expertise.
As research progresses, several promising biomarkers are being investigated for potential inclusion in standard NSCLC care. Dr. Yang pointed out that KRAS mutations occur in up to 40% of lung adenocarcinomas, particularly in codons G12, G13, and Q61. The KRAS G12C mutation is the most prevalent, followed by G12V and G12D mutations. He explained that G12D mutations are often associated with a lower tumor mutational burden and poorer response to chemoimmunotherapy, presenting a unique challenge in treatment.
Established KRAS G12C-specific therapies, such as sotorasib (Lumakras) and adagrasib (Krazati), are already available, while development is underway for targeted therapies directed at other KRAS mutations. Dr. Yang mentioned that zoldonrasib (RMC-9805), a KRAS G12D inhibitor, has shown promising results in clinical trials, with an overall response rate of 61%.
He also addressed mutations in tumor suppressor genes STK11 and KEAP1, which are present in up to 20% of lung cancers. These mutations are often co-mutated with KRAS and contribute to an immunosuppressive environment, leading to resistance against immunotherapy. Data from the phase 3 POSEIDON trial suggest that combining a CTLA-4 inhibitor with PD-L1 inhibitors and chemotherapy may improve outcomes for patients with these mutations, positioning them as potential biomarkers for aggressive immunotherapy strategies.
Moving forward, Dr. Yang discussed the role of MTAP deletions in cancer therapy. Occurring in up to 18% of lung cancers, MTAP deletion creates a metabolic vulnerability that can be exploited through therapeutic inhibition. Detection methods for MTAP include NGS, which can identify homozygous deletions, and IHC, which assesses protein expression. Dr. Yang recommended a diagnostic workflow that utilizes NGS for initial screening, followed by confirmatory IHC in specific cases.
Dr. Yang also explored the potential of TROP2 as a target for ADC development. While the phase 3 TROPION-Lung01 study demonstrated a progression-free survival benefit with the anti-TROP2 ADC datopotamab deruxtecan-dlnk (Dato-DXd), it did not show a statistically significant overall survival benefit. To enhance predictive capabilities, a new AI-driven approach has been developed to quantitatively assess TROP2 expression in tumor cells, which may lead to better response predictions in future studies.
As the field of lung cancer treatment continues to expand, Dr. Yang concluded with a call for a comprehensive approach that includes multiplex IHC and AI-driven insights alongside traditional genomic testing. He stated, “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.” The advancements in biomarker testing and therapeutic strategies signify a promising future for personalized medicine in the NSCLC population.
