Imagine a future where lung cancer treatment isn't just about attacking the tumor, but about understanding its unique vulnerabilities at a molecular level. We're not quite there yet, but groundbreaking research is rapidly reshaping the landscape of non-small cell lung cancer (NSCLC) management, moving beyond traditional genetic markers to embrace a new era of personalized therapies. Dr. Soo-Ryum (Stewart) Yang, a leading expert in the field, shed light on these exciting advancements during his presentation at the 20th Annual New York Lung Cancers Symposium®. His insights are revolutionizing how we approach this challenging disease.
Dr. Yang, Assistant Attending Pathologist and Co-Director of Clinical Biomarker Development at Memorial Sloan Kettering Cancer Center, highlighted four pivotal trends that are poised to redefine NSCLC treatment strategies: the burgeoning role of protein-based biomarkers in guiding antibody-drug conjugate (ADC) therapy, the surprising actionability of tumor suppressor genes, the therapeutic potential of synthetic lethality, and the transformative impact of computational pathology. But here's where it gets controversial: while these advancements offer immense promise, a persistent hurdle remains – the limited availability of tumor tissue for comprehensive analysis.
This scarcity underscores the urgent need for innovative diagnostic approaches. Dr. Yang advocates for the development and implementation of multiplex immunohistochemistry (IHC) techniques, combined with comprehensive next-generation sequencing (NGS) panels and the integration of artificial intelligence (AI). The goal? To deliver the next generation of personalized therapies to a larger proportion of NSCLC patients, even when tissue samples are limited. Let’s delve into the specifics of these groundbreaking advancements.
The Rise of Protein Biomarkers: A New Frontier for ADCs
For years, cancer treatment has heavily relied on identifying specific gene mutations to guide therapy. However, scientists are increasingly recognizing the importance of protein expression levels on the surface of cancer cells. These proteins are emerging as critical, actionable biomarkers that can unlock new treatment avenues. Think of it this way: instead of just looking for a typo in the cancer cell's DNA (the mutated gene), pathologists are now measuring the volume of the cancer cell's voice (the intensity of protein expression).
While PD-L1 IHC testing is already a standard practice for guiding checkpoint inhibitor therapy, IHC testing is now extending its reach to guide ADC usage. Dr. Yang emphasized two "must-test" protein biomarkers in NSCLC: HER2 and c-MET overexpression. And this is the part most people miss: these protein-level biomarkers are distinct from their genetic counterparts. This distinction is crucial. HER2 overexpression, for instance, is observed in up to 20% of patients, with the highest levels (IHC 3+) seen in approximately 3%. However, there's no direct correlation between HER2 mutation status and its overexpression. While most NSCLC cases with high-level gene amplification will exhibit IHC 3+ staining, the opposite isn't always true – not all IHC 3+ cases are driven by amplification.
The FDA's approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for HER2-positive (IHC 3+) solid tumors, including previously treated NSCLC patients, was a significant milestone. This approval was based on the phase 2 DESTINY-Lung01 study, which utilized HER2 scoring guidelines originally developed for gastric cancer. Dr. Yang argues that these gastric cancer guidelines should now be universally adopted for NSCLC testing to ensure consistent and accurate assessment of HER2 overexpression.
c-MET overexpression is also prevalent in NSCLC, with an actionable c-MET–high status (defined as over 50% of tumor cells with 3+ staining) found in up to 17% of EGFR wild-type cases. Similar to HER2 overexpression, c-MET overexpression can coexist with other driver mutations but remains a distinct biomarker from MET exon 14 skipping mutations and MET amplification.
The FDA's accelerated approval of telisotuzumab vedotin-tllv (teliso-V; Emrelis) in May 2025 for this patient population, based on data from the phase 2 LUMINOSITY trial, further solidifies the importance of c-MET overexpression as a therapeutic target.
Integrating HER2 and c-MET IHC screening into current diagnostic workflows presents a significant challenge. Dr. Yang proposes two primary strategies:
- Upfront Reflex Testing: Automatically order HER2 and c-MET IHC testing on the initial diagnostic sample as part of a comprehensive reflex biomarker panel alongside NGS and other IHC tests. This proactive approach ensures that these critical biomarkers are assessed early in the diagnostic process.
- Testing at Progression: Order the tests on a per-request basis upon disease progression, either on a new biopsy or an archived sample. This strategy aligns with their current approval in the second-line setting, focusing testing efforts on patients who are progressing on initial therapies.
Dr. Yang emphasizes that there's no one-size-fits-all solution. He recommends a flexible approach with standardized options, allowing institutions to develop optimized workflows based on multidisciplinary input and their specific resources. This highlights the importance of collaboration between pathologists, oncologists, and other healthcare professionals to ensure the best possible patient care. What workflow do you think is most effective and efficient?
Emerging Biomarkers on the Horizon
Beyond HER2 and c-MET, several promising biomarkers are under investigation and hold the potential to become part of the standard of care, further refining personalized treatment for NSCLC patients. It's like adding new tools to the toolbox, each designed to address specific vulnerabilities in the cancer cells.
KRAS Mutations: KRAS mutations are found in up to 40% of lung adenocarcinomas, with mutations in codons G12, G13, and Q61 being the most common. The KRAS G12C mutation is the most prevalent, followed by KRAS G12V and KRAS G12D mutations. Interestingly, KRAS G12D mutations are associated with never or light smoking history, a lower tumor mutational burden, and lower PD-L1 expression, correlating with poorer responses to chemoimmunotherapy. This makes them a particularly challenging subtype to treat. This is a key area of ongoing research and development.
Fortunately, KRAS G12C-specific targeted therapies, such as sotorasib (Lumakras) and adagrasib (Krazati), are already established and approved. Furthermore, the development of targeted therapies beyond KRAS G12C–directed agents, like multi-RAS and RAS(ON) inhibitors, are actively being explored in clinical trials. Dr. Yang highlighted zoldonrasib (RMC-9805), a KRAS G12D inhibitor, which demonstrated an impressive overall response rate of 61% (n = 11) and a disease control rate of 89% (n = 16) in a phase 1 study. The multi-RAS inhibitor daraxonrasib (RMC-6236) has also shown promise in KRAS G12V–mutant NSCLC, as well as in pancreatic cancer. Because KRAS mutations are easily detected by existing NGS and PCR technologies, they don't present the same workflow challenges as IHC testing for HER2 and c-MET.
STK11 and KEAP1 Mutations: STK11 and KEAP1 mutations are tumor suppressor genes that are mutated in up to 20% of lung cancers, often co-mutated with KRAS. Mutations in these genes promote an immunosuppressive tumor microenvironment, leading to primary resistance to immunotherapy. They are considered biomarkers of poor response to single-agent PD-1/PD-L1 inhibitors. But here's where it gets interesting: analysis of the phase 3 POSEIDON trial suggests a potential workaround. The addition of a CTLA-4 inhibitor to a PD-L1 inhibitor and chemotherapy improved progression-free survival (PFS) and overall survival (OS) in these patients. This positions STK11/KEAP1 mutations as potential biomarkers for escalating checkpoint therapy and could become valuable for identifying patients who need a more aggressive, multi-pronged immunotherapy approach. Importantly, detecting these mutations requires broad-panel NGS to identify the full range of inactivating mutations across these tumor suppressor genes; PCR is not a feasible approach.
MTAP Deletions and Synthetic Lethality: MTAP plays a crucial role in the purine salvage pathway. Its deletion in cancer cells impairs the activity of the enzyme PRMT5, creating a metabolic vulnerability. This metabolic vulnerability opens the door to an exciting therapeutic strategy called synthetic lethality. This “first hit” can be exploited by a “second hit”—the therapeutic inhibition of PRMT5 or MAT2a—to induce selective cancer cell death. MTAP deletions occur in up to 18% of lung cancers and are associated with poor outcomes, particularly with immunotherapy. They are an emerging therapeutic target, with promising clinical trial data for PRMT5 inhibitors in MTAP-deleted lung cancers. Detection methods include NGS, which detects homozygous deletion of the MTAP gene, and IHC, which detects the loss of MTAP protein expression. Dr. Yang proposed a diagnostic workflow involving NGS for initial screening, followed by confirmatory IHC in cases where the MTAP status is retained or borderline, especially in low-purity samples.
TROP2 and Computational Pathology: TROP2 is a cell surface protein widely expressed in NSCLC, making it an attractive target for ADC development. Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), an anti-TROP2 ADC, is being explored as a second-line agent. The phase 3 TROPION-Lung01 study showed a PFS benefit with Dato-DXd over docetaxel, a standard chemotherapy drug, but no statistically significant OS benefit. The trial didn't enrich for a biomarker, as previous studies found no correlation between TROP2 expression and response. But here's the twist: to improve predictive power, investigators developed an AI-driven method using computational pathology. This involves scanning an IHC slide and using an AI algorithm to measure the optical density of TROP2 staining in the membrane and cytoplasmic components of tumor cells. This generates a TROP2 quantitative continuous score (QCS) or normalized membrane ratio (NMR), which is then converted into a binary positive/negative result. When applied retrospectively to the TROPION-Lung01 study, TROP2 QCS/NMR positivity was predictive of higher response rates and longer PFS with Dato-DXd. While compelling, Dr. Yang noted that this proof of concept requires prospective validation in independent cohorts. Additionally, he raised concerns that the biomarker is currently tied to a specific, proprietary digital pathology ecosystem, raising questions about broader accessibility and implementation on other platforms. What are your thoughts on the integration and standardization of AI in pathology?
The Future of Personalized Medicine in NSCLC
The toolbox for fighting lung cancer is expanding dramatically, moving beyond an exclusive focus on genomics and into a more holistic approach that incorporates protein analysis, AI-driven insights, and novel therapeutic strategies like synthetic lethality. These advancements are making personalized medicine a reality for broader segments of the lung cancer population.
"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," Dr. Yang concluded. "In the next few years, broad-panel NGS and IHC, along with AI, are going to be the cornerstones of comprehensive biomarker testing in lung cancer." This bold statement underscores the transformative potential of these technologies to revolutionize NSCLC management and improve patient outcomes.
This progress is undeniably exciting, but it also raises important questions: How do we ensure equitable access to these advanced diagnostic technologies? How do we address the challenges of tissue scarcity? And how do we navigate the ethical considerations surrounding the use of AI in healthcare? Share your thoughts and perspectives in the comments below. Let's discuss the future of personalized medicine in NSCLC together!
