Navigating Biomarker-Driven Treatment in Advanced NSCLC Part 1

Key Takeaways:

• Biomarker testing has become a procedural tool for initial intervention after a new diagnosis of non–small cell lung cancer (NSCLC), which helps physicians determine appropriate treatment pathways and identify patients resistant to targeted therapies.
• Factors such as actionable genomic alteration (AGA), mutations, and tumor burden influence frontline treatment selection between targeted therapy, immunotherapy, and chemoimmunotherapy.
• When patients are not eligible for targeted therapy, treatment decisions are influenced by patient-related factors such as comorbidities, performance status, and personal preferences.

In this interview, Kelsey Pan, MD, MPH, assistant professor of medicine at Winship Cancer Institute, Emory University, discusses how medical developments are shaping clinical approaches to NSCLC treatment. Dr Pan shares insights on physician decision-making processes and the value of current targeted therapies.

Kelsey Pan, MD, MPH: My name is Kelsey Pan. I am an assistant professor of medicine and a thoracic medical oncologist at Winship Cancer Institute, Emory University. My clinical and research focus is on oncogene-driven NSCLC, including estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and metabolic equivalent of task (MET) alterations. I have a particular interest in central nervous system (CNS) metastases and leptomeningeal disease in this population. I serve as principal investigator or co-investigator on several clinical trials in this space, and I take part in institutional and national committees, including the American Society of Clinical Oncology (ASCO) Living Well Guidelines Committee.

How has biomarker testing changed your approach to treating patients with newly diagnosed advanced NSCLC?

Dr Pan: Biomarker testing is now one of the first steps we perform upon diagnosis of a new lung cancer, as it is critical for guiding initial (and subsequent) treatment strategies. Unlike a decade ago when advanced NSCLC was largely treated as one disease, it has since become a collection of molecularly defined subsets, each with its own distinct treatment pathways. Comprehensive next-generation sequencing (NGS) at diagnosis, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2, KRAS G12C, NRG1 and other emerging targets, determines whether a patient is a potential candidate for targeted therapies. Biomarker testing is increasingly being performed longitudinally, not just at diagnosis. As mechanism-directed treatment options expand, repeating testing at progression to identify acquired resistance mechanisms is becoming as important as the initial testing.

What factors drive your treatment selection between targeted therapies, immunotherapy, chemoimmunotherapy, and combination approaches in frontline treatment?

Dr Pan: First and foremost, we look at the genomic profile for the presence of an AGA; co-mutations can also inform disease biology and, in some cases, influence treatment selection. If an AGA is present, targeted therapy is often the preferred choice of frontline therapy as they offer superior efficacy compared to chemo/immunotherapy for certain subtypes. Chemotherapy may be combined with targeted therapy for advanced EGFR-mutant NSCLC, and this strategy is being investigated in other molecular subsets as well. For certain oncogene drivers, such as KRAS, targeted therapy is not yet the current standard-of-care therapy in the frontline setting outside of clinical trials; hence, they are treated initially with chemoimmunotherapy, followed by targeted therapy in the subsequent-line setting.

When a targeted therapy is not available or approved in the frontline setting, tumor-related factors, including programmed death-ligand 1 (PD-L1) status, tumor burden, and emerging predictive biomarkers like STK11 and KEAP1, are essential in determining treatment with chemoimmunotherapy vs immunotherapy alone. Patient related factors, including comorbidities, performance status, and goals or personal preferences, are just as important, particularly for combination regimens that carry additive toxicity.