Navigating Biomarker-Driven Treatment in Advanced NSCLC: Part II
Key Takeaways:
- Non-small cell lung cancer (NSCLC) disease progression complicates decision-making as targeted strategies related to treatment mechanism and sequencing are needed to manage therapy resistance.
- Barriers to care include testing access, insurance coverage, and underrepresentation in clinical trials, highlighting the need for more equitable health policies and research methods.
- Emerging research on NSCLC shows promising developments in care, especially for mutation-targeting therapies.
In this interview, Kelsey Pan, MD, MPH, assistant professor of medicine at Winship Cancer Institute, Emory University, discusses advances and challenges in enhancing NSCLC treatment. Dr Pan shares insights on resistance management, barriers to equitable care, and recent developments in research.
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.
What challenges do you encounter when managing acquired resistance to targeted therapies, and how do you approach treatment sequencing after disease progression?
Dr Pan: Resistance mechanisms are heterogeneous, and increasingly so with each successive line of therapy. On-target mutations, bypass pathway activation, and histologic transformation all present as clinical progression, but each may call for a different therapeutic strategy. Repeat biopsy, or plasma NGS when tissue is not feasible, is essential at progression. The growing number of resistance-directed agents is encouraging, but we often do not identify a targetable mechanism of resistance. Sequencing decisions also depend on the pattern of progression, not just the mechanism. Oligoprogression can often be managed with local therapy (such as radiation therapy and surgical resection) while continuing the same systemic regimen, whereas a more systemic or widespread progression usually requires a change in systemic therapy.
In your opinion, what are the biggest barriers to delivering precision oncology in NSCLC, including access to testing and treatment?
Dr Pan: Access to timely, comprehensive testing is still a significant barrier. Turnaround time, tissue adequacy, and insurance coverage for comprehensive NGS testing varies considerably by practice setting, and patients treated outside of academic centers are disproportionately affected. Cost and reimbursement for both testing and treatment with targeted therapies remain obstacles, particularly for patients without adequate insurance coverage.
As therapeutic options (including clinical trials) become more mechanism-directed, obtaining genomic testing not only at baseline but also at progression are important for treatment selection. Interpreting an NGS report and translating it into the optimal frontline or resistance-directed therapy requires ongoing education for oncologists as our field rapidly evolves. Inequity in clinical trial access remains a barrier; earlier phase trials, rarer alterations, or resistance settings are frequently concentrated at academic centers, which limit enrollment for patients who cannot travel. Finally, active CNS metastases and leptomeningeal disease are excluded or underrepresented in most trials, which leaves gaps in the evidence base and limits access to novel therapies for this patient population.
Are there any current trials you find particularly promising in the NSCLC treatment landscape?
Dr Pan: Several developments from this past year stand out. The 7-year update from the CROWN trial reinforced lorlatinib’s durability as frontline therapy in ALK-positive disease, including favorable long-term CNS control. Updated overall survival data from the CHRYSALIS-2 study of amivantamab plus lazertinib were notable in atypical EGFR-mutant NSCLC, a population that has historically lacked a defined standard of care. Sunvozertinib’s phase 3 data in EGFR exon 20 insertion-positive disease is another meaningful advancement for an alteration that has been difficult to target effectively.
There are ongoing trials evaluating PD-1/VEGF bispecific antibodies and antibody-drug conjugate combinations in driver-negative and squamous NSCLC, which may reshape frontline chemoimmunotherapy paradigms if survival data matures favorably. We also see a plethora of new ways to target KRAS non-G12C mutations through different mechanisms, including RAS(ON) G12D inhibitors, pan-RAS inhibitors, and protein degraders. While these have not yet become standard of care, they represent promising expansions for patients with the most common mutation we see in NSCLC, and clinical trial referral is the most important step for eligible patients.
