Lung Cancer Experts Highlight the Significance and Limitations of ADCs

Hear from the following lung cancer experts about the evolving use of antibody-drug conjugates (ADCs) in non–small cell lung cancer (NSCLC):

• Estelamari Rodriguez, MD, MPH, associate director, Community Outreach – Thoracic Oncology, Sylvester Comprehensive Cancer Center
• Tarek Mekhail, MD, MSc, FRCSI, FRCSEd, medical director, Thoracic Cancer Program, and associate executive director, AdventHealth Cancer Institute
• Balazs Halmos, MD, director, Thoracic Oncology, director, Clinical Cancer Genomics, Albert Einstein College of Medicine, Montefiore Einstein
• Susan Scott, MD, thoracic medical oncologist, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital; and assistant professor, oncology, Johns Hopkins University School of Medicine
• Julie Brahmer, MD, MSc, co-director, Upper Aerodigestive Department, Bloomberg-Kimmel Institute for Cancer Immunotherapy, co-director, Cancer Immunotherapy Program, director, Thoracic Oncology, and Marilyn Meyerhoff Professor in Thoracic Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Corey J. Langer, MD, director, Thoracic Oncology, Penn Medicine; and professor, medicine (hematology-oncology), the Hospital of the University of Pennsylvania, Perelman School of Medicine
• Benjamin P. Levy, MD, clinical director, Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital; and associate professor, oncology, Johns Hopkins University School of Medicine

ADCs represent an emerging class of therapeutics with promising clinical activity. Although some ADCs may not yet demonstrate superiority over traditional chemotherapy, advances in biomarker identification and drug development are expected to enhance their efficacy.

Although significant progress has been made in targeting actionable mutations, most patients without biomarker-driven treatment options require better post-chemotherapy strategies, where ADCs may play a crucial role. However, this class of agents remains in the early stages of clinical development, and their precise role in the NSCLC treatment paradigm is still being defined. The ideal ADC should deliver cytotoxic payloads with high specificity, but currently available ADCs are often associated with systemic toxicity, which may provide both bystander antitumor effects and unintended damage to normal tissues.

Exciting developments in the second-line NSCLC treatment setting include the HER3-targeting ADC patritumab deruxtecan. As ADCs advance, optimal treatment sequencing strategies will be critical to ensure the delivery of maximal clinical benefit from these agents that also maintains patient quality of life. Potential future FDA approvals of developmental ADCs will likely complicate treatment decision-making, necessitating improved patient selection and individualized therapy approaches.

In HER2-mutated NSCLC, trastuzumab deruxtecan has transformed patient care, as it is a well-tolerated treatment option with significant clinical benefit, including central nervous system penetration. However, the development of ADCs that improve upon those already used in clinical practice will require refinements in technology and patient selection strategies. Advancements in digital pathology and artificial intelligence are expected to enhance biomarker-driven NSCLC management approaches.

Despite skepticism regarding biomarker accessibility and other factors of ADC development, this class of agents is poised for continued expansion into the NSCLC treatment armamentarium. Future iterations of these agents will likely incorporate advanced biochemical engineering to improve tumor specificity and minimize off-target effects, solidifying ADCs as a cornerstone of precision oncology.