Precision Medicine Packs a Punch: Antibody-Drug Conjugates for Non-Small Cell Lung Cancer

• A monoclonal antibody that specifically targets an antigen expressed on the surface of tumor cells 
• A potent cytotoxic payload designed to destroy tumor cells upon internalization 
• A linker that covalently binds the antibody to the drug, ensuring selective release of the cytotoxic agent within the tumor. 

This targeted mechanism has fueled growing interest in ADCs for the treatment of various solid malignancies, including NSCLC, where therapeutic options remain limited for patients with advanced disease. In 2022, trastuzumab deruxtecan (T-DXd) became the first ADC approved by the US Food and Drug Administration (FDA) for NSCLC. As ADCs continue transitioning from the bench to the bedside, ACCC launched the initiative Antibody-Drug Conjugates: The Next Frontier of Targeted Therapies in Non-Small Cell Lung Cancer featuring 3 leading experts to discuss the latest developments in this therapeutic area.

Session 1: Targeted Therapy for Non‒Small Cell Lung Cancer: Toxicity Profile of Antibody-Drug Conjugates (ADCs) 

Beth Sandy, CRNP 
Thoracic Oncology Nurse Practitioner
Abramson Cancer Center, University of Pennsylvania 

In the first video of the 3-part series, Beth Sandy reviews the toxicity profiles and discusses management strategies for both approved and investigational ADCs. 

Based on the DESTINY-Lung02 trial, trastuzumab deruxtecan (T-DXd), the only FDA-approved ADC for NSCLC, has been associated with chemotherapy-like toxicities, including nausea, fatigue, neutropenia, and anemia. One of the most concerning adverse events is interstitial lung disease (ILD) or pneumonitis, which occurs in approximately 12.9% of patients, particularly those previously treated with immunotherapy. Given the risk of severe or fatal ILD, prompt recognition and management—including discontinuation of therapy for grade 2 or higher ILD—are essential.  

Other ADCs under investigation, such as datopotamab deruxtecan (Dato-DXd), patritumab deruxtecan (HER3-DXd), and sacituzumab govitecan (SG), present additional toxicity concerns, including stomatitis, ocular toxicities, and varying degrees of neutropenia. Managing these toxicities requires a proactive, multidisciplinary approach. Examples of supportive care strategies include prophylactic antiemetics for nausea and corticosteroid mouthwashes for stomatitis. Neutropenia may necessitate dose delays or granulocyte-colony stimulating factor (G-CSF) support, while blepharitis can be mitigated with artificial tears and avoidance of contact lenses. ILD monitoring is particularly critical, with patients requiring regular pulmonary assessment, CT scans for suspected cases, and early corticosteroid intervention for symptomatic cases. As research continues to refine ADC therapy for NSCLC, optimizing toxicity management will be key to balancing efficacy with patient safety in clinical practice. 

Session 2: ADCs Targeting TROP2 in NSCLC: Overview and Recent Data 

Benjamin P. Levy, MD 
Clinical Director of Medical Oncology
Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital  

TROP2-targeting ADCs have garnered significant attention due to the overexpression of TROP2 in NSCLC and its association with poor prognosis. Both Dato-DXd and SG have been evaluated in clinical trials against docetaxel in second-line NSCLC. The TROPION-Lung-01 trial demonstrated that Dato-DXd improved progression-free survival (PFS) but did not significantly extend overall survival (OS), leading to its discontinuation for broader second-line use. However, further studies suggest potential benefits in EGFR-mutated patients. Similarly, the EVOKE-01 trial investigating SG failed to show significant OS or PFS improvement over docetaxel, limiting its current regulatory prospects.  

Despite these setbacks, the general ADC safety profiles were favorable, with fewer dose interruptions than traditional chemotherapy. While neither drug is poised for immediate FDA approval, ongoing research aims to refine patient selection and optimize efficacy. The evolving ADC landscape underscores the need for biomarker-driven strategies and novel combinations, which may position TROP2-targeting ADCs as viable treatment options for select NSCLC patient subsets, particularly those with EGFR mutations.

Session 3: Antibody-Drug Conjugates (ADCs) for NSCLC: HER2 and HER3 

Alexander Spira MD, PhD, FACP, FASCO 
Co-Director, VCS Research Institute
Director, Thoracic and Phase I Program 
Clinical Assistant Professor 
Johns Hopkins School of Medicine 

HER2 and HER3 have emerged as promising targets for the treatment of NSCLC. Although HER3 lacks intrinsic kinase activity, it is expressed in over 80% of NSCLC tumors and contributes to resistance against EGFR-targeted therapies. Patritumab deruxtecan, abbreviated HER3-DXd, delivers a topoisomerase 1 inhibitor payload (deruxtecan) directly to HER3-expressing tumor cells. In phase 1 trials for EGFR-mutated NSCLC, it demonstrated a 39% confirmed response rate, a 72% disease control rate, and a median PFS of 8.2 months.

HER2 alterations in NSCLC are predominantly driven by activating mutations rather than overexpression, distinguishing lung cancer oncogenesis from HER2-driven breast cancer. NSCLC HER2 mutations result in constant receptor activation, fueling tumor growth. T-DXd, a HER2 -targeted ADC, has demonstrated impressive efficacy, with DESTINY-Lung02 trial data showing response rates of up to 56% and a median duration of response of 16.8 months. This success has led to FDA approval of T-DXd for HER2-mutated NSCLC. 

Additionally, zongertinib, a next-generation HER2 tyrosine kinase inhibitor (TKI), has shown remarkable activity in clinical trials, with a meaningful objective response rate (ORR) of 66.7% in patients with HER2-mutated NSCLC. With anticipated FDA approval in 2025, zongertinib may provide an important oral treatment alternative, especially for patients who may not tolerate ADC-related toxicities. 

Conclusion

As research continues to refine ADC design through improvements in monoclonal antibody specificity, linker stability, and payload selection, oncology clinicians must remain informed about the evolving role of these agents in NSCLC treatment. A comprehensive understanding of ADC mechanisms, toxicity management strategies, and emerging clinical trial data is essential for integrating these novel therapies into practice effectively. To gain deeper insights from leading experts in the field, explore the three-part video series linked above, which provides critical guidance on the latest developments and practical applications of ADCs in NSCLC care. 

This activity is supported by an educational grant from AstraZeneca.

Resources 

• Antibody–Drug Conjugates in Non-Small Cell Lung Cancer: State of the Art and Future Perspectives 

• The Clinical Development of Antibody-Drug Conjugates for Non-Small Cell Lung Cancer Therapy 

• Antibody-Drug Conjugates in Lung Cancer: Dawn of a New Era? 

• Diagnostic, Predictive, and Prognostic Biomarkers in Non-Small Cell Lung Cancer (NSCLC) Management 

• “Sky Is the Limit” for ADC Possibilities in NSCLC 

• Antibody-Drug Conjugates in Advanced Lung Cancer: Is This a New Frontier? 

• Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies 

• Antibody-Drug Conjugates for the Treatment of Non-Small Cell Lung Cancer with Central Nervous System Metastases