New Paper Alert! A Comprehensive Review of ADCs in Lung and Breast Cancer by the ETOP IBCSG Partners Foundation

A Comprehensive Review of ADCs in Lung and Breast Cancer by the ETOP IBCSG Partners Foundation

Authors: S. Peters, S. Loi, F. André, S. Chandarlapaty, E. Felip, S.P. Finn, P.A. Jänne, K.M. Kerr, E. Munzone, A. Passaro, M. Pérol, E.F. Smit, C. Swanton, G. Viale, R.A. Stahel

Published in Annals of Oncology, on April 2024

Introduction: Antibody-drug conjugates (ADCs) represent a promising therapeutic modality in cancer treatment. These complex molecules combine the targeting capabilities of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic agents. This review article provides a comprehensive overview of the development, benefits, challenges, and future directions of ADCs in thoracic and breast malignancies.

Design and Methods: The article discusses the key factors for successful ADC design, including optimal antibody selection, linker stability, and payload potency. It also highlights the importance of identifying suitable biomarkers to predict and enhance ADC efficacy.

What We Learned:

• ADCs in Thoracic Malignancies:
  • Trastuzumab deruxtecan (T-DXd) is approved for HER2-mutated metastatic non-small cell lung cancer (NSCLC), with an objective response rate (ORR) of 55%.
  • Patritumab deruxtecan (HER3-DXd) has shown promising activity in EGFR-mutated NSCLC, after EGFR TKI failure, with an ORR of 29.8%.
  • Datopotamab deruxtecan (Dato-DXd) in advanced NSCLC, ORR 26.4% vs 12.8% for docetaxel
  • Sacituzumab govitecan (SG) in previously treated NSCLC, failed to improve overall survival vs docetaxel.

• ADCs in Breast Cancer:
  • T-DXd is approved for HER2-positive and HER2-low metastatic breast cancer (MBC), with ORRs of 71% and 37.5%, respectively.
  • Sacituzumab govitecan is approved for metastatic triple-negative breast cancer (mTNBC) and HR+/HER2- MBC, with ORRs of ~30% in unselected patient populations.
  • Dato-DXd has demonstrated superiority over treatment of physician’s choice in HR+/HER2- MBC, with a progression-free survival (PFS) of 6.9 months.

• Potential Biomarkers of ADC Response:
  • Higher target antigen expression levels have been correlated with improved ADC efficacy in some trials.
  • Methods to improve quantification of antigen expression, such as immunofluorescence or mass spectrometry, may be needed.
  • Other potential biomarkers include receptor heterogeneity, conformation, and dimerization.

• Mechanisms of ADC Resistance:
  • Resistance mechanisms can be categorized into factors affecting antibody binding, internalization, lysosomal degradation, payload release, and oncogenic signaling pathways.
  • Extrachromosomal DNA (ecDNA) may play a crucial role in oncogene amplification and tumor evolution, contributing to resistance.

Key Highlights:

• ADCs have shown promising activity in thoracic and breast malignancies, particularly in biomarker-selected patient populations.
• 14 ADCs are currently approved, with over 100 in clinical development.
• Key ADC Trials:
  • Destiny-Lung01 and Destiny-Breast03 trials evaluated T-DXd in HER2-mutated metastatic NSCLC and HER2-positive metastatic breast cancer, respectively.
  • Patritumab Deruxtecan (HER3-DXd) assessed in EGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy
  • Datopotamab Deruxtecan (Dato-DXd) tested against docetaxel in the TROPION-Lung01 trial for previously treated advanced/metastatic NSCLC.
  • ASCENT Trial compared Sacituzumab Govitecan (SG) with physician’s choice treatment in metastatic triple-negative breast cancer.
• Identifying optimal biomarkers for patient selection and understanding mechanisms of resistance are critical for improving ADC efficacy.
• Combination strategies with targeted therapies, immunotherapies, and chemotherapies are being explored to enhance ADC efficacy.
• Next-generation ADCs with improved antibody targets, linkers, payloads, and novel approaches (e.g., bispecific antibodies, conditionally active biologics) are in development to enhance efficacy and reduce toxicity.

Key Takeaway Messages:

• ADCs represent a valuable therapeutic option in thoracic and breast malignancies, but further research is needed to optimize their use and overcome resistance mechanisms.
• Collaborative efforts between industry and academia are essential to accelerate research, prioritize important research questions, and ultimately improve patient outcomes.
• Effective biomarker identification, combination strategies, and development of next-generation ADCs hold the key to unlocking the full potential of these complex molecules in cancer treatment.

Summary by Amalya Sargsyan, MD

Antibody-drug conjugates in lung and breast cancer: Current evidence and future directions – a position statement from the ETOP IBCSG Partners Foundation

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