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May-June 2026 Volume 6 Issue 3

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Sequencing antibody‑drug conjugates in metastatic cancer (Review)

  • Authors:
    • Berun A. Abdalla
  • View Affiliations / Copyright

    Affiliations: Kscien Organization for Scientific Research (Middle East Office), Sulaymaniyah 46001, Iraq
    Copyright: © Abdalla et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 24
    |
    Published online on: March 9, 2026
       https://doi.org/10.3892/mi.2026.308
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Abstract

The therapeutic landscape of metastatic solid tumors has been fundamentally reshaped by the rapid development and regulatory approval of multiple antibody‑drug conjugates (ADCs) across breast, urothelial and lung cancers. As these targeted agents move into earlier lines of therapy, patients are experiencing prolonged survival and are increasingly becoming candidates for sequential ADC treatment. This evolution introduces a critical and complex clinical dilemma: The question of whether a second ‘Trojan Horse’ remains effective following the failure of a prior ADC, or whether shared resistance mechanisms undermine sequential efficacy. While the expanding ADC armamentarium provides new therapeutic opportunities, emerging real‑world data suggest that sequential use is frequently complicated by cross‑resistance, particularly when successive agents employ similar cytotoxic payloads such as topoisomerase I inhibitors. The present narrative review critically discusses the biological basis of resistance in the sequential ADC setting. The present review distinguishes between target‑mediated resistance, in which antigen downregulation limits drug delivery, and payload‑mediated resistance, in which intracellular mechanisms neutralize the cytotoxic component. By synthesizing clinical evidence from metastatic breast and urothelial carcinoma cohorts, the present review highlights the diminished efficacy often observed when changing targets without altering payload class. Therefore, a pragmatic sequencing framework emphasizing ‘payload swapping’ is proposed, prioritizing a change in cytotoxic mechanisms over antigen switching to optimize patient outcomes and minimize futile toxicity in this rapidly evolving therapeutic era.
View Figures

Figure 1

Conceptual framework illustrating the
sequencing of ADCs in metastatic cancer. ADC, antibody-drug
conjugate.
View References

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Copy and paste a formatted citation
Spandidos Publications style
Abdalla BA: Sequencing antibody‑drug conjugates in metastatic cancer (Review). Med Int 6: 24, 2026.
APA
Abdalla, B.A. (2026). Sequencing antibody‑drug conjugates in metastatic cancer (Review). Medicine International, 6, 24. https://doi.org/10.3892/mi.2026.308
MLA
Abdalla, B. A."Sequencing antibody‑drug conjugates in metastatic cancer (Review)". Medicine International 6.3 (2026): 24.
Chicago
Abdalla, B. A."Sequencing antibody‑drug conjugates in metastatic cancer (Review)". Medicine International 6, no. 3 (2026): 24. https://doi.org/10.3892/mi.2026.308
Copy and paste a formatted citation
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Spandidos Publications style
Abdalla BA: Sequencing antibody‑drug conjugates in metastatic cancer (Review). Med Int 6: 24, 2026.
APA
Abdalla, B.A. (2026). Sequencing antibody‑drug conjugates in metastatic cancer (Review). Medicine International, 6, 24. https://doi.org/10.3892/mi.2026.308
MLA
Abdalla, B. A."Sequencing antibody‑drug conjugates in metastatic cancer (Review)". Medicine International 6.3 (2026): 24.
Chicago
Abdalla, B. A."Sequencing antibody‑drug conjugates in metastatic cancer (Review)". Medicine International 6, no. 3 (2026): 24. https://doi.org/10.3892/mi.2026.308
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