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The Evolving Role of Bispecific Antibodies in Oncogene-Driven NSCLC

Jun Chih Wang1, Daniel Rosas1, Luis E Raez1

  • 1Memorial Healthcare System, Pembroke Pines, FL 33026, USA.

Cancers
|July 28, 2026
PubMed

Insights

Bispecific antibodies offer a new way to treat lung cancer by targeting multiple pathways. While effective in resistant cases, they complement, rather than replace, existing therapies like tyrosine kinase inhibitors.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Bispecific antibodies (bsAbs) represent a novel therapeutic strategy for oncogene-driven non-small-cell lung cancer (NSCLC).
  • They overcome resistance to tyrosine kinase inhibitors (TKIs) by simultaneously targeting multiple signaling pathways and engaging immune effectors.
  • bsAbs offer advantages over TKIs in addressing tumor heterogeneity and bypass signaling.

Purpose of the Study:

  • To review the principles of bsAb design and clinical evidence for agents like amivantamab and zenocutuzumab.
  • To compare the efficacy, toxicity, and CNS penetration of bsAbs against TKIs and antibody-drug conjugates (ADCs).
  • To discuss the role of bsAbs in current and future NSCLC treatment paradigms.

Main Methods:

  • Review of structural and biological principles of bsAb design.
  • Evaluation of clinical trial data (Phase I-III) for approved and investigational bsAbs.
  • Comparative analysis of bsAbs with TKIs and ADCs regarding clinical outcomes and safety profiles.

Main Results:

  • bsAbs show significant clinical activity, especially in TKI-resistant NSCLC and specific molecular subsets (e.g., EGFR exon 20 insertions, NRG1 fusions).
  • Limitations include intravenous administration and increased immune-mediated and thromboembolic toxicities.
  • bsAbs currently complement TKIs rather than replacing them in most clinical scenarios.

Conclusions:

  • bsAbs have a complementary role in multimodal NSCLC treatment, particularly in combination strategies.
  • Future research should focus on biomarker-driven patient selection and improved drug engineering.
  • Adaptive therapeutic sequencing frameworks are essential for integrating bsAbs effectively.
Keywords:
EGFRMETamivantamabantibody–drug conjugatesbispecific antibodiesnon-small-cell lung canceroncogene-driven NSCLCtargeted therapytyrosine kinase inhibitorszenocutuzumab

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