Advances in antibody-drug conjugate-based combination therapy strategies for non-small cell lung cancer
Yunqi Mi1, Shan Wang1, Yuhao Wang1
1Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Introduction:
Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer death worldwide. Although targeted therapies and immune checkpoint inhibitors have meaningfully improved outcomes for some patients, many still lack targetable mutations or quickly develop resistance. Antibody-drug conjugates (ADCs), which combine tumor-specific antibodies with potent cytotoxic payloads, have become an increasingly promising option.
Areas Covered:
This review looks at ADC-based combination strategies in NSCLC, grouped by key molecular targets such as Trop-2, HER2, HER3, c-Met, B7-H3, CEACAM5, and ITGβ6, along with bispecific ADCs. The literature was identified through searches of PubMed, ClinicalTrials.gov, and major oncology conference proceedings (including ASCO, ESMO, and WCLC). We examined published trial results, conference abstracts, and ongoing registered studies covering combinations with immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy, and other agents.
Expert Opinion:
ADC combinations are a fast-moving and exciting area in NSCLC. Trop-2 ADC plus ICI approaches show efficacy that appears strongly linked to PD-L1 levels, while certain EGFR-directed strategies, especially bispecific ADCs like izalontamab brengitecan with osimertinib, have demonstrated promising preliminary clinical activity. Still, success will hinge on strong single-agent activity, clear synergy, and reliable biomarkers for patient selection.
Insights
Antibody-drug conjugates (ADCs) combined with other therapies show promise for non-small cell lung cancer (NSCLC). Success depends on strong single-agent efficacy, synergy, and patient selection biomarkers.
Area of Science:
- Oncology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally.
- While targeted therapies and immune checkpoint inhibitors have improved outcomes, many patients lack targets or develop resistance.
- Antibody-drug conjugates (ADCs) offer a promising therapeutic strategy by combining targeted antibodies with cytotoxic payloads.
Purpose of the Study:
- To review current and emerging antibody-drug conjugate (ADC)-based combination strategies for non-small cell lung cancer (NSCLC).
- To explore combinations targeting key molecular markers including Trop-2, HER2, HER3, c-Met, B7-H3, CEACAM5, and ITGβ6.
- To examine combinations with immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, and chemotherapy.
Main Methods:
- Literature search of PubMed, ClinicalTrials.gov, and major oncology conference proceedings (ASCO, ESMO, WCLC).
- Review of published trial results, conference abstracts, and ongoing registered studies.
- Analysis of ADC combination strategies in NSCLC.
Main Results:
- Trop-2 ADC plus immune checkpoint inhibitor (ICI) approaches demonstrate efficacy potentially linked to PD-L1 levels.
- EGFR-directed strategies, including bispecific ADCs like izalontamab brengitecan with osimertinib, show promising preliminary clinical activity.
- Combination strategies are rapidly evolving in NSCLC treatment.
Conclusions:
- ADC combinations represent a dynamic and promising area in NSCLC therapy.
- Clinical success relies on robust single-agent activity, demonstrable synergy, and validated biomarkers for patient selection.
- Further research is needed to optimize ADC combination therapies for improved NSCLC patient outcomes.
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