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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis
Yueying Chen1, Yanjun Du2, Juan Ni1
1Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Background:
While developments in targeted therapy have marked a new epoch for non-small cell lung cancer (NSCLC) patients harboring actionable genomic alterations, the management of individuals resistant to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a formidable challenge.
Objectives:
This study was designed to evaluate the comparative efficacy and safety of available therapeutic regimens and to identify the optimal treatment strategy for patients with disease progression following EGFR-TKI therapy.
Design:
This is a systematic review and Bayesian network meta-analysis.
Data Sources And Methods:
Databases including PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, along with conference proceedings from January 1, 2020, to June 1, 2025, were searched. Randomized controlled trials (RCTs) assessing treatment options for advanced NSCLC patients resistant to EGFR-TKIs were eligible. We identified the optimal therapeutics through comparison of the surface under the cumulative ranking curves (SUCRA).
Results:
Overall, 19 RCTs involving 4,039 participants were identified. Meta-analysis indicated that sacituzumab tirumotecan (Sac-TMT) significantly improved progression-free survival (PFS; hazard ratio [HR] 0.20, 95% credible interval [CI] 0.13-0.30) and overall survival (OS; HR 0.36, 95% CI 0.20-0.66) compared to conventional chemotherapy as evidenced by its superior SUCRA values (0.997 for PFS and 0.946 for OS). Datopotamab deruxtecan (Dato-DXd) also demonstrated clinically meaningful efficacy outcomes. Specifically, Sac-TMT showed statistically superior PFS benefits relative to nearly all comparator regimens, including immune checkpoint inhibitor (ICI)-based and bispecific antibody (bsAb)-based strategies (all p < 0.05). Amivantamab in combination with lazertinib and chemotherapy (SUCRA = 0.816) and ivonescimab combined with chemotherapy (SUCRA = 0.779) both exhibited capabilities in prolonging PFS. Notably, the triplet regimen was associated with the highest incidence of severe-grade AEs compared to all other treatment options.
Conclusion:
Sac-TMT, Dato-DXd, and bsAbs-based regimens were identified as the most efficacious options with manageable toxicity for advanced NSCLC patients who progressed after EGFR-TKIs. These findings underscore the pivotal role of innovative therapeutic agents, illuminating potential treatment avenues for this difficult-to-treat refractory population.
Trial Registration:
This study was registered as INPLASY202510014.
Insights
Sacituzumab tirumotecan (Sac-TMT) and datopotamab deruxtecan (Dato-DXd) show superior efficacy for non-small cell lung cancer (NSCLC) patients resistant to EGFR-TKIs. These novel agents offer improved survival outcomes compared to chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Targeted therapies have advanced non-small cell lung cancer (NSCLC) treatment for patients with specific genomic alterations.
- Managing EGFR-TKI resistance in NSCLC remains a significant clinical challenge.
- Identifying optimal treatment strategies post-EGFR-TKI progression is crucial.
Purpose of the Study:
- To conduct a comparative evaluation of the efficacy and safety of available therapeutic regimens for advanced NSCLC.
- To determine the optimal treatment strategy for patients experiencing disease progression after EGFR-TKI therapy.
- To identify superior treatment options for EGFR-TKI-resistant NSCLC.
Main Methods:
- Systematic review and Bayesian network meta-analysis of randomized controlled trials (RCTs).
- Searched major databases (PubMed, Embase, Cochrane, Web of Science, ClinicalTrials.gov) and conference proceedings.
- Utilized Surface Under the Cumulative Ranking Curves (SUCRA) to rank treatment efficacy.
Main Results:
- Sacituzumab tirumotecan (Sac-TMT) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy (SUCRA: 0.997 for PFS, 0.946 for OS).
- Sac-TMT demonstrated superior PFS benefits over immune checkpoint inhibitors and bispecific antibodies (p < 0.05).
- Datopotamab deruxtecan (Dato-DXd) and bispecific antibody regimens also showed promising efficacy; triplet therapy had higher severe adverse events.
Conclusions:
- Sacituzumab tirumotecan (Sac-TMT) and datopotamab deruxtecan (Dato-DXd) are highly efficacious options for advanced NSCLC post-EGFR-TKI progression.
- Bispecific antibody-based regimens are also effective with manageable toxicity.
- Innovative agents like Sac-TMT and Dato-DXd represent crucial advancements for treating refractory NSCLC populations.
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