EGFR exon 20 insertion mutations remain one of the more challenging forms of EGFR-mutated lung cancer. Although targeted therapies such as amivantamab have improved outcomes, treatment options become limited once resistance develops.
TOGA’s Phase II DEFIANT study aims to address this unmet need and is expected to open across Australia and Taiwan in early 2027.
Why are EGFR Exon 20 Insertion Mutations Different?
EGFR exon 20 insertion mutations account for approximately 4% to 12% of EGFR-mutated NSCLC. Unlike the more common EGFR exon 19 deletion and exon 21 L858R mutations, they respond poorly to conventional EGFR tyrosine kinase inhibitors.
The development of targeted therapies such as amivantamab has improved outcomes for many patients. However, resistance inevitably develops, leaving patients with limited treatment options beyond chemotherapy. This represents one of the remaining areas of unmet need in precision lung cancer care.
What is Datopotamab Deruxtecan (Dato-DXd)?
Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC).
It combines:
- a humanised monoclonal antibody that recognises the TROP2 protein on cancer cells
- a stable, cleavable linker
- a potent topoisomerase I inhibitor payload called deruxtecan.
Rather than exposing the whole body to chemotherapy, the antibody delivers the drug directly to tumour cells expressing TROP2 before releasing its chemotherapy payload. This targeted approach aims to maximise anti-cancer activity while reducing exposure of healthy tissues.
Clinical Evidence Supporting Dato-DXd in NSCLC
Dato-DXd has demonstrated encouraging activity in patients with previously treated EGFR-mutated metastatic NSCLC.
In the phase 2 TROPION-Lung05 study, the confirmed objective response rate (ORR) among patients with EGFR-mutated NSCLC was 43.6%, increasing to 49.1% in patients with sensitising EGFR mutations or T790M following osimertinib.
Subsequently, a pooled analysis of TROPION-Lung05 and TROPION-Lung01 included 117 patients with EGFR-mutated NSCLC, demonstrating:
- ORR: 42.7%
- Disease control rate: 86.3%
- Median duration of response: 7.0 months
- Median progression-free survival: 5.8 months
- Median overall survival: 15.6 months
However, only a small number of patients had EGFR exon 20 insertion mutations. The TROPION clinical trial programme has therefore established proof of activity in EGFR-mutated NSCLC, but dedicated evidence for the exon 20 insertion population is still lacking.
The DEFIANT trial builds on evidence generated through the TROPION clinical trial programme (Table 1).
DEFIANT: A Dedicated Study for EGFR Exon 20 Insertion NSCLC
The DEFIANT trial is a phase 2 study evaluating datopotamab deruxtecan (Dato-DXd) in patients with metastatic EGFR exon 20 insertion NSCLC whose cancer has progressed following targeted therapy and chemotherapy.
Dato-DXd will be administered every three weeks until disease progression or unacceptable toxicity. The study’s primary endpoint is objective response rate, with secondary endpoints including progression-free survival, duration of response, overall survival, safety and patient-reported outcomes. Researchers will also investigate biomarkers such as TROP2 expression, circulating tumour DNA (ctDNA) dynamics and genomic changes associated with treatment response and resistance.
Why DEFIANT is different?
Although previous TROPION studies demonstrated encouraging activity in EGFR-mutated NSCLC, only a small number of participants had EGFR exon 20 insertion mutations. DEFIANT is the first study designed specifically for this molecular subgroup, with integrated translational research to investigate biomarkers of response, treatment resistance and circulating tumour DNA dynamics.
Further reading
- Ahn et al. (2025) Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol 43:260-272. doi: 10.1200/JCO-24-01544
- Ahn et al. (2025) A Pooled Analysis of Datopotamab Deruxtecan in Patients With EGFR-Mutated NSCLC. J Thor Oncol 20:1669 https://doi.org/10.1016/j.jtho.2025.06.002
- Okajima et al. (2021) Datopotamab Deruxtecan, a Novel TROP2-directed Antibody–drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells. Mol Cancer Ther 20:2329. doi: 10.1158/1535-7163.MCT-21-0206
- Sands et al (2025) Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. J Clin Oncol. 43:1254-1265. doi: 10.1200/JCO-24-01349
- Shimizu T (2023). First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01. J Clin Oncol. 41:4678-4687. doi: 10.1200/JCO.23.00059. Epub 2023 Jun 16. Erratum in: J Clin Oncol. 2026 Jun;44(16):1560. doi: 10.1200/JCO-26-00937.
- Vyse & Huang (2019) Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther.4:5. doi: 10.1038/s41392-019-0038-9.
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