Trop2-Targeted Datopotamab Deruxtecan Receives FDA Approval for EGFR-Positive Lung Cancer

The First and Only FDA-Approved Treatment After EGFR TKIs and Platinum-Based Chemotherapy

Lung cancer remains the leading cause of cancer death worldwide. In particular, in EGFR mutation -positive cases, resistance limits survival, making more effective targeted options especially necessary. The Daiichi Sankyo–AstraZeneca collaboration has developed the TROP2-targeted antibody–drug conjugate (ADC) datopotamab deruxtecan (Datroway), whose FDA second approval positions it as a candidate to fill this gap.

🔬 What Does the New Approval Cover?

📅 On June 23, 2025, the FDA granted the ADC datopotamab deruxtecan-dlnk (Datroway) the following indication through accelerated approval :

• Locally advanced or metastatic EGFR-mutant non-small cell lung cancer (NSCLC)
• Previously received EGFR-targeted therapy and platinum-based chemotherapy in adult patients

🔁 This is Datroway’s second FDA approval. Its first, in January 2025, covered HR-positive, HER2-negative metastatic breast cancer as an indication.

🔄 What Happened Previously?

Datroway first received FDA approval for breast cancer in January 2025. However, the European Medicines Agency (EMA) rejected the NSCLC application, and AstraZeneca withdrew it. This followed TROPION-Lung01 Phase 3 findings of limited overall survival benefit in that study.

The FDA accelerated approval focuses on response rate and duration of response as intermediate efficacy measures for assessment.

What Is TROP2, and Why Does It Matter?

TROP2 (Trophoblast Cell-Surface Antigen 2) is a cell-surface transmembrane glycoprotein involved in proliferation and metastasis. High TROP2 expression is common in NSCLC, particularly adenocarcinoma, with studies reporting approximately 60–65% . In EGFR-mutant lung adenocarcinoma, some series report TROP2 positivity above 80% . This high expression suggests TROP2-targeted treatments may also be effective in EGFR-mutant disease.

🧪 FDA Approval Through TROPION-Lung01 and TROPION-Lung05

🔹 TROPION‑Lung01 (Phase 3) – Randomized Controlled

• Design: Global, multicenter, open-label phase 3 RCT; datopotamab deruxtecan (6 mg/kg IV every 21 days) vs. docetaxel
• Scope: Advanced/metastatic NSCLC; actionable subtypes such as EGFR and ALK, and nonactionable tumors
• Prior treatment:
  • Actionable subtypes: After EGFR TKI + platinum chemotherapy
  • Others: After platinum chemotherapy ± PD‑1/PD‑L1 inhibitor
• Primary Endpoints: PFS (BICR), OS. Secondary: ORR, DoR, DCR, TTR, safety
• Patients: Approximately 600 patients (299/305 randomized)
• Results:
  • ORR: 26.4% vs 12.8% (docetaxel)
  • Median PFS: 4.4 vs 3.7 months; HR 0.75 (p=0.004)
  • Median OS (nonsq): 14.6 vs 12.3 months (not significant)

📌 The EGFR-mutant subgroup supported FDA approval, but the study did not include only EGFR-mutant patients.

🔹 TROPION‑Lung05 (Phase 2) – Single-Arm

• Design: Global, multicenter, open-label phase 2 single-arm trial
• Scope: Advanced/metastatic NSCLC; subtypes including EGFR, ALK, ROS1, BRAF, RET, MET
• Criterion: Progression after at least one EGFR-TKI and one platinum-based chemotherapy
• Primary Endpoint: ORR (BICR). Secondary: DoR, DCR, CBR, PFS, OS, safety
• Patients: 137 patients (Asia, Europe, North America)
• Results: EGFR-mutant subgroup ORR ~43.6%

Because selection required progression after TKI + platinum, FDA approval rests on EGFR-mutant subgroup data.

📋 Summary Comparison

📊 Pooled Data Supporting FDA Approval

⚠️ Limitations

• Lung05 is single-arm, not randomized
• No control arm
• No separation by EGFR mutation subtype
• No stratification by TROP2 expression
• Limited CNS involvement data

In summary

FDA accelerated approval requires awaiting confirmatory phase 3 data. Although the EGFR-mutant response signal in TROPION-Lung01 is important, an overall survival advantage has not yet been clearly demonstrated. This calls for cautious optimism about clinical adoption.

🎯 What Is Datroway, and How Does It Work?

Datroway targets tumors with high TROP2 expression as an ADC (antibody–drug conjugate). Its payload, a topoisomerase I inhibitor (DXd), directly targets tumor-cell DNA, causing cell death.

Sequence of Action:

1. TROP2 recognition and binding
2. Cellular uptake
3. DXd release in lysosomes
4. DNA damage and apoptosis
5. A ‘bystander’ effect on neighboring cells

🧬 Why Might Some Tumors Not Respond?

Potential Datroway resistance mechanisms include:

• Reduced or lost TROP2 expression
• Failure to internalize TROP2 (impaired endocytosis)
• Failure to cleave the linker in lysosomes
• Resistance to topoisomerase I inhibition
• DXd efflux from cells
• Tumor microenvironment barriers to the drug

These factors may cause efficacy to vary among patients.

⚠️ Known Side Effects

The most frequently reported Datroway adverse events:

🔴 In particular, interstitial lung disease (including pneumonia) is a serious effect requiring close monitoring.

🌍 What Is the Situation in Türkiye?

• ✅ FDA Approval: Yes (January and June 2025)
• ❌ Licensing in Türkiye: Not yet
• 💳 SGK Reimbursement: Currently excluded

Access may therefore require overseas procurement and overseas-patient consent processes.

🔚 Conclusion and Future Perspectives

Datroway’s second FDA approval shows, in EGFR-mutant NSCLC, that TROP2-targeted ADCs have entered practice. Although survival benefit remains unclear, high response rates and its biological mechanismsuggest greater future use in combination regimens.

Manage preferences to view external content