Next Steps After Resistance to Tagrisso

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의학에 관련해서는 비슷하게 나오는 것 같다. 

✅ Next Steps After Resistance to Tagrisso (Osimertinib) in Lung Cancer Patients

When a patient with EGFR-mutant non-small cell lung cancer (NSCLC) develops resistance to Tagrisso (Osimertinib), the next steps depend on the specific mechanism of resistance. The approach includes a combination of molecular testing, targeted therapies, chemotherapy, and clinical trial options.

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🚩 1. Identify the Mechanism of Resistance

(a) Molecular Testing

• Liquid Biopsy (ctDNA Analysis): Non-invasive method to detect resistance mutations in the blood.
• Tissue Biopsy: Recommended if liquid biopsy is inconclusive, especially to detect histologic changes like small cell transformation.
• Next-Generation Sequencing (NGS): Comprehensive profiling to identify resistance mechanisms such as:
  • EGFR C797S mutation
  • MET amplification
  • HER2 amplification
  • KRAS mutations
  • Small cell lung cancer transformation

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🚀 2. Treatment Options Based on Resistance Mechanisms

(1) EGFR C797S Mutation

• If in Trans (opposite allele) with T790M:
  • Combination of 1st-generation EGFR-TKI (e.g., gefitinib, erlotinib) + Tagrisso.
• If in Cis (same allele) with T790M:
  • Limited efficacy with current EGFR-TKIs.
  • 4th-generation EGFR inhibitors (e.g., BLU-945, JIN-A02) in clinical trials.
  • Consider chemotherapy or clinical trials.

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(2) MET Amplification (~15-30% cases)

• Combination therapy with Tagrisso + MET inhibitors:
  • Capmatinib, Tepotinib, Savolitinib.

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(3) HER2 Amplification (~5-10% cases)

• Consider HER2-targeted therapies:
  • Trastuzumab deruxtecan (T-DXd) or other HER2 inhibitors.

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(4) Small Cell Lung Cancer (SCLC) Transformation (~5-15% cases)

• Switch to platinum-based chemotherapy used for SCLC:
  • Cisplatin + Etoposide.
• Tissue biopsy required to confirm transformation.

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(5) BRAF, KRAS, and Other Mutations

• KRAS G12C mutation: Use KRAS inhibitors (e.g., sotorasib, adagrasib).
• BRAF V600E mutation: Combination of BRAF inhibitor (dabrafenib) + MEK inhibitor (trametinib).

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💡 3. Options When No Targetable Resistance Mutation Is Found

• Platinum-based chemotherapy remains the standard option:
  • Pemetrexed + cisplatin/carboplatin ± bevacizumab.
• Immunotherapy ± chemotherapy:
  • Although EGFR-mutant NSCLC responds less favorably to immunotherapy, it can be considered after TKI and chemotherapy failure.

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📊 4. Clinical Trials

• 4th-generation EGFR-TKIs targeting C797S and other mutations are under investigation:
  • BLU-945, JIN-A02, BBT-207.
• Trials combining EGFR-TKIs with other pathway inhibitors (e.g., MET, HER2, ALK inhibitors).

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🗂️ Summary of Management After Tagrisso Resistance

Resistance MechanismNext Step

EGFR C797S (trans)	Tagrisso + 1st-gen EGFR-TKI combination
EGFR C797S (cis)	4th-gen EGFR-TKI (clinical trial), chemotherapy
MET Amplification	Tagrisso + MET inhibitor
HER2 Amplification	HER2-targeted therapy
SCLC Transformation	Platinum-based chemotherapy (SCLC regimen)
KRAS, BRAF mutations	Targeted therapies for specific mutations
Unknown Mechanism	Chemotherapy, clinical trial, immunotherapy

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✅ Key Takeaways

• Molecular testing is essential to guide the next treatment.
• Combination therapies targeting resistance mechanisms can prolong survival.
• Clinical trials provide access to novel therapies, especially for complex resistance patterns.

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Q1: How effective are 4th-generation EGFR inhibitors like BLU-945 and JIN-A02 in overcoming C797S resistance?

Q2: What are the latest clinical trial options available for Tagrisso-resistant NSCLC patients?

Q3: How does small cell transformation affect the prognosis and treatment of NSCLC patients after Tagrisso resistance?