Exploring Second-Line Treatment Options Including Targeted Radiation and Surgery for the Management of EGFR-Mutant mNSCLC

EP: 1.The Evolution of EGFR-Mutated Advanced NSCLC Treatment: Present Considerations and Future Treatment Options

EP: 2.Has Combination Therapy Become the New Frontline Treatment Standard for EGFR-Mutant Metastatic NSCLC?

EP: 3.Decision Points to Consider When Choosing Treatment With Monotherapy or Combination Therapy for EGFR-Mutant mNSCLC

EP: 4.Evaluating Patient Preferences for the Treatment of EGFR-Mutant mNSCLC

EP: 5.Comparing the Combination Therapies for the Treatment of EGFR-Mutant mNSCLC

EP: 6.Considering Resistance Mechanisms When Choosing Therapy in the Frontline Setting

EP: 7.The Importance of Maintaining Quality of Life and Intervening Early When Adverse Events Occur in the Frontline Treatment Setting

EP: 8.Weighing the 1-Year Projected Overall Survival Benefit With MARIPOSA in the Frontline Treatment of EGFR-Mutant mNSCLC

EP: 9.Discussing the Time and Financial Toxicities Associated With Combination Therapies and Potential Mitigation Strategies

EP: 10.Discussing Potential Combination Therapy Medication-Associated Toxicities With Patients

EP: 11.Evaluating the Clinical Utility of Subcutaneous Amivantamab in the Treatment of EGFR-Mutant mNSCLC

EP: 12.The Importance of Multidisciplinary Collaboration With Subspecialty Physicians in the Toxicity Management With Treatment

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EP: 13.Exploring Second-Line Treatment Options Including Targeted Radiation and Surgery for the Management of EGFR-Mutant mNSCLC

EP: 14.Tissue vs Plasma Biopsy After First Disease Progression in EGFR-Mutant NSCLC

EP: 15.Deciding Between a Biomarker-Directed Approach and a Biomarker-Agnostic Approach for Second-Line Treatment of EGFR-Mutant NSCLC

EP: 16.Continuing the Targeted TKI in the Second Line for the Treatment of EGFR-Mutant NSCLC

EP: 17.When to Consider Retreatment With Chemotherapy After FLAURA2 for EGFR-Mutant NSCLC

EP: 18.Patient Case Presentation: A 45-Year-Old With Newly Diagnosed EGFR-Mutant mNSCLC and Liver Metastases

EP: 19.Patient Case Presentation: A 69-Year-Old With Newly Diagnosed EGFR-Mutant mNSCLC and Symptomatic Brain Metastases

This segment explores how frontline therapy choices significantly influence second-line treatment strategies for EGFR-mutant metastatic non–small cell lung cancer (mNSCLC), emphasizing the chess-like strategic thinking required in treatment sequencing. The discussion reinforces the principle of using the best drugs first while maintaining strategic flexibility for disease progression. A critical component of second-line management involves leveraging local therapies, particularly radiation, for oligoprogressive disease. When patients experience progression at only a few sites while maintaining systemic control on their current regimen, radiation therapy becomes the preferred first-line intervention, allowing continuation of effective systemic therapy rather than immediate treatment switching.

The approach to second-line treatment planning requires comprehensive reassessment including repeat genomic testing to identify potential small cell transformation or new resistance mechanisms. Clinical trial evaluation at both institutional and neighboring facilities is essential, as the lung cancer field evolves rapidly with new approvals like trastuzumab deruxtecan in the EGFR setting. The treatment selection process must integrate available options with individual patient characteristics and tumor biology. For brain metastases, a staged approach is often employed where asymptomatic patients begin with tyrosine kinase inhibitors followed by brain MRI assessment at 6 weeks, with radiation reserved for cases showing inadequate response.

The potential for aggressive multimodal approaches in select patients is illustrated through a remarkable case example where a patient with extensive disease including brain, liver, and multiple pulmonary metastases achieved dramatic response to FLAURA-2 therapy, ultimately undergoing surgical resection of residual disease that showed less than 10% viable tumor. This case demonstrates the importance of consolidative local therapy when minimal residual disease remains, as leaving low-burden tumor can lead to resistance clone development and subsequent progression. The example emphasizes that while such dramatic responses are not typical, they highlight the value of aggressive, multidisciplinary approaches in young, healthy patients where curative intent may be achievable through combined systemic and local therapies.