Dr. Ticiana Leal introduces the discussion on treatment selection and sequencing in EGFR-mutated advanced non-small cell lung cancer (NSCLC), emphasizing that biomarker testing results must be available before initiating any frontline treatment discussion. With osimertinib monotherapy, osimertinib plus chemotherapy, and amivantamab plus lazertinib all now guideline-recommended, she reviews the comparative efficacy data driving patient discussions.

Dr. Leal discusses the clinical and molecular features most useful for identifying patients likely to benefit from frontline treatment intensification in EGFR-mutated NSCLC. Across FLAURA2 and MARIPOSA, patients with TP53 co-mutations, positive baseline circulating tumor DNA (ctDNA), baseline brain metastases, and EGFR L858R mutation status, which are all associated with worse prognosis on monotherapy, consistently derived benefit from combination strategies, reinforcing the relevance of these markers for treatment selection.

Dr. Leal describes her real-world experience managing toxicity across frontline combination regimens in EGFR-mutated NSCLC. With osimertinib plus chemotherapy (FLAURA2 regimen), most grade 3 or higher adverse events occur during the carboplatin-pemetrexed-osimertinib induction phase, with hematologic toxicities being the primary driver of dose reduction or interruption; her practice manages these toxicities with familiar protocols, achieving dose intensity consistent with trial data. During chronic pemetrexed-osimertinib maintenance, fatigue, anemia, edema, and gradually rising creatinine are the most encountered issues, raising an open clinical question about optimal pemetrexed duration; average time on pemetrexed in FLAURA2 was approximately 8 months, with patients then continuing osimertinib monotherapy for over 30 months.

Dr. Leal addresses time toxicity data from Dr. Florez and colleagues comparing the clinic and at-home time burden across EGFR-mutated NSCLC frontline regimens. Both intravenous and subcutaneous amivantamab-lazertinib combinations carried higher time toxicity than osimertinib-chemotherapy or osimertinib monotherapy, driven largely by the prophylactic regimens required for dermatologic prophylaxis education and anticoagulation for thromboembolic risk reduction. She notes that with subcutaneous amivantamab now available, infusion-related burden is substantially reduced, and she actively transitions eligible patients to the subcutaneous formulation to minimize both time burden and administration-related adverse events.

Dr. Leal outlines her approach to second-line treatment selection following progression on frontline osimertinib monotherapy in EGFR-mutated NSCLC. She recommends repeat molecular testing at progression, particularly liquid biopsy for rapid, noninvasive results, ideally complemented by tissue biopsy to characterize resistance mechanisms and exclude histologic transformation such as small cell transformation. Common resistance mechanisms include C797S mutations and MET alterations. Clinical factors informing second-line selection include performance status, organ function (particularly renal function given platinum-based chemotherapy considerations), burden and sites of progression (with consideration of localized radiation for limited progression, including CNS-limited disease), social support, and patient preference regarding treatment intensity.

Dr. Leal compares amivantamab plus chemotherapy (MARIPOSA-2) with datopotamab deruxtecan (from the pooled TROPION-Lung01 and TROPION-Lung05 analysis) in the second-line setting for EGFR-mutated NSCLC. Datopotamab deruxtecan, now FDA-approved for previously treated patients, demonstrated promising median PFS, OS of approximately 15 months, and notable CNS activity with an intracranial response rate of approximately 40%. As a monotherapy administered intravenously once every 3 weeks, she describes it as straightforward to incorporate clinically. Distinct toxicities associated with this TROP2-directed antibody-drug conjugate with a topoisomerase 1 inhibitor payload include mucositis (managed with prophylactic dexamethasone mouthwash), interstitial lung disease requiring close symptom monitoring, and ocular toxicities, predominantly dry eyes, mitigated with prophylactic eye drops and baseline ophthalmologic evaluation.

Dr. Leal addresses CNS disease management in EGFR-mutated NSCLC, noting that baseline brain metastases represent a high-risk feature associated with worse prognosis and shorter PFS. Potent EGFR tyrosine kinase inhibitors, particularly osimertinib and lazertinib, remain most valuable for CNS control and reducing CNS progression risk in patients without baseline brain involvement. Amivantamab, an EGFR-MET bispecific antibody, has also demonstrated CNS benefit in both MARIPOSA and MARIPOSA-2. Notably, datopotamab deruxtecan, an antibody-drug conjugate not traditionally expected to cross the blood-brain barrier effectively, also demonstrated CNS activity in the pooled TROPION-Lung01/05 analysis. She emphasizes the importance of investigating CNS efficacy early in drug development to inform sequencing strategies that control CNS disease, reduce progression risk, and delay whole brain radiation given its neurologic toxicity.