Real-World Toxicity Management in EGFR-Mutated Non-Small Cell Lung Cancer: Combination Regimen Adverse Events

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.

With amivantamab plus lazertinib, the regimen has evolved substantially since the original MARIPOSA data through transition from intravenous to subcutaneous amivantamab, meaningfully reducing administration time (a 5-minute injection versus a 5-hour infusion) and administration-related adverse events. Dermatologic toxicity remains the most common driver of dose interruption or reduction with this combination, mitigated through the extended prophylactic skin regimen from the COCOON strategy. Cohort 1 of the COPERNICUS trial, evaluating subcutaneous amivantamab plus lazertinib with this prophylaxis, demonstrated significant reductions in cutaneous adverse events, paronychia, administration-related events, and thromboembolic events. When dose modification is needed for this combination, it is most commonly attributable to amivantamab rather than lazertinib.