C79-12 Non-small Cell Lung Cancer With EGFR D770_n771insg Demonstrating an Extended Response to Osimertinib: Case Report

Introduction Lung cancer remains the leading cause of cancer-related death worldwide. GLOBOCAN 2022 estimates ∼2.48 million new cases and 1.82 million deaths. Non-small-cell lung cancer (NSCLC) comprises ∼85% of cases. Routine genotyping has shifted care toward personalized therapy. Third-generation EGFR inhibitors, notably Osimertinib, are standard first-line treatment for tumors with exon 19 deletions or exon 21 L858R substitutions. In the phase III FLAURA trial, Osimertinib nearly doubled progression-free survival (18.9 vs 10.2 months) and improved overall survival versus earlier TKIs. EGFR exon 20 insertions constitute a biologically distinct subgroup (1-2% of NSCLC). Retrospective data show modest activity for Osimertinib monotherapy (PFS 2.3-3.6 months; ORR 5-6%), underscoring the need for variant-specific strategies. Case Presentation A 63-year-old non-smoker female presented with worsening dyspnea and cough. Chest CT showed a right upper-lobe mass, mediastinal lymphadenopathy, and scattered bilateral pulmonary nodules, without extrathoracic disease. Bronchoscopic biopsy confirmed lung adenocarcinoma, positive for TTF-1 and Napsin A. Next-generation sequencing identified an EGFR D770_N771insG exon 20 insertion; ALK, ROS1, and KRAS were wild type, and the PD-L1 tumor proportion score was <1%. As no approved targeted option was available for this mutation at the time, she began off-label Osimertinib 80 mg daily. After eight weeks, CT imaging showed 35% reduction in tumor burden, accompanied by symptom relief. Toxicities were limited to grade 1 rash and diarrhea. Disease control was maintained for 11 months before radiographic progression prompted a transition to platinum-pemetrexed chemotherapy. Discussion Exon 20 insertions remain a challenging subset of EGFR mutations. Their position within the loop region of the tyrosine kinase domain alters the drug-binding pocket and limits activity of first- and second-generation TKIs. Amivantamab combined with platinum-pemetrexed chemotherapy is currently the most effective first-line option, with a reported progression-free survival of approximately 11.4 months, and newer TKIs—including Sunvozertinib and CLN-081—are under investigation. Previous reports include a patient with the same D770_N771insG variant who experienced disease control beyond two years on first-line Osimertinib, and another case describing a complete radiographic response with the related D770_N771insSVD insertion. While most exon 20 insertions confer resistance to approved EGFR TKIs, select variants near codons 770-771 may retain partial sensitivity. Our patient achieved an 11-month response to standard-dose Osimertinib, adding to a small number of encouraging reports. In settings where exon 20-specific inhibitors are unavailable, a carefully monitored trial of Osimertinib may be reasonable. Continued molecular profiling and reporting of rare responders are needed to refine mutation-specific treatment strategies.