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Targeted therapy is the standard treatment for driver-mutated lung cancer, but its efficacy in multiple primary lung cancers (MPLCs) remains limited due to significant inter-lesional molecular heterogeneity. We present a case of synchronous MPLC with 34 bilateral pulmonary nodules. The dominant right upper lobe lesion was an EGFR L858R-mutated adenocarcinoma that responded to osimertinib, while other nodules progressed. Switching to chemoimmunotherapy induced regression of all lesions, enabling surgical resection. Postoperative pathological analysis revealed two resected lesions with discordant molecular profiles-one EGFR-mutated and one driver-negative. Despite adjuvant therapy, the patient developed early recurrence as non-small cell lung carcinoma-not otherwise specified with no driver mutation and died within 6 months post-radiotherapy. This case highlights the limitations of single-agent targeted therapy in MPLC, challenges the assumption that driver-negative lesions typically follow an indolent course, and supports early chemotherapy-based systemic combination strategies to address the significant molecular heterogeneity in MPLC.