Osimertinib With or Without Primary Lung Tumor Resection for EGFR-Mutant Oligometastatic Non-Small Cell Lung Cancer

This is a multicenter, open-label, parallel-group, randomized controlled phase III trial evaluating primary lung tumor resection in patients with EGFR-mutated oligometastatic stage IV non-small cell lung cancer treated with first-line osimertinib. The study includes two eligibility assessments. During the first assessment, participants must have histologically or cytologically confirmed stage IV non-small cell lung cancer harboring an EGFR exon 19 deletion or exon 21 L858R mutation, a dominant and potentially resectable primary lung tumor, no more than three involved organs, and no more than 10 distant metastatic lesions. All enrolled participants will receive protocol-defined induction treatment with osimertinib 80 mg orally once daily for 12 weeks. After induction, participants will undergo restaging. Only participants with partial response or stable disease according to RECIST version 1.1 who remain medically and technically suitable for primary lung tumor resection will undergo randomization. Eligible participants will be randomly assigned in a 1:1 ratio to one of two groups: 1. Osimertinib alone; or 2. Primary lung tumor resection followed by continued osimertinib. Randomization will be stratified by EGFR mutation subtype, presence of brain metastases, and number of distant metastatic lesions. Participants assigned to the surgical group will undergo therapeutic resection of the primary lung tumor after randomization. The surgical approach and extent of resection will be selected by the treating thoracic surgeon according to accepted standards of care. Osimertinib will generally be resumed 1 to 2 weeks after surgery when wound healing is considered adequate. Participants in both groups will continue osimertinib until disease progression, unacceptable toxicity, withdrawal, or another protocol-defined reason for treatment discontinuation. Tumor assessments will be performed approximately every 12 weeks and evaluated according to RECIST version 1.1. Local treatment of distant metastatic lesions may be provided when clinically indicated according to standard of care and institutional practice for the PTR group, as permitted by the protocol. The primary objective is to compare progression-free survival between the two treatment groups. Secondary and exploratory objectives include overall survival, treatment-related adverse events, pathologic response of the primary tumor, quality of life, local-regional progression-free survival, distant metastasis progression-free survival, brain metastasis progression-free survival, polymetastatic progression-free survival, systemic therapy-free survival, and exploratory molecular biomarker outcomes.