Osimertinib is a standard first-line treatment for patients with metastatic non-small cell lung cancer harboring an epidermal growth factor receptor exon 19 deletion or exon 21 L858R mutation. Although osimertinib can provide effective disease control, most patients eventually experience disease progression, and the primary lung tumor may remain an important site of treatment resistance.
This multicenter, randomized, open-label phase III trial will evaluate whether surgical removal of the primary lung tumor, in addition to continued osimertinib treatment, prolongs progression-free survival in patients with EGFR-mutated oligometastatic non-small cell lung cancer.
All participants will initially receive osimertinib 80 mg orally once daily for 12 weeks. Participants who have a partial response or stable disease according to RECIST version 1.1 and remain suitable for surgery will be randomly assigned in a 1:1 ratio to continue osimertinib alone or to undergo primary lung tumor resection followed by resumption of osimertinib. The study will also evaluate overall survival, safety, pathologic response, quality of life, patterns of disease progression, and changes in molecular biomarkers.
Histologically or cytologically confirmed NSCLC.
Age ≥18 years.
AJCC 8th edition stage IV NSCLC.
EGFR sensitizing mutation limited to exon 19 deletion or exon 21 L858R.
Pathology other than non-small cell lung cancer (NSCLC), or failure to meet the EGFR mutation criteria specified in this study.
EGFR mutation other than exon 19 deletion or exon 21 L858R.
Involvement of more than 3 organs by tumor lesions at post-induction restaging, before randomization.
Total number of distant metastatic lesions greater than 10 at post-induction restaging, before randomization.
Parallel
Primary Tumor Resection
Procedure/SurgeryParticipants assigned to the experimental arm will undergo therapeutic resection of the primary lung tumor after randomization. Acceptable procedures include lobectomy, sleeve lobectomy, bilobectomy, segmentectomy, and wedge resection. The surgical approach may include video-assisted thoracic surgery or thoracotomy. Pneumonectomy and sleeve pneumonectomy are not permitted. The procedure is intended to achieve maximal regional disease control and tumor-free resection margins whenever feasible.
Osimertinib
DrugOsimertinib will be administered orally at a dose of 80 mg once daily as first-line systemic therapy. Treatment will be continued until disease progression, unacceptable toxicity, withdrawal of consent, or fulfillment of other protocol-defined discontinuation criteria. Dose interruption or reduction will be permitted for treatment-related adverse events according to the study protocol.
Progression-Free Survival
Progression-free survival is defined as the time from randomization to the first documented occurrence of disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. Participants without an event will be censored at the date of their last adequate disease assessment.
Overall Survival
Overall survival is defined as the time from randomization to death from any cause. Participants who are alive at the end of follow-up will be censored at the date they were last known to be alive.
Number of Participants With Treatment-Related Adverse Events
Treatment-related adverse events will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and proportion of participants experiencing treatment-related adverse events will be summarized by treatment group.
Pathologic Response of the Primary Lung Tumor
Percentage of residual viable tumor cells in the resected primary lung tumor. Major pathologic response is defined as ≤10% residual viable tumor, and pathologic complete response as no residual viable tumor. This outcome will be assessed only in the surgical arm.
Change From Baseline in Quality-of-Life Score
Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, version 3.0 (EORTC QLQ-C30 v3.0), together with the lung cancer-specific module (EORTC QLQ-LC13). Scores for each scale and single-item measure are linearly transformed to a 0-100 scale. Higher scores on the QLQ-C30 Global Health Status/Quality of Life and functional scales indicate better quality of life or functioning, whereas higher scores on the QLQ-C30 symptom scales and QLQ-LC13 symptom scales or items indicate greater symptom burden. No combined total score will be calculated.
Local-Regional Progression-Free Survival
Time from randomization to the first occurrence of progression in the primary lung tumor, ipsilateral thorax, regional lymph nodes, or pleura, or death from any cause, whichever occurs first. Participants without an event will be censored at their last adequate disease assessment.
Distant Metastasis Progression-Free Survival
Time from randomization to the first occurrence of distant progression, a new distant metastatic lesion, or death from any cause, whichever occurs first. Participants without an event will be censored at their last adequate disease assessment.
Brain Metastasis Progression-Free Survival
Time from randomization to the first occurrence of intracranial progression, a new brain metastasis, or death from any cause, whichever occurs first. Participants without an event will be censored at their last adequate disease assessment.
Polymetastatic Progression-Free Survival
Time from randomization to the first radiographic documentation of more than 10 distant metastatic lesions or death from any cause, whichever occurs first. Participants without an event will be censored at their last adequate disease assessment.
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