A Multicenter, Randomized Controlled Phase III Clinical Trial of Primary Tumor Resection in Patients With Oligometastatic EGFR-Mutant Non-Small Cell Lung Cancer After EGFR-Targeted Therapy
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.
• WHO performance status 0-1. Patients with brain metastases must be conscious; patients with bone metastases must not have irreversible severe events such as severe pathological fracture.
• Disease distribution meeting all of the following criteria:
∙ no more than 3 involved organs;
‣ one dominant pulmonary primary lesion;
‣ the maximal diameter of the dominant pulmonary primary lesion is greater than any single distant metastatic lesion;
‣ total number of distant metastatic lesions fewer or equal to 10.
• The primary lung tumor is considered resectable by the investigator and thoracic surgeon, with surgery intended for maximal regional control.
• The patient is able to take oral medication and is expected to receive first-line osimertinib induction therapy.
• Major organ function and pulmonary reserve are adequate to tolerate the planned surgery.
⁃ After 12 weeks of protocol-defined osimertinib induction, the patient must have PR or SD by RECIST 1.1 and remain eligible for randomization.
• Subjects may proceed to randomization only if all of the following criteria are met:
• The subject has received first-line protocol-defined osimertinib induction according to the study protocol, consisting of osimertinib once daily (QD) for 12 weeks, and has completed the pre-randomization evaluation.
• Restaging imaging has been completed after 12 weeks of induction therapy, and the response is assessed as partial response (PR) or stable disease (SD) according to RECIST version 1.1. In addition, the maximal diameter of the target primary lung tumor before surgery must be greater than the sum of the maximal diameters of the metastatic tumors. PET-CT before surgery or before randomization is recommended to evaluate for newly developed extrathoracic metastases, bone metastases, or mediastinal lymph node involvement. If PET-CT is not performed, the preoperative or pre-randomization imaging assessment should include contrast-enhanced CT scans of the chest and abdomen, including the liver and adrenal glands; brain imaging should be completed with contrast-enhanced CT or MRI. Pleural or peritoneal metastasis confined to a single cavity (for example, unilateral pleural disease) and amenable to treatment may be considered a single metastatic lesion.
• If either of the following conditions is present on restaging imaging:
• the sum of the longest diameters (SLD) of the primary lung tumor after treatment falls within the range of less than 30% decrease and less than 20% increase (that is, -30% \< SLD change \< +20%); or
• the total number of distant metastatic lesions is 6 to 10, then the treatment response of the other distant target metastatic lesions must additionally meet an SLD reduction of at least 30% in order for the subject to remain eligible for randomization.
• 4\. Estimated life expectancy is greater than 3 months, as judged by the investigator.
• 5\. The subject remains suitable for primary lung tumor resection, as assessed by the investigator and thoracic surgeon, and has no major comorbidity that would increase surgical risk to an unacceptable level.