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:

• Osimertinib alone; or
• 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.

This study consists of 2 screening phases:

Part 1 screening (before osimertinib induction):

Patients must meet the baseline eligibility criteria, including stage IV NSCLC, EGFR sensitizing mutation (exon 19 deletion or L858R), resectable dominant primary lung lesion, and adequate performance status and organ function.

Part 2 screening (after 12 weeks of protocol-defined osimertinib induction and before randomization):

Patients must complete 12 weeks of osimertinib 80 mg once daily and undergo restaging evaluation. Only patients with partial response (PR) or stable disease (SD) by RECIST 1.1, and who remain suitable for thoracic surgery, will proceed to randomization.

Disease distribution must satisfy all of the following: no more than 3 involved organs, one dominant pulmonary primary lesion, the maximal diameter of the dominant primary lung lesion greater than any individual distant metastatic lesion, and a total number of distant metastatic lesions fewer or equal than 10. Pleural or peritoneal metastasis confined to a single cavity and amenable to treatment may be considered a single metastatic lesion.

Inclusion criteria

for screening part 1

• 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.

Inclusion criteria

for Screening Part 2

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.

• Estimated life expectancy is greater than 3 months, as judged by the investigator.

• 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.

Exclusion criteria

Subjects meeting any of the following criteria will be excluded from this study. If any of these conditions are identified only after completion of the 12-week induction phase, the subject will not proceed to randomization.

• 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.
• Total number of distant metastatic lesions greater than 10.
• No clearly dominant primary pulmonary lesion, or the maximal diameter of the dominant primary pulmonary lesion is not greater than any individual distant metastatic lesion.
• Diffuse pleural or peritoneal carcinomatosis that cannot be clearly localized and treated with local definitive therapy.
• Progressive disease (PD) on imaging evaluation after 12 weeks of protocol-defined osimertinib induction.
• Judged by the investigator or thoracic surgeon to be no longer suitable for thoracic surgery after induction therapy.
• Any systemic therapy other than the protocol-defined osimertinib induction for the current stage IV NSCLC.
• Any prior EGFR-TKI, chemotherapy, immunotherapy, or other systemic anticancer therapy for the current stage IV NSCLC, except for the protocol-defined osimertinib induction.
• Pregnant, breastfeeding, or planning pregnancy during the study period.
• Any condition that, in the investigator's judgment, makes the subject unsuitable for participation in this study, or highly likely to be unable to comply with the study procedures, restrictions, or requirements.