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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 154
- 试验地点
- 1
- 主要终点
- Progression-Free Survival
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Because one treatment group undergoes surgery, participants and treating investigators will be aware of treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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-
- •Patients with brain metastases must be conscious; patients with bone metastases must not have irreversible severe events such as severe pathological fracture.
- •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.
- •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.
- •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.
- •Disease distribution after induction therapy 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
- •After 12 weeks of protocol-defined osimertinib induction, the patient must have PR or SD by RECIST 1.1 and remain eligible for randomization.
- •If either of the following conditions is present on restaging imaging:
- •Poor primary tumor response: 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
- •Polymetastatic condition: 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.
排除标准
- •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 at post-induction restaging, before randomization.
- •Total number of distant metastatic lesions greater than 10 at post-induction restaging, before randomization.
- •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 at post-induction restaging, before randomization
- •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.
研究组 & 干预措施
Osimertinib Plus Primary Tumor Resection
Participants will receive osimertinib 80 mg orally once daily for 12 weeks before randomization. After randomization, participants assigned to this arm will undergo therapeutic resection of the primary lung tumor. Osimertinib will generally be resumed 1 to 2 weeks after surgery when wound healing is considered adequate and will be continued until disease progression, unacceptable toxicity, withdrawal, or another protocol-defined reason for treatment discontinuation.
干预措施: Primary Tumor Resection (Procedure)
Osimertinib Alone
Participants will receive osimertinib 80 mg orally once daily for 12 weeks before randomization. After randomization, participants assigned to this arm will continue osimertinib 80 mg once daily until disease progression, unacceptable toxicity, withdrawal, or another protocol-defined reason for treatment discontinuation.
干预措施: Osimertinib (Drug)
Osimertinib Plus Primary Tumor Resection
Participants will receive osimertinib 80 mg orally once daily for 12 weeks before randomization. After randomization, participants assigned to this arm will undergo therapeutic resection of the primary lung tumor. Osimertinib will generally be resumed 1 to 2 weeks after surgery when wound healing is considered adequate and will be continued until disease progression, unacceptable toxicity, withdrawal, or another protocol-defined reason for treatment discontinuation.
干预措施: Osimertinib (Drug)
结局指标
主要结局
Progression-Free Survival
时间窗: From randomization to disease progression or death, assessed up to 24 months after randomization.
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.
次要结局
- Overall Survival(From randomization to death from any cause, assessed up to 48 months after randomization.)
- Number of Participants With Treatment-Related Adverse Events(From the first dose of osimertinib through 28 days after the last dose)
- Pathologic Response of the Primary Lung Tumor(At primary lung tumor resection, generally within 12 weeks after randomization)
- Change From Baseline in Quality-of-Life Score(Before osimertinib induction, at week 12 before randomization, and at 12 and 24 months after randomization.)
研究者
Statistical Center, NTUHCTC
National Taiwan University Hospital
National Taiwan University Hospital