Local consolidative therapy for the primary tumor in EGFR-mutant advanced non-small cell lung cancer following osimertinib plus chemotherapy: a protocol for a single-arm, open-label, phase 2 trial

Introduction

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have become the standard of care for patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, demonstrating superior response rates and longer progression-free survival (PFS) compared with conventional chemotherapy (1-4). The advent of third-generation TKIs, such as osimertinib, has further improved outcomes by enhancing the control of central nervous system (CNS) metastases (5) and prolonging overall survival (OS) (6,7). Accordingly, osimertinib is now recommended as the preferred first-line treatment for EGFR-mutant NSCLC in major clinical guidelines (8-11). Nevertheless, acquired resistance typically develops within 1–2 years and remains a major limitation of EGFR-targeted therapy.

To address this challenge, various strategies have been proposed, with particular attention given to combination approaches involving EGFR-TKIs with platinum-based chemotherapy, anti-angiogenic therapies, or bispecific antibodies (12-16). The NEJ009 trial first demonstrated that adding platinum-doublet chemotherapy to first-line gefitinib significantly improved PFS and response rates in patients with EGFR-mutant NSCLC, although this benefit did not translate into prolonged OS (12,13). Building on this concept, the FLAURA2 trial showed that osimertinib plus pemetrexed and platinum as first-line therapy significantly improved PFS compared with osimertinib monotherapy, highlighting the potential of combination regimens as a new therapeutic standard (14). These findings have led to the increasing adoption of combination therapies in real-world clinical practice.

In parallel, several studies have suggested that adding local consolidative therapy (LCT), such as surgery or radiotherapy, to EGFR-TKI monotherapy may prolong survival in selected patients by controlling the primary tumor (17-19). Although LCT carries a risk of procedure-related morbidity, its benefits appear to outweigh potential harms in appropriate candidates (17-19). Most existing studies, however, have been restricted to patients receiving TKI monotherapy and highly selected subgroups, such as those with oligometastatic or limited residual disease. Importantly, pathological complete response (CR) in the primary tumor lesion after EGFR-TKI treatment is rare, even in patients who achieve radiologic response (20,21). This observation underscores the persistence of residual disease at the primary site despite systemic control and supports the rationale for incorporating LCT to achieve durable local control.

Despite these insights, the role of LCT in the setting of systemic combination therapy remains poorly defined, particularly in broader real-world populations beyond traditional oligometastatic criteria. The present study aims to evaluate the clinical outcomes and safety of LCT targeting primary tumors in patients with EGFR-mutant advanced NSCLC who achieve disease control after induction treatment with osimertinib plus chemotherapy. We hypothesize that LCT administered after systemic disease control will improve PFS compared with historical outcomes of systemic therapy alone. By analyzing real-world data that includes patients beyond oligometastatic criteria, this study seeks to clarify the clinical role of LCT after combination therapy and to identify patient subgroups most likely to benefit. The study protocol is presented in accordance with the SPIRIT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-922/rc).

Methods

Study design and setting

This is a prospective, single-arm, open-label phase II exploratory study conducted across multiple tertiary referral hospitals in Republic of Korea. The trial evaluates the clinical impact of local therapy targeting the primary tumor in patients with EGFR-mutant advanced NSCLC who achieve disease control following first-line combination therapy with osimertinib, pemetrexed, and platinum (FLAURA2 regimen). As a single-arm study, outcomes will be interpreted in the context of historical data from previous studies, including the FLAURA2 trial.

Patients will be recruited consecutively at participating institutions during the planned enrollment period. Eligible candidates will be identified through routine clinical practice in collaboration with each institution’s multidisciplinary lung cancer team. All sites will adhere to a common protocol for eligibility assessment, local treatment decision-making, and biomarker sampling. Trial coordination, data collection, and management will be centrally overseen by the principal investigator and the coordinating research team at the lead site, with support from investigators at each participating hospital. Given the anticipated low risk and limited sample size, no independent steering, adjudication, or monitoring committee has been established.

Patient enrollment began on July 1, 2025, and is expected to be completed by June 30, 2028. Participants will be followed for at least 24 months after the last enrollment to ensure sufficient events for robust estimation of both the median PFS and 2-year OS. The primary completion date—the final data collection date for primary and key secondary endpoints—is projected to be June 30, 2030, and the overall study completion date for June 30, 2031.

The study was approved by the Institutional Review Board (IRB) of Pusan National University Hospital (No. 2505-013-151) and will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. As the central coordinating institution, Pusan National University Hospital serves as the primary ethical review board for all participating sites under a unified protocol. Written informed consent will be obtained from all participants by qualified investigators before enrollment. This trial is registered at ClinicalTrials.gov (NCT07073365). Any significant protocol modifications, including changes to eligibility criteria, study endpoints, or statistical analyses, will be submitted to the IRB and updated in the trial registry as required. Protocol version 1.0, finalized in May 2025, was used for this submission.

Treatment plan

Before enrollment, all patients will undergo a baseline imaging, including a contrast-enhanced chest and abdominal computed tomography (CT), brain magnetic resonance imaging (MRI), and ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan, to assess disease extent, CNS involvement, and detect occult lesions. Eligible patients will then receive four cycles of induction therapy with osimertinib (80 mg orally once daily) plus pemetrexed and platinum-based chemotherapy administered every 3 weeks. Treatment response will be evaluated using chest and abdominal CT, along with ¹⁸F-FDG PET/CT; brain imaging will be performed in patients with baseline brain metastases or when clinically indicated.

Patients achieving CR, partial response (PR), or stable disease (SD) after induction therapy will be reviewed by a multidisciplinary team (MDT) including medical oncologists, thoracic surgeons, radiation oncologists, and radiologists. Based on MDT recommendations, patient preference, and technical feasibility, LCT for the primary tumor—either surgery or radiotherapy—will be offered. Eligibility for LCT will be determined according to the following principles:

• Disease control at all sites (CR/PR/SD) after induction therapy;
• Primary lung lesion showing PR or SD;
• No new progression on restaging imaging;
• Technical feasibility of local intervention and adequate patient fitness.

Residual or multiple metastatic lesions will not preclude LCT if systemic disease is controlled and local therapy is clinically appropriate. MDT discussion is held weekly, and eligible patients will undergo LCT within 8–12 weeks after assessment. The timing and modality of LCT will be recorded. Local treatment of residual metastatic lesions may also be permitted at the discretion of the treating physician.

After induction therapy, maintenance treatment with osimertinib (80 mg once daily) and pemetrexed (every 3 weeks) will continue until disease progression, unacceptable toxicity, or patient withdrawal. LCT will generally be delivered concurrently with maintenance treatment, although temporary interruption of systemic therapy may be allowed for treatment-related toxicity or recovery from surgery. Supportive care consistent with standard clinical practice is permitted, but other investigational anticancer agents or systemic treatments not specified in the protocol are prohibited. A schematic of the study process is shown in Figure 1.

Figure 1 Flowchart of the study. Patients with EGFR-mutant advanced NSCLC will receive four cycles of induction therapy with osimertinib plus chemotherapy. Those achieving disease control will be evaluated by an MDT for eligibility to undergo salvage local therapy to the primary tumor (surgery or radiotherapy), with optional treatment to residual metastatic lesions. Follow-up will assess PFS, OS, local control, toxicity, and QoL. CtDNA will be analyzed at baseline and post-induction. CR, complete response; CT, computed tomography; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; LCT, local consolidative therapy; MDT, multidisciplinary team; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; PR, partial response; QoL, quality of life; SD, stable disease.

Induction therapy may be discontinued or modified in cases of unacceptable toxicity, disease progression, or patient withdrawal. Dose adjustments will follow institutional guidelines and standard practice. LCT will not be performed if contraindications develop, the patient’s condition deteriorates, or the patient declines.

Patient adherence will be monitored through regular clinical visits, direct supervision of hospital-administered treatments, and review of prescription records for oral osimertinib.

Circulating tumor DNA (ctDNA) analysis

CtDNA will be assessed at two pre-specified time points: baseline (before initiation of systemic therapy) and post-induction (after completion of induction therapy but before local treatment). CtDNA analysis will be performed using a commercially validated targeted next-generation sequencing (NGS) platform (AlphaLiquid^®100, IMBdx, Seoul, Republic of Korea), which is approved for clinical use in the Republic of Korea and enables the detection of major driver and resistance mutations in lung cancer. Mutation calls will be interpreted using standardized bioinformatic pipelines provided by the manufacturer. Biological specimens will not be stored for future unspecified research, and no ancillary studies are planned. The ctDNA results at each time point will be correlated with clinical outcomes, including PFS and OS.

Eligibility criteria

Patients will be eligible for enrollment if they meet all of the following criteria:

• Provision of written informed consent;
• Age ≥20 years at the time of enrollment;
• Histologically or cytologically confirmed NSCLC;
• Presence of an activating EGFR mutation (exon 19 deletion or exon 21 L858R point mutation);
• Initially diagnosed with unresectable stage III or IV disease according to the 9^th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual;
• Completion of baseline brain MRI prior to enrollment to evaluate CNS involvement, consistent with the FLAURA2 trial;
• Completion of four cycles of first-line osimertinib, pemetrexed, and platinum (FLAURA2 regimen);
• Radiologically confirmed disease control (CR, PR, or SD) after induction therapy;
• Presence of a residual primary lung tumor suitable for local therapy (surgery or radiotherapy), as determined at reassessment, with systemic disease controlled by induction therapy;
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion criteria are as follows:

• Progressive disease during or after induction therapy with osimertinib plus chemotherapy;
• Residual or metastatic lesions deemed unsuitable for local therapy based on MDT evaluation;
• Untreated or uncontrolled brain metastases at enrollment;
• Contraindications to surgery or radiotherapy, as determined by the treating physician or MDT;
• Another active malignancy requiring ongoing systemic treatment.

Key definitions were adapted from the reference (15) to ensure consistency. Oligo-organ metastasis was defined as involvement of no more than three extracranial organ systems, regardless of the number of lesions, reflecting evidence that the number of involved organs may be more prognostic than the number of lesions. Oligometastasis was defined as the presence of ≤5 extrathoracic metastatic lesions. Complete LCT refers to definitive local treatment of all detectable residual lesions, including both the primary tumor and metastatic sites, whereas partial LCT refers to local therapy limited to the primary tumor.

Endpoints

The primary endpoint is PFS, defined as the time from study enrollment to radiographic or clinical disease progression or death from any cause, whichever occurs first.

Secondary endpoints include OS, local control rate at the primary tumor site, treatment-related toxicity assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, and patterns of disease progression. Patterns of progression will be categorized by the site of first recurrence as local (primary tumor site), regional (thoracic lymph nodes), or distant (metastatic organ). Quality of life (QoL) will also be evaluated using validated patient-reported outcome instruments where applicable.

The exploratory endpoints include assessment of ctDNA status before and after induction therapy. The association between ctDNA clearance and clinical outcomes will be analyzed to explore its potential role as a predictive biomarker.

Sample size estimation

This study is designed to estimate PFS in patients with EGFR-mutant advanced NSCLC who undergo LCT after achieving disease control with first-line osimertinib plus chemotherapy. A precision-based approach was adopted to provide a robust estimate of PFS in a real-world population. The sample size calculation focused on the precision of estimating the median PFS, a commonly used summary measure of time-to-event outcomes.

Based on prior reports suggesting a median PFS of approximately 25.5 months with combination therapy, a sample size of 70 patients is required to estimate the median with a two-sided 95% confidence interval width of ±3 months, calculated using Greenwood’s approximation. This level of precision is considered sufficient to inform future hypothesis-generating studies. The planned enrollment of 70 patients also incorporates an allowance for up to 5% dropout.

Data collection and management

Clinical data, including demographic characteristics, disease status, treatment details, radiological findings, laboratory results, and all adverse events (AEs), will be prospectively collected using standardized electronic case report forms (eCRFs). Serious AEs will be reported promptly to the IRB and managed according to institutional guidelines. Safety monitoring will be overseen by the principal investigator, who may implement study modifications in response to safety concerns. Data entry and management will be performed by qualified site personnel and reviewed regularly to ensure accuracy and completeness.

Radiological assessments, including response after induction therapy and follow-up imaging, will be performed according to institutional protocols and recorded in the study database. Imaging, treatment, and laboratory data will be collected at prespecified time points: baseline, post-induction therapy, pre-local therapy, and routine follow-up. Information on AEs, ctDNA results, and QoL assessments (if performed) will also be captured in the eCRFs.

To promote participant retention, follow-up visits will be scheduled at regular intervals with reminders provided by the study team. Participants who discontinue study interventions will be encouraged to continue scheduled assessments. For those who withdraw consent for further treatment but allow data use, survival status and outcome data will be collected from medical records and follow-up contacts.

Patient confidentiality will be protected in accordance with applicable regulations. Each participant will be assigned a unique study identifier, and no personally identifiable information will appear in study reports or publications. All study data will be stored on secure, password-protected institutional servers with access restricted to authorized personnel. Linking logs will be maintained separately to preserve confidentiality, and data integrity will be ensured through built-in range checks and periodic verification.

Statistical analysis

The full analysis set will include all enrolled patients who receive at least one cycle of induction therapy and undergo a post-induction radiological response assessment. Patients who discontinue therapy before completing one cycle or who lack response assessment will be excluded from the efficacy analysis. All other protocol deviations will be documented, and patients will remain evaluable unless their data are deemed non-assessable. Descriptive statistics will be used to summarize baseline characteristics, treatment delivery, and safety outcomes. Categorical variables will be reported as frequencies and percentages, and continuous variables as medians with interquartile ranges.

The primary endpoint, PFS, will be estimated using the Kaplan-Meier method with corresponding 95% CIs. Both the median PFS and 1-year PFS rate will be reported. PFS is defined as the time from initiation of first-line systemic therapy to radiological progression or death from any cause. Patients without events will be censored at the date of last follow-up. Secondary endpoints, including OS, local control rate, and failure patterns, will also be analyzed using Kaplan-Meier estimates and descriptive statistics. OS is defined as the time from initiation of first-line systemic therapy to death from any cause.

Treatment-related AEs will be summarized by frequency and grade according to CTCAE version 5.0. If QoL data are available, longitudinal analyses will be used to evaluate changes over time.

Exploratory analyses will evaluate the association between post-induction ctDNA status (detectable vs. undetectable) and clinical outcomes using log-rank tests and Cox proportional hazards models. Predefined subgroup analyses will compare outcomes according to local therapy modality (surgery vs. radiotherapy), ctDNA status after induction therapy (detectable vs. undetectable), extent of LCT (complete vs. partial), and metastatic disease burden (oligometastasis vs. non-oligometastasis; oligo-organ vs. multi-organ involvement).

No interim analyses or formal stopping rules are planned. The principal investigator may terminate the trial early in the event of unexpected safety concerns, feasibility issues, or other significant considerations. Missing data will be handled using complete-case analysis, with sensitivity analyses performed if appropriate. All statistical tests will be two-sided with a significance level of 0.05. Analyses will be performed using IBM SPSS Statistics for Windows (version 29.0; IBM Corp., Armonk, NY, USA).

Discussion

Despite significant advances in the treatment of EGFR-mutant NSCLC, acquired resistance remains a major clinical challenge following first-line therapy, even with third-generation EGFR-TKIs such as osimertinib. The FLAURA2 trial demonstrated that combining osimertinib with platinum-based chemotherapy significantly improves PFS compared with monotherapy, leading to a paradigm shift toward combination strategies in the first-line setting (11). Nevertheless, achieving durable disease control remains challenging, and strategies are required to further delay resistance.

LCT of the primary tumor has shown promising outcomes in patients with oncogene-driven NSCLC treated with EGFR-TKIs, particularly those with limited residual or oligometastatic disease (14-16). However, most existing studies have focused on patients receiving TKI monotherapy and have restricted LCT to highly selected subgroups with minimal disease burden. Consequently, the role of LCT following systemic combination therapy in broader patient populations remains largely unexplored. Whether definitive local control of the primary tumor confers an additional survival benefit in patients treated with upfront EGFR-TKIs plus chemotherapy remains an open and clinically relevant question.

This prospective, single-arm, phase II study is designed to address this gap by evaluating the impact of LCT on primary tumors in patients with EGFR-mutant advanced NSCLC who achieve disease control after induction treatment with osimertinib plus chemotherapy. Importantly, this study is not limited to patients with oligometastatic disease, thereby reflecting a more inclusive, real-world population. In addition, the study will explore the prognostic value of ctDNA clearance after induction therapy as a potential biomarker for treatment response and relapse risk. Collectively, these findings may help define the role of LCT in the era of combination treatment for EGFR-mutant NSCLC and provide evidence to guide future clinical practice and prospective randomized trials.

Some limitations should be acknowledged. First, as a single-arm trial, it lacks a control group for direct comparison, which may limit the interpretation of treatment efficacy. Second, the study population is restricted to patients who have achieved disease control following first-line combination therapy and are eligible for local treatment, potentially introducing a selection bias. Third, as this is a protocol study, long-term outcomes, such as OS, remain hypothetical and will require future validation. In terms of operational challenges, heterogeneity in local therapeutic approaches—particularly regarding the choice between surgery and radiation, as well as the timing of intervention—may complicate protocol adherence. Furthermore, the long follow-up period poses the risk of patient dropout and incomplete data collection. To address these issues, this study will implement standardized treatment guidelines and a centralized data management system. Regular monitoring and active patient engagement strategies will also be employed to maintain data integrity and ensure follow-up compliance throughout the study period.

The results of this study will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals, and updates on ClinicalTrials.gov. There are no publication restrictions imposed by the sponsor. Participants who express interest in the study findings will be provided with a summary of the results upon request.

Authorship for publications arising from this study will follow the guidelines of the International Committee of Medical Journal Editors (ICMJE). No professional medical writers will be used in the preparation of study manuscripts. The full study protocol will be made publicly available through the journal publication and trial registry entry. De-identified participant-level datasets and statistical analysis code will not be publicly posted but may be available to qualified researchers upon reasonable request, subject to institutional and regulatory approvals.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-922/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-922/prf

Funding: This work was supported by a clinical research grant from the Pusan National University Hospital [2025]. The sponsor (Biomedical Research Institute, Pusan National University Hospital) had no role in the study design; collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. The investigators have full access to all data and take full responsibility for the study. No contractual agreements exist that restrict investigator access to the data or the decision to publish the study results.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-922/coif). All authors report that this study was supported by a clinical research grant from Pusan National University Hospital. In addition, M.H.K. has received honoraria for lectures from AstraZeneca and Yuhan, outside the submitted work. S.H.K. has received honoraria for lectures from Amgen, AstraZeneca, Boryung, and Yuhan, outside the submitted work. J.S.E. has received research grants or contracts from Boryung, Yuhan, and Boehringer Ingelheim, and has participated on advisory boards for MSD, AstraZeneca, IMBdx, Amgen, Roche, Yuhan, and Takeda, and has received honoraria for lectures from Yuhan, Merck, Amgen, AstraZeneca, Roche, Boehringer Ingelheim, Mundipharma, MSD, Novartis, Daiichi Sankyo/Astra Zeneca, IMBdx, and Takeda, outside the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Pusan National University Hospital (No. 2505-013-151). Written informed consent will be obtained from all participants before enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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