A protocol for a systematic review with prospective individual patient data meta-analysis in EGFR mutant NSCLC with brain metastases to assess the effect of SRS + Osimertinib compared to Osimertinib alone: the STARLET collaboration

Background Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor ( EGFR ) gene are a heterogenous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer generation targeted therapies in the central nervous system. We present a protocol for an individual patient data prospective meta-analysis (IPD-PMA) to evaluate whether the addition of stereotactic radiosurgery (SRS) before Osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. Methods Randomised controlled trials (RCTs) will be eligible if they included: participants with BM arising from EGFR mutant NSCLC and suitable to receive Osimertinib both in the first- and second-line settings (P); comparisons of SRS followed by Osimertinib versus Osimertinib alone (I, C); and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, [ClinicalTrials.gov][1] and the World Health Organisation’s International Clinical Trials Registry Platform’s Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intra-cranial progression free survival, as determined by RANO-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life and adverse events of special interest. Effect differences will be explored among pre-specified subgroups. Ethics and dissemination Approved by each trials ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. Prospero registration CRD42022330532 Strengths and Limitations of this study ### Competing Interest Statement SL: research funding and honoraria from AstraZeneca. YYS: Honoraria: AstraZeneca, Janssen ASah: research grants (Institution) from Elekta AB, Varian, Seagen Inc and BrainLAB. Consulting fees from Varian, Elekta (Gamma Knife Icon), BrainLAB, Merck, Abbvie and Roche. Honoraria: AstraZeneca, Elekta AB, Varian, BrainLAB, Accuray, Seagen Inc. MBP: speaker fees AZ, BMS, MSD, Roche. AN: research grants from Varian Medical Systems Ltd. RAS: advisory board: Amgen, Astra-Zeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma Biotechnology, Roche, Taiho, Takeda, Thermo Fisher, Yuhan Corporation, research grant: Astra-Zeneca, Boehringer Ingelheim FHJ: clinical trial funding, received honoraria and participated in advisory boards for Astra Zeneca. She has received payments and honoraria from BeiGene and MSD for lectures and presentations. Her work is supported by the Peter Mac Foundation and the Victorian Cancer Agency. BJS: Advisory Board/Honoraria from AstraZeneca, Pfizer, Novartis, Roche, Takeda, Merck, Bristol Mysers Squibb, Janssen, Amgen, Eli Lilly IT: Honorarium Elekta, MSD CH: advisory boards with Abbvie, Amgen, AstraZeneca, Bayer, BMS, Eisai, EMD Serono, Janssen, Jazz, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, research grants: AstraZeneca, EMD Serono, Roche CKL: Advisory board: Amgen, Astra Zeneca, GSK, Merck KGA, Norvatis, Pfizer, Roche, Takeda, Boehringer-Ingelheim, Yuhan. Research Funding (Institution): Astra Zeneca, Roche, Merck KGA, Amgen KR, AP, MD, DS, ASac, JT, CNL, WYK, YH, YA, JL, CY, MCL, and APT have no competing interests. CH, SL, FHJ, CKL, YY, RAS and IT are study chairs on the included trials. ### Clinical Trial NCT03497767 and [NCT03769103][2] ### Funding Statement OUTRUN was funded by the following: Sponsored by Trans Tasman Radiation Oncology Group (TROG) Cancer Research, ESR funding from AstraZeneca, National University Health System (NUHS) Seed Fund, NUHSRO/2019/053/RO5+5/Seed-Mar/06), National University Health System (NUHS) Medical Research Application (HREF) - Cancer Fund, National University Cancer Institute, Singapore (Gift from Mr Sajiv Misra via Phoenix Advisers Pte Ltd), The Royal Australian New Zealand College of Radiologists (RANZCR) Research Grant. LUOSICNS was funded by ESR funding from AstraZeneca. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Melbourne Health Human Research Committee of Melbourne, Australia gave ethical approval for OUTRUN (TROG 17.02, [NCT03497767][3]). British Columbia Cancer Agency Research Ethics Board of University of British Columbia, Canada gave ethical approval for LUOSICNS ([NCT03769103][2]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. * AESI : adverse events of special interest ASCO : American Society of Clinical Oncology ASTRO : American Society for Radiation Oncology BM : brain metastases EGFR : epidermal growth factor receptor FDA : U.S. Food and Drug Administration GRADE : Grading of Recommendations Assessment, Development and Evaluation () ic-PFS : intracranial disease progression-free survival IPD : individual patient data NSCLC : Non-small-cell lung cancer OS : overall survival PRISMA-P : Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension for protocols (P) RCT : randomised controlled trial SNO : Society for Neuro-Oncology SRS : Stereotactic radiosurgery STARLET : oSimertinib with or without sTereotActic Radiosurgery in egfr non-small cell Lung cancEr with brain metastases TKI : tyrosine kinase inhibitors [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03769103&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F31%2F2023.07.30.23293383.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03497767&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F31%2F2023.07.30.23293383.atom