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
Authors: Robledo Kristy P , Lefresne Shilo , Yang Yu , Sahgal Arjun , Pinkham Mark B , Nichol Alan , Soo Ross Andrew , Parmar Ambika , Hegi-Johnson Fiona , Doherty Mark , Solomon Benjamin J , Shultz David , Tham Ivan WK , Sacher Adrian , Tey Jeremy , Leong Cheng Nang , Koh Wee Yao , Huang Yiqing , Ang Yvonne , Low Jiali , Yong Clement , Lim Mei Chin , Tan Ai Peng , Lee Chee Khoon , Ho Cheryl 
Published: August 2023

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 fromEGFRmutant 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.govand 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

The use of an individual patient data (IPD) meta-analysis will give increased statistical power for the relative comparison of SRS followed by Osimertinib versus Osimertinib alone on intracranial progression-free survival. Such a meta-analysis will also enable the exploration of subgroups.

Frequency of outcome assessment and outcome measures may be collected and reported differently across included trials, which may lead to some imprecision. Harmonisation of clinical trial protocols through prospective meta-analysis will address some of these limitations.

A limitation of this study is that the searches will only be conducted until late 2023 and any studies that are registered after this time will not be included.