Treating brain metastases in non-small cell lung cancer patients: what have we learnt from pharmaceutical recent clinical trials?

ABSTRACT

Introduction: Brain metastases (BMs) develop in up to 40% of patients with non-small cell lung cancer (NSCLC). In many recent practice-changing clinical trials, patients with BM were included; however, only few trials reported intracranial efficacies in either post hoc or pre-planned analysis. Clinically meaningful intracranial efficacy data of novel agents have not been completely disclosed.

Areas covered: The authors performed a systemic review of recent pharmaceutical clinical trials, mainly pivotal or practice-changing trials. Some of the prospective clinical trials focused on patients with NSCLC and BM. The authors collected and compared intracranial efficacy reports of chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), ALK inhibitors, and immune checkpoint inhibitors.

Expert opinion: Many clinical trials, especially those on ‘brain-active’ EGFR-TKIs and ALK inhibitors, have robust reports of intracranial efficacies either as post hoc or pre-planned analysis. Physicians should interpret this data with caution and apply the results to patients accordingly. For the design of future clinical trials, enrolling patients with only BM, incorporating novel risk classifications, pre-planning intracranial efficacy endpoints, reporting prior local brain therapies, and applying novel response evaluation criteria are emerging trends in this area.

KEYWORDS:

• ALK rearrangement
• brain metastases
• clinical trials
• EGFR mutation
• immune checkpoint inhibitor
• non-small cell lung cancer

Declaration of interest

JCH Yang is a consultant and has received honoraria from Boehringer Ingelheim, Roche, Chugai Pharmaceutical Co. Ltd, Merck Sharp and Dohme, AstraZeneca, and Novartis. He is also a consultant for Genentech, Clovis Oncology, Eli Lilly and Company, Merck Serono, Celgene, Astellas, Bayer AG, Pfizer Inc, Ono Pharmaceutical Co. Ltd, Bristol-Myers Squibb, Yuhan, Daiichi Sankyo and Hansoh Pharmaceutical Co. Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Lung-specific Graded Prognostic Assessment (GPA) provides a facile and accurate tool to estimate survival, and an updated version incorporates EGFR and ALK gene alterations into the prognostic index (Lung-molGPA).

• Chemotherapy, chemotherapy in combination with bevacizumab, first- and second-generation EGFR-TKIs, and crizotinib all reported outcomes in patients with brain metastases.

• Novel molecular-targeted agents, such as osimertinib, ceritinib, and alectinib, have reported clinically meaningful intracranial efficacy data in post hoc and pre-planned analyses.

• Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, also reported outcomes in patients with brain metastases in prospective clinical trials.

• Evolution continues in the field of clinical trial design of novel ‘brain-active’ drugs. Pre-planning intracranial efficacy endpoints, reporting prior local brain therapies, and applying novel response evaluation criteria are trends in this area.

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Additional information

Funding

This manuscript has not been funded.