• Sarah B Goldberg, Kurt A Schalper, Scott N Gettinger, Amit Mahajan, Roy S Herbst, Anne C Chiang, Rogerio Lilenbaum, Frederick H Wilson, Sacit Bulent Omay, James B Yu, Lucia Jilaveanu, Thuy Tran, Kira Pavlik, Elin Rowen, Heather Gerrish, Annette Komlo, Richa Gupta, Hailey Wyatt, Matthew Ribeiro, Yuval Kluger, Geyu Zhou, Wei Wei, Veronica L Chiang, and Harriet M Kluger.
• Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. Electronic address: sarah.goldberg@yale.edu.
• Lancet Oncol. 2020 May 1; 21 (5): 655663655-663.

BackgroundWe did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort.MethodsThis was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070.FindingsBetween March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths.InterpretationPembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted.FundingMerck and the Yale Cancer Center.Copyright © 2020 Elsevier Ltd. All rights reserved.

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