Systemic treatment options for non-small-cell lung cancer (NSCLC) with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in advanced non-squamous NSCLC patients with BMs.This was a multicentre, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients were treatment-naïve metastatic non-squamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy, and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) intravenously on day 1 of each 21-day cycle for four cycles, followed by maintenance with camrelizumab (200 mg) and pemetrexed (500 mg/m2) every 21 days until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed intracranial objective response rate (iORR) according to modified Response Evaluation Criteria in Solid Tumours version 1.1, which was primarily analysed in the efficacy analysis set (EAS).Forty-five patients were enrolled and treated (full analysis set [FAS]), with 40 patients having at least one post-baseline tumour assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% CI 9.2-17.3). The confirmed iORR was 52.5% (95% CI 36.1-68.5) in EAS and 46.7% (95% CI 31.7-62.1) in FAS. The extracranial ORR was 47.5% (95% CI 31.5-63.9) and 42.2% (95% CI 27.7-57.8), respectively. Median intracranial progression-free survival (iPFS) was 7.6 months (95% CI 4.6-not reached [NR]), median overall PFS was 7.4 months (95% CI 4.4-NR) and median overall survival was 21.0 months (95% CI 15.9-NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decreased (six [13.3%]) and anemia (four [8.9%]). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy-Lung scores (P = 0.025, P < 0.001).Camrelizumab plus pemetrexed and carboplatin showed activity with manageable toxicity, and improved cognitive function and quality of life for non-squamous NSCLC patients with BMs in the first-line setting.Copyright © 2023. Published by Elsevier Inc.