Background Immunotherapy targeting the PD-1 axis has activity in several tumor types. We aimed to determine the efficacy and safety of pembrolizumab in patients with untreated brain metastases. Here we present results from a Phase II trial of the PD-1 inhibitor pembrolizumab in patients with new or progressive brain metastases from melanoma or non-small cell lung cancer (NSCLC). Methods Thirty-six patients were enrolled, 18 with melanoma and 18 with NSCLC. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in longest diameter without associated neurologic symptoms or the need for corticosteroids. NSCLC patients had tumor tissue demonstrating PD-L1 expression. Patients were treated with pembrolizumab 10 mg/kg every two weeks until progression, and brain metastasis response was assessed every eight weeks by modified RECIST. The primary endpoint was brain metastasis response rate and the analysis was performed on an intent-to-treat basis. The trial is ongoing and here we present an early analysis. The study is registered with clinicaltrials.gov, number NCT02085070. Findings Brain metastasis response rate was 22% and 33% among patients with melanoma and NSCLC, respectively. Responses were durable, with all but one patient who responded demonstrating an ongoing response at the time of data analysis. Treatment-related serious and grade 3–4 adverse events were rare and included transaminitis, colitis, pneumonitis, fatigue, endocrine abnormalities, and acute kidney injury (1 patient each). Serious neurological adverse events included cognitive dysfunction and seizures (1 and 3 patients, respectively), due to pembrolizumab, metastases or both. Interpretation Pembrolizumab demonstrates activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, indicating that there may be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock-out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

Background PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). Methods We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naïve patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. Findings Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18.8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients). Interpretation Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as...