Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.

BACKGROUND: We 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. METHODS: This 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. FINDINGS: Between 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. INTERPRETATION: Pembrolizumab 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. FUNDING: Merck and the Yale Cancer Center.

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.

Nutrient analysis of school lunches and anthropometric measures in a private and public school in Chennai, India.

School lunch programs have been implemented as a method to facilitate better learning environments for children. These programs bring together the importance of adequate nutrition for academic performance, growth and development. This study served to assess the impact of the School Lunch Program in India and observe measures related to nutrition adequacy and stunting in school aged children in Chennai, India. Dietary and anthropometric data were collected among students of ages 7 to 10 in a privately funded (n = 64) and a publicly funded school (n = 28). Bioelectrical Impedance Analysis was assessed for private school students. BMI for Age Z-scores for the private school (0.05 ± 1.36) (mean ± standard deviation) and public school (- 0.91 ± 2.01) were significantly different (p = 0.008). Additionally, 32% of public school students exhibited mild stunting, classified as Z-scores less than - 1. Total calories consumed during the private school lunch was 269 ± 112 and 463 ± 234 for the publically funded school. Analysis of nutritional parameters of meals suggest that adequacy was otherwise fair during this singular analysis but does not provide evidence to correlate body composition and long term implications of malnutrition with this study population. Additional longitudinal analysis is required to better assess these implications.

A new strategy for the in vitro selection of stapled peptide inhibitors by mRNA display.

Hydrocarbon stapled peptides are promising therapeutics for inhibition of intracellular protein-protein interactions. Here we develop a new high-throughput strategy for hydrocarbon stapled peptide discovery based on mRNA display of peptides containing α-methyl cysteine and cyclized with m-dibromoxylene. We focus on development of a peptide binder to the HPV16 E2 protein.

Nutrient Intake of Elite Canadian and American Athletes with Spinal Cord Injury.

The nutrient needs of athletes with Spinal Cord Injury (SCI) are dependent on their physiological alterations and training status. Limited research is available regarding dietary intake of elite athletes with SCI and possible nutrient deficiencies. Therefore, the purpose of this study was to examine dietary intake of elite athletes with SCI, and determine dietary intake inadequacies based on the Estimated Average Requirement (EAR) comparisons. Additionally, the average energy and macronutrient (carbohydrate, protein, and fat) intake was compared based on level of injury (C level, T1-T6, T7-T12, Lumbar). A total of 39 athletes with a SCI completed a self-reported 24 hour diet recall in autumn and 27 athletes returned to complete a second data collection period (winter). Nutrient inadequacy was estimated by the proportion of athletes with mean intakes below the EAR through the Research Solutions Food Processor Diet Analysis Software (ESHA). Although Macronutrients for both men and women were within acceptable macronutrient distribution range (AMDR) recommendations, low EAR's for various nutrients were consistently found for both men and women. No significant differences were found for energy or macronutrient intake between groups based on level of lesion. Further research is needed to examine nutrient intake using other methods of dietary assessment and to determine the factors that may lead to nutrient insufficiency among elite athletes with SCI.