Bristol-Myers Squibb.

B a c k g r o u n d : I n t h e p h a s e I I I C h e c k M a t e 2 2 7 s t u d y , fi r s t-l i n e nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; !10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. Clinical trial registration: NCT02477826.

Summary Background In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma (aRCC) randomised to nivolumab had an overall survival (OS) benefit versus everolimus. We compared health-related quality of life (HRQoL) between treatment arms and explored the relationship with OS. Methods In this open-label study (NCT01668784) in 146 oncology centres in 24 countries, patients with aRCC were randomised (1:1; block size of 4) to receive nivolumab 3 mg/kg by 60-minute intravenous infusion every 2 weeks or everolimus 10 mg tablet orally once daily. The study was stopped early at the planned interim analysis in July 2015 as the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed for survival. At the interim analysis, HRQoL was assessed using the Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. FKSI-DRS completion rate was calculated using number of patients with at least one baseline assessment and at least one post-baseline assessment. FKSI-DRS completion was defined as completion of five or more items; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. No adjustments were made for EQ-5D missing data. Descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures (MMRM) were used. Analyses were powered according to the original study protocol. A correlation between baseline HRQoL and OS was performed. Findings Patients were randomised from October 2012 through March 2014. HRQoL data were collected at baseline for 362 (88%) of 410 (nivolumab) and 344 (84%) of 411 (everolimus) randomised patients. The mean difference (95% CI) in FKSI-DRS score between nivolumab and everolimus arms was 1·6 (1·4–1·9, p<0·001) with descriptive statistics and 1·7 (1·2–2·1, p<0·001) with MMRM analysis. More patients experienced clinically meaningful HRQoL improvement with nivolumab versus everolimus (200 [55%] of 361 vs 126 [37%] of 343, respectively; p<0·001). Median (95% CI) time to improvement in HRQoL was shorter in patients treated with nivolumab (4·7 [3·7–7·5] months) versus everolimus (not reached [range not estimable]). A positive correlation between OS and FKSI-DRS (r=0·27; p≤0·001), EQ-5D utility (r=0·24, p≤0·001), and EQ-5D VAS (r=0·26, p≤0·001) baseline scores across both arms was observed. Interpretation Nivolumab treatment was associated with HRQoL improvement compared with everolimus in previously treated patients with aRCC. Funding Bristol-Myers Squibb. Dr. Motzer received support through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment.

No abstract

The relative contributions of the sympathetic nervous system and the adrenal medullae, the two components of the sympathoadrenal system, to the manifestations of hypoglycemia are largely unknown. We tested the hypothesis that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural activation. To do so, we quantitated neurogenic symptoms, as well as norepinephrine (NE) kinetics and selected hemodynamic changes, during hyperinsulinemic euglycemic and stepped hypoglycemic clamps in 15 healthy control subjects (Controls) and four bilaterally adrenalectomized patients (ADX). Plasma epinephrine responses to hypoglycemia were virtually absent in ADX, as expected. Neurogenic symptom scores increased to higher values during the hypoglycemic compared with the euglycemic clamps in both Controls (P < 0.0001) (e.g., final scores of 7.8 +/- 1.2 vs. 3.0 +/- 0.7) and ADX (P < 0.0001) (e.g., final scores of 10.8 +/- 4.1 vs. 2.5 +/- 1.0). Plasma NE concentrations (P < 0.0001) and systemic NE spillover (P = 0.0007) increased during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. Similarly, heart rate increased (P = 0.0104), diastolic blood pressure decreased (P = 0.0003), and forearm blood flow increased (P < 0.0001) during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. These data indicate that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural, rather than adrenomedullary, activation. They also suggest that the plasma NE and hemodynamic responses to hypoglycemia are largely the result of adrenomedullary, rather that sympathetic neural, activation.

Purpose To predict the development of glaucomatous visual field (VF) defects using Fourier-domain optical coherence tomography (FD-OCT) measurements at baseline visit. Design Multi-center longitudinal observational study. Glaucoma suspects and pre-perimetric glaucoma participants in the Advanced Imaging for Glaucoma Study. Methods The optic disc, the peripapillary retinal nerve fiber layer (NFL), and macular ganglion cell complex (GCC) were imaged with FD-OCT VF was assessed every 6 months. Conversion to perimetric glaucoma was defined by VF pattern standard deviation (PSD) or glaucoma hemifield test (GHT) outside normal limits on 3 consecutive tests. Hazard ratios were calculated with the Cox proportional hazard model. Predictive accuracy was measured by the area under the receiver-operating-characteristic curve (AUC). Results Of 513 eyes (309 participants), 55 eyes (46 participants) experienced VF conversion during 41 ± 23 months of follow-up. Significant (p<0.05, Cox regression) FD-OCT risk factors included all GCC, NFL, and disc variables, except for horizontal cup-to-disc ratio. GCC focal loss volume (FLV) was the best single predictor of conversion (AUC=0.753, p<0.001 for test against AUC = 0.5). Those with borderline or abnormal GCC-FLV had a 4-fold increase in conversion risk after 6 years (Kaplan-Meier). Optimal prediction of conversion was obtained using the glaucoma composite conversion index (GCCI) based on a multivariate Cox regression model that included GCC-FLV, inferior NFL quadrant thickness, age, and VF PSD. GCCI significantly improved predictive accuracy (AUC=0.783) over any single variable (p=0.04). Conclusions Reductions in NFL and GCC thickness can predict the development of glaucomatous VF loss in glaucoma suspects and pre-perimetric glaucoma patients.

. PPAR␣ activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans.