SummaryBackground Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the effi cacy and safety of panitumumab combined with cisplatin and fl uorouracil as fi rst-line treatment for these patients.

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We develop graphical and numerical methods for checking the adequacy of generalized linear mixed models (GLMMs). These methods are based on the cumulative sums of residuals over covariates or predicted values of the response variable. Under the assumed model, the asymptotic distributions of these stochastic processes can be approximated by certain zero-mean Gaussian processes, whose realizations can be generated through Monte Carlo simulation. Each observed process can then be compared, both visually and analytically, to a number of realizations simulated from the null distribution. These comparisons enable one to assess objectively whether the observed residual patterns reflect model misspecification or random variation. The proposed methods are particularly useful for checking the functional form of a covariate or the link function. Extensive simulation studies show that the proposed goodness-of-fit tests have proper sizes and are sensitive to model misspecification. Applications to two medical studies lead to improved models.

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Purpose: This phase III study compared clinical efficacy and safety of the biosimilar ABP 215 with bevacizumab reference product (RP) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Patients and Methods: Patients were randomized 1:1 to ABP 215 or bevacizumab 15 mg/kg every three weeks for 6 cycles. All patients received carboplatin and paclitaxel every three weeks for !4 and 6 cycles. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% confidence interval (CI) of the risk ratio was within the margin of 0.67 to 1.5. Secondary endpoints included risk difference of ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS); pharmacokinetics, adverse events (AEs), and incidence of antidrug antibodies (ADAs) were monitored. Results: A total of 820 patients were screened; 642 were randomized to ABP 215 (n ¼ 328) and bevacizumab (n ¼ 314). Overall, 128 (39.0%) and 131 (41.7%) patients in the ABP 215 and bevacizumab groups, respectively, had objective responses [ORR risk ratio: 0.93 (90% CI, 0.80-1.09)]. In the ABP 215 and bevacizumab group, 308 (95.1%) and 289 (93.5%) patients, respectively, had at least 1 AE; 13 (4.0%) and 11 (3.6%) experienced a fatal AE. Anti-VEGF toxicity was low and comparable between treatment groups. At week 19, median trough serum drug concentration was 132 mg/mL (ABP 215 group) and 129 mg/mL (bevacizumab group). No patient tested positive for neutralizing antibodies. Conclusions: ABP 215 is similar to bevacizumab RP with respect to clinical efficacy, safety, immunogenicity, and pharmacokinetics. The totality of evidence supports clinical equivalence of ABP 215 and bevacizumab.

PurposeThis study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 215 with bevacizumab in healthy males.MethodsIn this randomized, single-blind, single-dose, three-arm, parallel-group study, healthy subjects were randomized to receive ABP 215 (n = 68), bevacizumab (US) (n = 67), or bevacizumab (EU) (n = 67) 3 mg/kg intravenously. Primary endpoints were area under the serum concentration–time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (C max). Secondary endpoints included safety and immunogenicity.ResultsAUCinf and C max were similar across the three groups. Geometric means ratio (GMR) for C max and AUCinf, respectively, was 0.98 and 0.99 for ABP 215 versus bevacizumab (US); 1.03 and 0.96 for ABP 215 versus bevacizumab (EU); and 1.05 and 0.97 for bevacizumab (US) versus bevacizumab (EU). The 90% confidence intervals for the GMRs of AUCinf and C max were within the prespecified standard PK bioequivalence criteria of 0.80 to 1.25. The incidence of adverse events (AEs) was 47.1, 32.8, and 61.2% in the ABP 215, bevacizumab (US) and bevacizumab (EU) groups, respectively. When analyzed by investigational site, the incidence and severity of AEs were comparable in the ABP 215 and bevacizumab groups. There were no AEs leading to study discontinuation. No binding or neutralizing anti-drug anti-bodies was detected.ConclusionsThis study demonstrated the PK similarity of ABP 215 to both bevacizumab (US) and bevacizumab (EU), and of bevacizumab (US) to bevacizumab (EU). Safety and tolerability were comparable between treatments and no subject developed binding or neutralizing anti-drug anti-bodies.

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• Anaemic young adults with ESRD may afford higher CBF and OEF. • Anaemic young adults with ESRD maintain a normal CMRO 2 . • Cognitive function was still impaired in young ESRD adults. • The severity of cognitive dysfunction correlated with CBF and OEF changes.