In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship ...between pembrolizumab dose, exposure, and response to define an effective dose for these patients.
Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration–time curve at steady state over 6 weeks (AUCss–6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure–safety relationship was assessed by logistic regression of pembrolizumab AUCss–6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.
Overall response rates were 15% 95% confidence interval (CI) 7%–28% at 2 mg/kg Q3W, 25% (18%–33%) at 10 mg/kg Q3W, and 21% (95% CI 14%–30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss–6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure–response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure–safety analysis showed the AE incidence to be similar among the clinically tested doses.
No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2–10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.
NCT01295827.
Pembrolizumab is a potent immune‐modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE‐001, ‐002, and ‐006 studies. Longitudinal tumor size modeling was pursued to quantify ...exposure‐response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE‐001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.
Hexaploid bread wheat evolved from a rare hybridisation, which resulted in a loss of genetic diversity in the wheat D-genome with respect to the ancestral donor, Aegilops tauschii. Novel genetic ...variation can be introduced into modern wheat by recreating the above hybridisation; however, the information associated with the Ae. tauschii accessions in germplasm collections is limited, making rational selection of accessions into a re-synthesis programme difficult. We describe methodologies to identify novel diversity from Ae. tauschii accessions that combines Bayesian analysis of genotypic data, sub-species diversity and geographic information that summarises variation in climate and habitat at the collection point for each accession. Comparisons were made between diversity discovered amongst a panel of Ae. tauschii accessions, bread wheat varieties and lines from the CIMMYT synthetic hexaploid wheat programme. The selection of Ae. tauschii accessions based on differing approaches had significant effect on diversity within each set. Our results suggest that a strategy that combines several criteria will be most effective in maximising the sampled variation across multiple parameters. The analysis of multiple layers of variation in ex situ Ae. tauschii collections allows for an informed and rational approach to the inclusion of wild relatives into crop breeding programmes.
A liquid metal filament supported on a dielectric substrate was directed to fragment into an ordered, mesoscale particle ensemble. Imposing an undulated surface perturbation on the filament forced ...the development of a single unstable mode from the otherwise disperse, multimodal Rayleigh–Plateau instability. The imposed mode paved the way for a hierarchical spatial fragmentation of the filament into particles, previously seen only at much larger scales. Ultimately, nanoparticle radius control is demonstrated using a micrometer scale switch.
Nanoscale copper rings of different radii, thicknesses, and widths were synthesized on silicon dioxide thin films and were subsequently liquefied via a nanosecond pulse laser treatment. During the ...nanoscale liquid lifetimes, the rings experience competing retraction dynamics and thin film and/or Rayleigh–Plateau types of instabilities, which lead to arrays of ordered nanodroplets. Surprisingly, the results are significantly different from those of similar experiments carried out on a Si surface. We use hydrodynamic simulations to elucidate how the different liquid/solid interactions control the different instability mechanisms in the present problem.
To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC).
PK dependencies in OS were ...evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL
), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL
subgroups.
A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma HR = 0.98; 95% confidence interval (CI), 0.94-1.02 and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL
-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL
paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL
-OS association (multivariate-adjusted CL
HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC).
These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL
with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.
.
Because of the rigid coupling between the upper dentition and the skull, instrumented mouthguards have been shown to be a viable way of measuring head impact kinematics for assisting in understanding ...the underlying biomechanics of concussions. This has led various companies and institutions to further develop instrumented mouthguards. However, their use as a research tool for understanding concussive impacts makes quantification of their accuracy critical, especially given the conflicting results from various recent studies. Here we present a study that uses a pneumatic impactor to deliver impacts characteristic to football to a Hybrid III headform, in order to validate and compare five of the most commonly used instrumented mouthguards. We found that all tested mouthguards gave accurate measurements for the peak angular acceleration, the peak angular velocity, brain injury criteria values (mean average errors < 13, 8, 13%, respectively), and the mouthguards with long enough sampling time windows are suitable for a convolutional neural network-based brain model to calculate the brain strain (mean average errors < 9%). Finally, we found that the accuracy of the measurement varies with the impact locations yet is not sensitive to the impact velocity for the most part.
Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration ...in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately I
max
or exactly e
Imax
− 1), the time to reach I
max
/2 (TI
50
), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of I
max
.
Metal films of nanoscale thickness, deposited on substrates and exposed to laser heating, provide systems that involve several interesting multiphysics effects. In addition to fluid mechanical ...aspects associated with a free boundary setup, other relevant physical effects include phase change, thermal flow, and liquid-solid interactions. Such films are challenging to model, in particular because inertial effects may be relevant, and large contact angles require care when considering the long-wave formulation. Applications of nanoscale metal films are numerous, and the materials science community is actively pursuing more complex setups involving templated films and substrates, bimetallic films and alloys, and a variety of elemental film geometries. The goal of this review is to discuss our current understanding of thin metal film systems, while also providing an overview of the challenges in this research area, which stands at the intersection of fluid mechanics, materials science, and thermal physics.
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