Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody–drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently ...linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score = −0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %), and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer.
Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score.
Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, −3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease.
A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
•TOT-HER3 trial showed antitumor activity of pre-operative HER3-DXd in HR+/HER2-negative early breast cancer.•HER3-DXd increased immune infiltration, suppressed proliferation, and switched tumors to a less proliferative phenotype.•HER3-DXd showed clinical and biological activity independently of baseline ERBB3 mRNA and HER3 protein levels.•These results encouraged investigation of HER3-DXd as potential neoadjuvant treatment in the ongoing SOLTI-VALENTINE trial.
•Post-impact damage propagation in tension in woven carbon/epoxy laminates is studied.•The monitoring of damages is based on Digital Image Correlation and RX Tomography.•The propagation of cracks is ...governed by the resin damages and by delamination.•A FEM based on Semi-Continuous strategy is developed to represent these propagations.•This new modelling strategy well represent the damage initiation and propagation.
This article concerns the experimental and numerical study of post-impact damage propagation in thin carbon/epoxy woven composite laminates loaded in fatigue tension. Low velocity normal drop weight impact tests are first performed. Post-impact fatigue tensile tests are then carried out. They are controlled in displacement. The monitoring is based on Digital Image Correlation and RX tomography. The influence of the impact energy and the tensile fatigue loading on the post-impact damage propagation is studied. The damage propagation is governed by matrix damage, with the emergence of tows/resin splittings and intra-tows crackings as well as delamination when the plies have different orientations. When the impact energy or the displacement level increases, the post-impact damage initiates sooner and propagate faster. In some cases, that can lead to a quasi-instantaneous failure identical to that observed for quasi-static tensile loading. The FEM based semi-continuous approach, initialy developped for the modelling of impact damage, is extended to fatigue loading for carbon/epoxy woven laminates. Fatigue damage laws, based on experimental observations are implemented. The modelling well correlates the experimental results in terms of damage propagation scenario and speed depending on the number of cycles for laminates made up of plies with the same orientation.
An explicit finite element modeling of the 5-harness satin woven composite material is proposed in this paper. It is based on the semi-continuous approach. The bundles are modeled with rod elements ...and a specific damageable shell element is used to stabilize this truss structure. As the woven pattern geometry plays a key role in damage initiation and propagation, the rods located at the crimp regions where warp and weft yarns cross each other have been offset to represent the bundles undulations. The main objective of the presented modeling strategy is to represent local bending stiffness variations and damage initiation at the crimp regions without using artificial parameters, but only geometric and material parameters.
The method has been implemented into the explicit finite element code RADIOSS. The modeling strategy is validated by representing a three-point bending test and a drop weight test. It provides good prediction for the local bending stiffness, the impact force history and the damage size and shape. The strain concentration at the crimp regions is well represented.
Background: Platinum-based chemotherapy is standard second-line treatment of patients with advanced ovarian cancer (AOC) in late relapse. Pegylated liposomal doxorubicin (PLD) has significant ...single-agent activity in this setting. Therefore, we evaluated the use of PLD plus carboplatin in this patient population.
Patients and methods: PLD 30 mg/m2 followed by carboplatin at area under the curve (AUC) 5 mg·min/ml, repeated every 28 days for a maximum of nine cycles, was administered to 104 women with AOC relapsing ≥6 months after completion of first- or second-line therapy with platinum-taxane-based regimens.
Results: Overall response was 63%, with a 38% complete response, median progression-free survival of 9.4 months, and median overall survival (OS) of 32 months. Grade 3 or 4 neutropenia occurred in 51% of patients, but febrile neutropenia in only 3%. Nonhematologic toxic effects were primarily grades 1 and 2, with low rates of alopecia and neurotoxicity.
Conclusions: PLD plus carboplatin is highly effective, prolongs OS, and is well tolerated in women with AOC in late relapse previously treated with both platinum and taxanes. Evaluation of this regimen in phase III trials is warranted.
This article concerns the study of post-impact damage propagation in two thin hybrid woven composite laminates loaded in tension. Low velocity normal drop weight impact tests are first performed. ...Post-impact quasi-static tensile tests are then carried out and monitored by Digital Image Correlation. The influence of the impact energy variation on the fracture surfaces and the residual strength is studied. In order o have a better understanding of the mechanisms involved into the hybrid laminates, four monomaterial sample configurations are also tested. When the damage after impact is barely visible, the sample behaves as a non-impacted sample. When the damage is visible, it propagates whatever the impact energy. The damage grows in the direction perpendicular to the loading for all the monomaterial laminates while two different damage scenarios are observed for the hybrid laminates. The residual strength evolves in three steps depending on the impact energy: first a very low decrease, then an important drop and finally a plateau.
This article concerns the modelling of post-impact damage propagation in thin woven composite laminates. Simulations of low velocity impacts and post-impact quasi-static tension are performed on ...single-material and hybrid laminates. The modelling is based on the semi-continuous approach implemented into the explicit finite element code RADIOSS. The bundles are modelled with rod elements and a specific damageable shell element is used to stabilize this truss structure. Improvements are brought with the introduction of a compressive failure criterion for the rod elements and the development of a pseudo-plastic law with damaging for in in-plane shear. The results provided by the modelling well correlates the experimental observations in terms of damage propagation and load-displacement curves for all the configurations studied.
This paper focuses on the study of interlaminar fracture of composite materials in mode III using the Modified Split Cantilever Beam (MSCB) test. MSCB test is applied to investigate the dependency of ...the mode III energy release rate on geometric parameters (specimen width, and thickness), initial crack length, loading condition and crack front material layup. A non perforated release film is introduced to create delamination at the mid-plane of the tested specimens. Three sets of samples (a total of 56 samples) are fabricated and tested from Unidirectional Glass fibers. The length of the specimens is 154 mm. The first set of tests is conducted for three different widths (35 mm, 20 mm, 12 mm) to select the most appropriate width that leads to a crack initiation prior to specimen failure. The remaining sets of tests are conducted with different loading conditions, different thickness, different initial crack length, and different lay up orientations at the crack front (0/0, +45/−45, 0/45, and 0/90). Results show that both width selection and load configuration are of extreme importance for the success of the test. The energy release rate (GIIIc) increases with increasing thickness and width. The stacking orientation at the crack front shows minor influence on GIIIc.
This paper deals with static indentation of sandwich beams with a foam core. An analytical model is presented assuming that the specific response of foams in compression can be assimilated to an ...elastic–perfectly plastic behavior. The elastic part is represented using Vlasov’s model. The displacements and stress calculated with this two parameters model are compared with results given by Winkler’s theory and Finite Element Method. Vlasov’s idealization gives more accurate results that Winkler’s model. A complete study of the influence of the parameters of Vlasov’s model is performed. Then, plasticity is added to the model to represent the non-linear response of the core. The load–displacement response of sandwich beams under static indentation is calculated and compared to experimental and Finite Element results. A good correlation is found. The size of the area where the foam is crushed given by the developed model is in good agreement with Finite Element analysis.
The purpose of this study is to evaluate and compare the ability of various composite structures to dissipate the energy generated during a crash. To this end, circular composite tubes were tested in ...compression in order to identify their behavior and determine their absorbing capabilities using the specific energy absorption (energy absorbed per unit weight). Several composite tubular structures with different materials and architectures were tested, including hybrid composition of carbon–aramid and hybrid configuration of 0/90 UD with woven or braided fabric. Several inventive and experimental trigger systems have been tested to try and enhance the absorption capabilities of the tested structures. Specific energy absorption values up to 140 kJ.kg−1 were obtained, achieving better than most instances from the literature, reaching around 80 kJ.kg−1. Specimens with 0°-oriented fibers coincidental with the direction of compression reached the highest specific energy absorption values while those with no fiber oriented in this direction performed poorly. Moreover, it has consequently been established that in quasi-static loading, a unidirectional laminate oriented at 0° and stabilized by woven plies strongly meets the expectations in terms of energy dissipation. Incidentally, an inner constrained containment is more effective in most cases, reducing the initial peak load without drastically reducing the specific energy absorption value.
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