Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
In this ...phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell ...carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
The median overall survival was 25.0 months (95% confidence interval CI, 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 95% CI, 3.68 to 9.72; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
We present a simple representation of the hydrodynamic Green functions grounded on the free propagation of a vector field without any constraints (such as incompressibility) coupled with a gradient ...gauge in order to enforce these constraints. This approach involves the solution of two scalar problems: a couple of Poisson equations in the case of the Stokes regime, and a system of diffusion/Poisson equations for unsteady Stokes flows. The explicit and closed-form expression of the Green function for unsteady Stokes flow is developed. The relevance of this approach resides in its conceptual simplicity and it enables us to focus on the intrinsic singularities (Stokesian paradoxes) associated with the propagation of the stresses in incompressible flows under unsteady Stokes conditions, determining the occurrence of power-law tails in the velocity profile arbitrarily far away from the location of the impulsive force.
Abstract Background The randomized, phase 3 CheckMate 025 study of nivolumab ( n = 410) versus everolimus ( n = 411) in previously treated adults (75% male; 88% white) with advanced renal cell ...carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Design, setting, and participants Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention Nivolumab 3 mg/kg every 2 wk or everolimus 10 mg once daily. Results and limitations The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32–0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. Conclusion The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. Patient summary We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.
This article develops a modal expansion (in terms of functions exponentially decaying with time) of the force acting on a micrometric particle and stemming from fluid inertial effects (usually ...referred to as the Basset force) deriving from the application of the time-dependent Stokes equation to model fluid–particle interactions. One of the main results is that viscoelastic effects induce the regularization of the inertial memory kernels at t=0, eliminating the 1/t-singularity characterizing Newtonian fluids. The physical origin of this regularization stems from the finite propagation velocity of the internal shear stresses characterizing viscoelastic constitutive equations. The analytical expression for the fluid inertial kernel is derived for a Maxwell fluid, and a general method is proposed to obtain accurate approximations of it for generic complex viscoelastic fluids, characterized by a spectrum of relaxation times.
The equivalence between parabolic transport equations for solute concentrations and stochastic dynamics for solute particle motion represents one of the most fertile correspondences in statistical ...physics originating from the work by Einstein on Brownian motion. In this article, we analyze the problems and the peculiarities of the stochastic equations of motion in microfluidic confined systems. The presence of solid boundaries leads to tensorial hydrodynamic coefficients (hydrodynamic resistance matrix) that depend also on the particle position. Singularity issues, originating from the non-integrable divergence of the entries of the resistance matrix near a solid no-slip boundary, determine some mass-transport paradoxes whenever surface phenomena, such as surface chemical reactions at the walls, are considered. These problems can be overcome by considering the occurrence of non vanishing slippage. Added-mass effects and the influence of fluid inertia in confined geometries are also briefly addressed.
This paper develops the bitensorial formulation of the system of singularities associated with unbounded and bounded Stokes flows. The motivation for this extension is that Stokesian singularities ...and hydrodynamic fundamental solutions are multi-point functions, and bitensor calculus provides either the proper geometrical setting, in order to avoid inconsistencies and misunderstandings on the role of the different tensorial indices, or a way for compactly deriving hydrodynamic properties. A first relevant result is to provide a clear definition of the singularities (both bounded and unbounded) in Stokes flow, specifying the associated differential equations and boundary conditions. Using this formalism for bounded flows, we show the existence of an integro-differential operator providing the whole system of hydrodynamic singularities by acting on the unbounded Green function (Stokeslet) at its pole and we derive its explicit representation in terms of moments. In the case of an immersed body in a unbounded fluid, we show that, the operator furnishing the disturbance field of a purely $ n $-th order ambient flow, is a generalized $ n $-th order Faxén operator, i.e., it yields the $ n $-th moment on the body if applied to a generic ambient flow, and that a generic disturbance field can be expressed by a summation of the generalized $ n $-th order Faxén operators. Furthermore, we find that the operator providing the disturbance of an ambient flow coincides with the reflection operator for the Stokes solutions in the same flow geometry. We apply this result to the paradigmatic case of fundamental singularities for the Stokes flow bounded by a plane. In this way, we obtain in an alternative and easy way the image system for the Sourcelet and the Rotlet (already derived in the literature) and for the Source Doublet and the Strainlet (presented here for the first time).
Background Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all ...mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration CESC IOV 2023-78. Keywords: Metastatic renal cell carcinoma, Immunotherapy, Immune checkpoint inhibitor, Clinical practice, Real-world, IMDC score, Meet-URO score, Prospective, Retrospective
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