Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.

Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity.

Clinical Benefit-Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors.

Nivolumab 240 mg every 2 weeks is approved in China by the National Medical Product Agency for squamous cell carcinoma of the head and neck and gastric cancer, based on population pharmacokinetic (PPK) analyses and benefit-risk assessment of safety/efficacy in solid tumors, including Chinese and global populations. The aim of this assessment was to investigate exposure and risk for adverse events (AEs) with flat dosing compared with weight-based dosing. Nivolumab 240-mg and 3-mg/kg every-2-week exposures in Chinese patients were simulated using PPK modeling, and AEs in Chinese and pooled global populations were compared by dosing regimen, exposure, and weight.

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.

Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial.

Introduction: Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC.

Methods: CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.

Using Modified RECIST and Alpha-Fetoprotein Levels to Assess Treatment Benefit in Hepatocellular Carcinoma.

Background And Aims: Assessing treatment responses in hepatocellular carcinoma (HCC) is challenging, and alternative radiologic methods of measuring treatment response are required. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC and alpha-fetoprotein (AFP) levels were assessed in a post hoc analysis of a phase II study of brivanib, a selective dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling.

Methods: HCC patients were treated with first-line (cohort A; n = 55) or second-line (cohort B; n = 46) brivanib alaninate 800 mg once daily.

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

Background: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.

Methods: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

Background: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer.

Methods: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA.

Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma.

Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.

Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily.

A 40-week double-blind aripiprazole versus lithium follow-up of a 12-week acute phase study (total 52 weeks) in bipolar I disorder.

Background: This study followed manic or mixed bipolar I subjects for an additional 40 weeks after initial randomization to 12 weeks of lithium versus aripiprazole monotherapy. This is the only long-term, double-blind study comparing lithium and aripiprazole.

Methods: Patients continued receiving either aripiprazole 15 or 30 mg/day, or lithium 900, 1200 or 1500 mg/day in a double-blind fashion for 40 weeks after completing a 12-week double-blind study (52 weeks total treatment).

Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma.

Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has demonstrated encouraging antitumor activity in preclinical and phase I studies. We performed a phase II open-label study of brivanib as first-line therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma.

Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily.

Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study.

Objective: This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.

Methods: Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to lithium or valproate monotherapy could enter a 46-week extension treatment with open-label adjunctive aripiprazole plus lithium (ARI + LI) or valproate (ARI + VAL). Safety, efficacy and functioning were assessed.

Caveolin-1 is critical for the maturation of tumor blood vessels through the regulation of both endothelial tube formation and mural cell recruitment.

In the normal microvasculature, caveolin-1, the structural protein of caveolae, modulates transcytosis and paracellular permeability. Here, we used caveolin-1-deficient mice (Cav(-/-)) to track the potential active roles of caveolin-1 down-modulation in the regulation of vascular permeability and morphogenesis in tumors. In B16 melanoma-bearing Cav(-/-) mice, we found that fibrinogen accumulated in early-stage tumors to a larger extent than in wild-type animals.

Glucocorticoids modulate tumor radiation response through a decrease in tumor oxygen consumption.

Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO(2)) through inhibition of mitochondrial respiration.

Experimental Design: The effect of three glucocorticoids (hydrocortisone, dexamethasone, and prednisolone) on pO(2) was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO(2) (t(max), 30 min after administration), perfusion, oxygen consumption, and radiation sensitivity were studied.

Mechanism of reoxygenation after antiangiogenic therapy using SU5416 and its importance for guiding combined antitumor therapy.

Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor.

Determination of the maturity and functionality of tumor vasculature by MRI: correlation between BOLD-MRI and DCE-MRI using P792 in experimental fibrosarcoma tumors.

Using hypercapnia and carbogen as functional markers of vessel maturation and function, we compared blood oxygen level-dependent (BOLD) contrast with standard dynamic contrast-enhanced (DCE)-MRI quantitative parameters in murine fibrosarcoma. Our results show that there was no correlation between vessel maturity and contrast-agent uptake rate (K(in) (Trans)) or contrast agent efflux rate (k(ep)). In addition, DCE-MRI provided higher estimates of the fraction of functional tumor compared to BOLD-MRI.

Preclinical safety and antitumor efficacy of insulin combined with irradiation.

Background And Purpose: We have previously reported that insulin significantly enhances tumor oxygenation (pO(2)) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials.

Complex relationship between changes in oxygenation status and changes in R*2: the case of insulin and NS-398, two inhibitors of oxygen consumption.

Insulin and NS-398 have been reported to inhibit oxygen consumption in experimental tumor models, thereby increasing oxygenation and radiosensitization. The aim of this work was to use MRI to study changes in murine FSaII tumor hemodynamics after administration of those oxygen consumption inhibitors. A multiple-echo gradient-echo (GRE) MRI sequence (4.

Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery.

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence.

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Purpose: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation.

The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*-weighted GRE signal within tumors.

Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated.

Early reoxygenation in tumors after irradiation: determining factors and consequences for radiotherapy regimens using daily multiple fractions.

Purpose: To characterize changes in the tumor microenvironment early after irradiation and determine the factors responsible for early reoxygenation.

Methods And Materials: Fibrosarcoma type II (FSaII) and hepatocarcinoma transplantable liver tumor tumor oxygenation were determined using electron paramagnetic resonance oximetry and a fiberoptic device. Perfusion was assessed by laser Doppler, dynamic contrast-enhanced MRI, and dye penetration.

Tumor radiosensitization by antiinflammatory drugs: evidence for a new mechanism involving the oxygen effect.

We hypothesized that nonsteroidal antiinflammatory drugs (NSAIDs) might enhance tumor radiosensitivity by increasing tumor oxygenation (pO2), via either a decrease in the recruitment of macrophages or from inhibition of mitochondrial respiration. The effect of four NSAIDs (diclofenac, indomethacin, piroxicam, and NS-398) on pO2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO2 (t(max), 30 minutes after administration), perfusion, oxygen consumption, and radiation sensitivity were studied.

Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment.

Purpose: The aim of this work was to study changes in the tumor microenvironment early after an antiangiogenic treatment using thalidomide (a promising angiogenesis inhibitor in a variety of cancers), with special focus on a possible "normalization" of the tumor vasculature that could be exploited to improve radiotherapy.

Experimental Design: Tumor oxygenation, perfusion, permeability, interstitial fluid pressure (IFP), and radiation sensitivity were studied in an FSAII tumor model. Mice were treated by daily i.

Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia?

T2*-weighted gradient-echo magnetic resonance imaging (T2*-weighted GRE MRI) was used to investigate spontaneous fluctuations in tumour vasculature non-invasively. FSa fibrosarcomas, implanted intramuscularly (i.m.

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications.

This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained.