Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed ...death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study.
To evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC.
IMvigor210 enrolled 315 patients with mUC with progression during or following platinum-based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age ≥18 yr, creatinine clearance ≥30ml/min, and Eastern Cooperative Oncology Group performance status 0–1, with no limit on prior lines of treatment.
Patients in this cohort received atezolizumab 1200mg intravenously every 3 wk until loss of clinical benefit.
Centrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing.
Three hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first-line subgroup), ORR was 25% (95% confidence interval: 14–38), and median OS was 9.6 mo (95% confidence interval: 5.9–15.8). No significant differences in efficacy or toxicity by therapy line were observed.
Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated.
We investigated effects of previous treatment in patients with metastatic urothelial carcinoma that progressed after platinum-based therapy. Atezolizumab was active and tolerable no matter how many treatment regimens patients had received. ClinicalTrials.gov, NCT02108652.
Outcomes by prior regimens were examined in a phase 2 atezolizumab study in platinum-treated urothelial carcinoma. Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with metastatic urothelial carcinoma across all lines of therapy evaluated.
"No" is our answer to the question in our title. In moral psychology, a purity violation (defined as an immoral act committed against one's own body or soul) was theorized to be a homogeneous moral ...domain qualitatively distinct from other moral domains. In contrast, we hypothesized heterogeneity rather than homogeneity, overlapping rather than distinct domains, and quantitative rather than qualitative differences from other hypothesized domains (specifically, autonomy, which is harm to others). Purity has been said to consist of norms violations of which elicit disgust and taint the soul. Here we empirically examined homogeneity: whether violations of body (e.g., eating putrid food) belong in the same moral domain as violations of the soul unrelated to bodily health (e.g., selling one's soul, desecrating sacred books). We examined distinctness: whether reactions to purity violations differ in predicted ways from those to violations of autonomy. In four studies (the last preregistered), American Internet users (in Studies 2 and 4, classified as politically conservative or liberal; Ns = 80, 96, 1,312, 376) were given stories about violations based on prior studies. Nonhealth purity violations were rated as relatively more disgusting, but less gross (the lay term for the reaction to putrid things) and more likely to taint the soul than were health-related ones. Surprisingly, both health and nonhealth purity violations were typically judged as only slightly immoral if at all. Autonomy violations were rated as more disgusting and tainting of the soul than were purity violations.
Abstract Background Sorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials. Sorafenib and bevacizumab combination has shown manageable toxicity ...in phase I trials in solid tumours. The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours. Methods Open-label, uncontrolled, multicenter, phase II clinical trial. Eligibility criteria: age ⩾ 18 years, histologically confirmed measurable advanced NETs; 1 prior chemotherapy allowed; ECOG-PS 0–2. Patients were treated during 6 months and followed up for an additional 6 months. Treatment: sorafenib 200 mg bid (days 1–5 of each week) and bevacizumab 5 mg/kg once every 2 weeks (day 1, week 1). Tumour response was performed according to RECIST (v1.0) every 2 months during the treatment period. Adverse events were graded according to CTCAE (v3.0). Findings 44 Patients enrolled, 59.1% men, median age 60 years (range 32–76). 70.5% carcinoid tumours, 29.5% pancreatic tumour. Baseline target lesions mainly in the liver (86.4%). Global PFSR was 90.9% (91.7% carcinoid tumours and 88.9% pancreatic tumours). Median PFS was 12.4 months, median TTP was 14.5 months, ORR was 9.4% and DCR was 95.1%. Most common grade 3–4 toxicities: asthenia (11.4%) and hand–foot skin reaction (15.9%). Interpretation Sorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy. Further development of this combination is not warranted and a sequential approach is recommended instead.
Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate ...to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease.
•Several therapeutic strategies with CPIs are being developed in first-line mUC.•The JAVELIN Bladder 100 approach aimed to prolong the benefit of first-line CT.•Avelumab maintenance after non-progression to platinum-based CT increases OS in mUC.•CPI monotherapy may be an option for selected patients no candidates for upfront CT.•Avelumab maintenance is a first paradigm shift in the management of mUC in 20 years.
Purpose
Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment of metastatic urothelial carcinoma (mUC) upon platinum-based chemotherapy according to the positive results of ...large clinical trials. Nevertheless, results from unselected populations reflecting real-world data (RWD) are highly informative to the clinician. We reviewed daily clinical practice outcomes in patients with mUC who received atezolizumab in our institution.
Methods
Here we evaluated the clinical activity and safety of atezolizumab in an unselected population of mUC patients who received atezolizumab between 2018 and 2022 reflecting RWD. Efficacy and safety information were retrospectively collected.
Results
A total of 63 patients were included. The mean age was 68 years and the objective response rate was 14.3%. The median progression-free survival was 3 months and the median overall survival 6 months. At 1 year, 42% of the patients were alive. ECOG (0 vs 1) and neutrophil–lymphocytes ratio < 2 at the start of ICI were positive prognostic factors that discriminated between long vs short survivors. Overall tolerance was good with no new safety signals. Five patients (17%) had treatment-related adverse events grade ≥ 2 that required corticosteroids.
Conclusion
In this retrospective study, atezolizumab was an effective and tolerable treatment option for patients with mUC after progression to platinum-based chemotherapy. Yet, patient selection remains critical to improve outcomes.
We report the synthesis and structural diversity of Zn(II) metal-organic framework (MOF) with in situ formation of tetrazole ligand 3-ptz 3-ptz = 5-(3-pyridyl)tetrazolate as a function pH. By ...varying the initial reaction pH, we obtain high-quality crystals of the noncentrosymmetric three-dimensional MOF Zn(3-ptz)2 , mixed phases involving the zinc-aqua complex Zn(H2O)4(3-ptz)2·4H2O, and two-dimensional MOF crystals Zn(OH)(3-ptz) with a tunable microrod morphology, keeping reaction time, temperature, and metal–ligand molar ratio constant. Structures are characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and UV–vis spectroscopy. We discuss the observed structural diversity in terms of the relative abundance of hydroxo-zinc species in solution for different values of pH.
We describe the structure and properties of Zn(C6H4N5)N3 n , a new nonporous three-dimensional high-energy metal–organic framework (HE-MOF) with enhanced thermal stability. The compound is ...synthesized by the hydrothermal method with in situ ligand formation under controlled pH and characterized using single-crystal X-ray diffraction, elemental analysis, and Fourier transform infrared. The measured detonation temperature (T det = 345 °C) and heat of detonation (ΔH det = −0.380 kcal/g) compare well with commercial explosives and other nitrogen-rich HE-MOFs. The velocity and pressure of denotation are 5.96 km/s and 9.56 GPa, respectively. Differential scanning calorimetry analysis shows that the denotation of Zn(C6H4N5)N3 n occurs via a complex temperature-dependent mechanism.
► Online SPE–HPLC–MS/MS method for three antitumor drugs in a combined anticancer therapy. ► Harmonized sample treatment for plasma and whole blood samples. ► Analytical method validated. ► Real ...samples of plasma and blood from patients under oncologic therapy were measured and results are included.
Docetaxel and temsirolimus are some of the most used drugs in a wide range of solid tumors. In preclinical studies, mTOR inhibitors such as temsirolimus have demonstrated synergistic cytotoxic effects with taxanes providing the rationale for combination studies. These anticancer agents exhibit a narrow therapeutic concentration range and due to their high inter- and intra-individual pharmacokinetic variability, therapeutic dose monitoring by highly sensitive methods as LC–MS/MS are important for clinical research. Therefore, the aim of this study was to develop and validate a sensitive, fast and convenient method for the simultaneous identification and quantification of docetaxel, temsirolimus and its main metabolite, sirolimus, using paclitaxel, another anticancer drug, as the internal standard. These analytes were quantified by an integrated online solid phase extraction–high performance liquid chromatography–tandem mass spectrometry (SPE–HPLC–MS/MS) system. Separation was performed on a Zorbax eclipse XDB-C8 (150mm×4.6mm, 5μm) column. The mass spectrometer tandem quadruple detector was equipped with jet stream electrospray ionization, monitored in multiple reactions monitoring (MRM) and operated in positive mode. A combination of protein precipitation with methanol/zinc sulphate (70:30) (v/v) and online SPE using a Zorbax eclipse plus C8 (12.5mm×4.6mm, 5μm) cartridge was used to extract the compounds. This method allows the use of the same reagents, sample treatment and analytical technique independently of whether the samples are whole blood or plasma. The method has been successfully validated and applied to real samples. It is a suitable method for dose adjustment and for evaluating potential drug interactions during combined treatments.
Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and ...high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 PD-L1) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. Methods For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov , number NCT02108652. Findings Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 30% patients), diarrhoea (14 12% patients), and pruritus (13 11% patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. Funding F Hoffmann-La Roche, Genentech.
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