Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study.

Background: Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial.

Biomarker analyses from the phase III randomized CLEAR trial: lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.

Background: In CLEAR, lenvatinib + pembrolizumab (L + P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses.

Patients And Methods: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens.

Handgrip Strength and Upper Limb Anthropometric Characteristics among Latin American Female Volleyball Players.

In volleyball, the upper limb dimensions and grip strength greatly influence offensive and defensive movements during a match. However, the relationship between these parameters remains underexplored in elite female volleyball players. This study aimed to contrast the upper limb anthropometric characteristics and handgrip strength (HGS) of female elite volleyball players against a control group.

Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.

Background: Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear.

Patients And Methods: The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen.

Case: A Case of Pembrolizumab Induced Myocarditis and Complete Heart Block.

Use of checkpoint inhibitor pembrolizumab has continued to grow since its approval in 2014. Rare instances of conduction side effects have been described including brady and tachyarrhythmias, heart block and even cardiac arrest. We present a case of Pembrolizumab induced myocarditis and persistent third-degree heart block.

Livestock and environmental characterization of Colombian municipalities: study of vesicular stomatitis.

Amid the surge in data volume generated across various fields of knowledge, there is an increasing necessity for advanced analytical methodologies to effectively process and utilize this information. Particularly in the field of animal health, this approach is pivotal for enhancing disease understanding, surveillance, and management. The main objective of the study was to conduct a comprehensive livestock and environmental characterization of Colombian municipalities and examine their relationship with the distribution of vesicular stomatitis ().

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study.

JCO We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]).

Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.

Background: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented.

A plain language summary exploring a new treatment combination for untreated locally advanced or metastatic urothelial cancer: enfortumab vedotin plus pembrolizumab.

What Is This Summary About?: This summary provides the results of a study of two treatments for cancer, enfortumab vedotin and pembrolizumab, that were studied together against locally advanced or metastatic urothelial cancer (la/mUC), a cancer that occurs most commonly in the bladder.

What Were The Results?: In the 45 patients studied, around 16% did have serious side effects, but most side effects were manageable. Twenty-four percent of patients, however, stopped the study treatment because of their side effects.

Correction: AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK.

[This corrects the article DOI: 10.1371/journal.pcbi.

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK.

PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed.

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study.

Background: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy.

Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study.

Background: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.

Methods: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

Background: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.

Methods: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab).

Anti-CD73 antibody activates human B cells, enhances humoral responses and induces redistribution of B cells in patients with cancer.

Background: CD73 is widely expressed on immune cells playing a critical role in immunomodulatory functions including cell adhesion and migration, as a costimulatory molecule for T cells and in production of adenosine. The function of CD73 expressed on B cells has not been fully characterized. Mupadolimab is an anti-human CD73 antibody that activates B cells.

Cellular and molecular effects of PNCK, a non-canonical kinase target in renal cell carcinoma.

Renal cell carcinoma (RCC) is a fatal disease when advanced. While immunotherapy and tyrosine kinase inhibitor-based combinations are associated with improved survival, the majority of patients eventually succumb to the disease. Through a comprehensive pan-cancer, pan-kinome analysis of the Cancer Genome Atlas (TCGA), pregnancy-upregulated non-ubiquitous calcium-calmodulin-dependent kinase (PNCK), was identified as the most differentially overexpressed kinase in RCC.

Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets.

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer.

Purpose: Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin.

Methods: In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.

Cognitive reserve and its correlates in child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder.

Aim: To analyze cognitive reserve (CR) in child and adolescent offspring of patients diagnosed with schizophrenia (SZ-off) or bipolar disorder (BD-off) and compare them with a group of community controls (CC-off). We also aimed to investigate whether there was an association between CR and clinical and neuropsychological variables according to group.

Methods: The study included 46 SZ-off, 105 BD-off and 102 CC-off.

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

Background: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue.

Methods: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors.

Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738).

A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects.

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

Background: 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.

Methods: 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).