Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies.

Introduction: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy.

Areas Covered: This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy.

Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study.

Purpose: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab.

Methods: Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m every 3 weeks.

Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.

Background: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.

Methods: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries.

Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study.

Background: The anti-programmed death 1 monoclonal antibody pembrolizumab has shown antitumour activity and is a first-line and second-line treatment option for patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer. We report updated 3-year safety and efficacy outcomes from the phase 1 study, KEYNOTE-001.

Methods: KEYNOTE-001 is a multicohort, open-label, phase 1 study of pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in treatment naive or previously treated patients with locally advanced or metastatic non-small-cell lung cancer with measurable disease at baseline.

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC.

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.

Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.

Background: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.

Methods: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles.

Real-World Treatment Patterns, Overall Survival, and Occurrence and Costs of Adverse Events Associated With Second-Line Therapies for Medicare Patients With Advanced Non-Small-Cell Lung Cancer.

Introduction: Real-world data on current treatment practices for non-small-cell lung cancer (NSCLC) are needed to understand the place in therapy and potential economic impact of newer therapies.

Patients And Methods: This retrospective cohort study identified patients ≥ 65 years old in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with first-time diagnosis of stage IIIB/IV NSCLC from 2007-2011 who received second-line therapy after first-line platinum-based chemotherapy from 2007 through mid-2013. Second-line regimens, health care resource use, adverse events (AEs), and associated costs were analyzed descriptively.

Real-World Treatment Patterns, Overall Survival, and Occurrence and Costs of Adverse Events Associated With First-line Therapies for Medicare Patients 65 Years and Older With Advanced Non-small-cell Lung Cancer: A Retrospective Study.

Purpose: This study sought to better understand real-world treatment patterns, overall and non-small-cell lung cancer (NSCLC)-specific survival, adverse event (AE) occurrence, and economic impact of first-line cancer therapies in Medicare patients.

Patients And Methods: This retrospective cohort study identified patients ≥ 65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database who received a first-time advanced (stage IV) NSCLC diagnosis from 2007 to 2011, and who received first-line platinum-based chemotherapy from 2007 through mid-2013. First-line regimens, healthcare resource use, occurrence of AEs, and associated costs (2013 US dollars) were analyzed.

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial.

Background: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs).

Methods: In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries.

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.

Background: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).

Methods: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression.

Development of a Companion Diagnostic for Pembrolizumab in Non-Small Cell Lung Cancer Using Immunohistochemistry for Programmed Death Ligand-1.

Context .- Programmed death ligand-1 (PD-L1) expression by tumors may enable them to avoid immunosurveillance. Objective .

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.

Background: Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.

Methods: We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries.

Pembrolizumab for the treatment of non-small-cell lung cancer.

Background: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit.

Methods: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients).

Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.

Background: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

Methods: This double-blind, randomised, placebo-controlled trial was done in 90 international centres.

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS.

Thromboembolic events with estramustine phosphate-based chemotherapy in patients with hormone-refractory prostate carcinoma: results of a meta-analysis.

Background: Combinations of cytotoxic chemotherapy with estramustine phosphate (EMP), a nornitrogen mustard-estrogen conjugate, are used to treat patients with hormone-refractory prostate carcinoma (HRPC). However, thromboembolic events (TE), including deep venous thrombosis (DVT), pulmonary embolism, stroke, myocardial infarction, and arterial thrombosis, are significant toxicities of these regimens. The current study sought to establish the rate of TE and to determine risk factors for TE.