Comparative Safety Assessment of High and Low Doses of Anlotinib in Combination with PD-1 Monoclonal Antibody for Advanced Non-small Cell Lung Cancer Patients.

Background: The advent of immunotherapy has revolutionized non-small cell lung cancer (NSCLC) treatment. Anlotinib (AN), a multitargeted tyrosine kinase inhibitor, holds promise in combination with PD-1 monoclonal antibody therapy. Understanding the impact of optimal dosage is pivotal. Objective: This study aims to assess the comparative efficacy of high-dose AN versus low-dose AN when combined with PD-1 monoclonal antibody for the treatment of NSCLC. Methods: A total of 70 patients with NSCLC undergoing PD-1 monoclonal antibody therapy at our hospital from June 2020 to January 2022 were selected. The low-dose group (n=33) received AN at 8 mg and 10 mg. In comparison, the high-dose group (n=37) received AN at 12 mg. Comparative analyses included assessment of clinical efficacy, adverse reactions, prognosis, survival, changes in T lymphocyte subsets, inflammatory factors pre and post-chemotherapy, and treatment satisfaction. Results: No significant difference was observed in clinical efficacy and prognosis between the two groups (P > .05). The low-dose group exhibited fewer adverse reactions and inflammatory responses, along with improved immune function post-treatment (P < .05). Treatment satisfaction was higher in the low-dose group compared to the high-dose group (P < .05). Conclusions: Findings suggest that combining low-dose AN with PD-1 monoclonal antibody therapy is a safer approach in the treatment of advanced NSCLC. These findings advocate for the adoption of a tailored, lower-dose AN regimen, presenting a clinically sound and patient-centered strategy in the ongoing pursuit of optimized treatment modalities for advanced NSCLC.

Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae?

To date, more than 100 million people worldwide have recovered from COVID-19. Unfortunately, although the virus is eradicated in such patients, fibrotic irreversible interstitial lung disease (pulmonary fibrosis, PF) is clinically evident. Given the vast numbers of individuals affected, it is urgent to design a strategy to prevent a second wave of late mortality associated with COVID-19 PF as a long-term consequence of such a devastating pandemic. Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

BACKGROUND AND AIMS: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.

Chitosan coated synergistically engineered nanoemulsion of Ropinirole and nigella oil in the management of Parkinson's disease: Formulation perspective and In vitro and In vivo assessment.

The research presented aims at developing Ropinirole hydrochloride (RHCl) nanoemulsion (NE) with nigella oil for Parkinson's disease (PD). In silico study was done to explore interactions of ropinirole and thymoquinone at receptor site (TNF-α and NFK-ß). Ropinirole and Thymoquinone forms a hydrogen bond with residue Arginine 201 and residue Arginine 253 with a bond length of 1.89 Å and 2.30 Å at the NF-κß receptor. NE was optimized using Central Composite Rotatable Design (CCRD). The globule size of chitosan coated NE, Polydispersity index (PDI) and zeta potential were 183.7 ± 5.2 nm, 0.263 ± 0.005, and 24.9 mV respectively. NE exhibited 85.28% transmittance showing the formulation was clear and transparent. TEM showed that NE had spherical globules with no aggregation. The formulation had a stable pH value of 5.8 ± 0.18. In vitro release and permeation studies exhibited 2 folds and 3.4 folds enhancement when compared with the drug suspension. Neurobehavioral activity and biochemical parameters corroborated well with the pharmacokinetic results. Histopathological study and immunohistochemical analysis were performed to get better picture of 6-OHDA induced toxicity and reversal of PD symptoms. Thus, the NE tailored is a promising synergistic approach yielding enticing outcomes for better management of PD related symptoms.

Assessment of transporter-mediated efflux of nintedanib using in vitro cell line models of idiopathic pulmonary fibrosis.

Objective: We aimed to investigate the involvement of efflux transporters, including multidrug resistant protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), MRP2, and breast cancer resistance protein (BCRP), in the intracellular accumulation of the antifibrotic agent nintedanib in fibrotic lung cells. Methods: We used transforming growth factor-ß1 (TGF-ß1)-treated human lung fibroblasts (WI-38) and alveolar epithelial cells (A549) as in vitro models. The expression and activities of efflux transporters in TGF-ß1-treated WI-38 and A549 cells were evaluated using immunoblotting and flow cytometry. Cells were treated with nintedanib and then incubated with inhibitors of these transporters. The intracellular concentration of nintedanib was determined. Results: MDR1, MRP1, MRP2, and BCRP were found to be expressed in WI-38 and A549 cells with or without TGF-ß1 stimulation, with the exception of MRP2 in WI-38 cells. The efflux activities of these transporters were observed in these cells. MDR1 inhibitors significantly increased the intracellular accumulation of nintedanib, whereas MRP inhibitors did not show an effect. The BCRP inhibitor significantly increased the transporter activity in A549 cells but not in WI-38 cells. Conclusion: This study suggests that the efflux via MDR1 and BCRP is involved in the intracellular accumulation of nintedanib in fibrotic lung cells.

Identification and characterization of novel metabolites of nintedanib by ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry with in silico toxicological assessment.

RATIONALE: Nintedanib, an oral, triple angiokinase inhibitor, is used alongside docetaxel in the management of locally recurrent non-small-cell lung cancer and idiopathic pulmonary fibrosis. The present study deals with the identification and characterization of in vitro and in vivo stable and reactive (if any) metabolites of nintedanib and sheds light on some novel metabolites of the drug which have not been reported previously. METHODS: The study involved an oral administration of the drug to male Wistar rats, followed by collection of the biological matrices (urine, plasma and feces) at specific intervals for determination of in vivo metabolites. In addition, in vitro studies were performed on human and rat liver microsomes in the presence of appropriate co-factors. The samples were subjected to protein precipitation and nitrogen evaporation prior to ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry analysis. The toxicities of all the metabolites were assessed in silico, employing ADMET Predictor™. RESULTS: A total of 18 metabolites of nintedanib were identified in all the matrices, of which nine were found to be novel and unreported previously. The unreported metabolites were elucidated as oxidative, demethylated and glucuronide conjugates of nintedanib. Interestingly, acetonitrile adducts of a few metabolites (low concentration) were also observed. No reactive metabolites were observed in this study. CONCLUSIONS: Characterization of hitherto unknown in vitro and in vivo metabolites of nintedanib adds to the existing knowledge on the metabolism of the drug. Identification on the basis of the solvated adducts can be a useful approach for characterization of minor metabolites, which remain undetected owing to sensitivity issues.

Real world experience of poly (ADP-ribose) polymerase inhibitor use in a community oncology practice.

OBJECTIVE: This study aims to describe the real-world experience, including the clinical and financial burden, associated with PARP inhibitors in a large community oncology practice. METHODS: Retrospective chart review identified patients prescribed olaparib, niraparib or rucaparib for maintenance therapy or treatment of recurrent ovarian, primary peritoneal or fallopian tube cancer across twelve gynecologic oncologists between December 2016 and November 2018. Demographic, financial and clinical data were extracted. One PARP cycle was defined as a single 28-day period. For patients treated with more than one PARPi, each course was described separately. RESULTS: A total of 47 patients and 506 PARP cycles were identified (122 olaparib, 24%; 89 rucaparib, 18%; 294 niraparib, 58%). Incidence of grade ≥ 3 adverse events were similar to previously reported. Toxicity resulted in dose interruption, reduction and discontinuation in 69%, 63% and 29% respectively. Dose interruptions were most frequent for niraparib but resulted in fewer discontinuations (p-value 0.01). Mean duration of use was 7.46 cycles (olaparib 10.52, rucaparib 4.68, niraparib 7.34). Average cost of PARPi therapy was $8018 per cycle. A total of 711 phone calls were documented (call rate 1.4 calls/cycle) with the highest call volume required for care coordination, lab results and toxicity management. CONCLUSIONS: Although the toxicity profile was similar to randomized clinical trials, this real-world experience demonstrated more dose modifications and discontinuations for toxicity management than previously reported. Furthermore, the clinical and financial burden of PARP inhibitors may be significant and future studies should assess the impact on patient outcomes.

Interactions between opioids and cannabinoids: Economic demand for opioid/cannabinoid mixtures.

BACKGROUND: Opioid abuse remains a significant public health challenge. With continuing emergence of novel psychoactive substances (e.g., synthetic cannabinoids found in "K2" or "spice" preparations), the co-administration of opioids and other novel drugs is likely to become more prevalent, which might increase the risk for abuse and other adverse effects. This study examined whether the synthetic cannabinoid receptor agonist JWH-018 alters the reinforcing effectiveness of the mu opioid receptor agonist remifentanil in rhesus monkeys (n = 4) using economic demand analyses. METHODS: Lever presses delivered intravenous infusions of a drug or drug mixture according to a fixed-ratio schedule. For each condition, the ratio progressively increased in quarter-log unit steps across sessions yielding a demand curve: consumption (infusions obtained) was plotted as a function of price (fixed-ratio value). RESULTS: When available alone, remifentanil (0.00032 mg/kg/infusion) occasioned the highest consumption at the lowest cost and highest essential value, while JWH-018 (0.0032 mg/kg/infusion) alone occasioned lower unconstrained demand and essential value. Unconstrained demand for a mixture of remifentanil and JWH-018 was lower than for remifentanil alone, but essential value of the mixture was not significantly different from that of remifentanil alone. CONCLUSION: These data indicate that synthetic cannabinoids such as JWH-018 might alter some aspects of opioid self-administration (i.e., decreased consumption at the lowest price) but do not enhance reinforcing effectiveness as measured by sensitivity of consumption to increasing costs. Opioid/cannabinoid mixtures do not appear to have greater or lesser abuse potential compared with opioids alone.

Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

Cost-Effectiveness of Niraparib Versus Routine Surveillance, Olaparib and Rucaparib for the Maintenance Treatment of Patients with Ovarian Cancer in the United States.

OBJECTIVES: The aim was to evaluate the cost-effectiveness of niraparib compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer (OC). METHODS: A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS, olaparib, and rucaparib from a US payer perspective. The model considered recurrent OC patients with or without germline BRCA mutations (gBRCAmut and non-gBRCAmut), who were responsive to their last platinum-based chemotherapy regimen. Model health states were: progression-free disease, progressed disease and dead. Mean progression-free survival (PFS) was estimated using parametric survival distributions based on ENGOT-OV16/NOVA (niraparib phase III trial), ARIEL3 (rucaparib phase III trial) and Study 19 (olaparib phase II trial). Mean overall survival (OS) benefit was estimated as double the mean PFS benefit based on the relationship between PFS and OS observed in Study 19. Costs included: drug, chemotherapy, monitoring, adverse events, and terminal care. EQ-5D utilities were estimated from trial data. RESULTS: Compared to RS, niraparib was associated with an incremental cost-effectiveness ratio (ICER) of US$68,287/QALY and US$108,287/QALY for gBRCAmut and non-gBRCAmut, respectively. Compared to olaparib and rucaparib, niraparib decreased costs and increased QALYs, with a cost saving of US$8799 and US$22,236 versus olaparib and US$198,708 and US$73,561 versus rucaparib for gBRCAmut and non-gBRCAmut, respectively. CONCLUSIONS: Niraparib was estimated to be less costly and more effective compared to olaparib and rucaparib, and the ICER fell within an acceptable range compared to RS. Therefore, niraparib may be considered a cost-effective maintenance treatment for patients with recurrent OC.

Assessment of PKA and PKC inhibitors on force and kinetics of non-failing and failing human myocardium.

AIMS: Heart failure (HF) is a prevalent disease that is considered the foremost reason for hospitalization in the United States. Most protein kinases (PK) are activated in heart disease and their inhibition has been shown to improve cardiac function in both animal and human studies. However, little is known about the direct impact of PKA and PKC inhibitors on human cardiac contractile function. MATERIAL AND METHODS: We investigated the ex vivo effect of such inhibitors on force as well as on kinetics of left ventricular (LV) trabeculae dissected from non-failing and failing human hearts. In these experiments, we applied 0.5 µM of H-89 and GF109203X, which are PKA and PKC inhibitors, respectively, in comparison to their vehicle DMSO (0.05%). KEY FINDINGS AND CONCLUSION: Statistical analyses revealed no significant effect for H-89 and GF109203X on either contractile force or kinetics parameters of both non-failing and failing muscles even though they were used at a concentration higher than the reported IC50s and Kis. Therefore, several factors such as selectivity, concentration, and treatment time, which are related to these PK inhibitors according to previous studies require further exploration.

[Hygienic assessment of indoles in the diet of medical students].

A number of studies have shown the relationship between the regular consumption of cruciferous vegetables and the risk of malignant tumors in certain localizations, the activation of mechanisms of alimentary adaptation of the organism under conditions of alien loads, by inducing enzymes of the biotransformation system of xenobiotics. The cruciferous vegetables are distinguished by the presence of minor components, such as indole-3-carbinol, formed during the hydrolysis of glucosinolates. The aim of the investigation was a retrospective study of the content of indoles in students' diet with subsequent quantitative analysis in different comparison groups. The study involved 250 students from a medical university aged 21 to 27 years. To assess the actual nutrition, the developed questionnaires were used, which included the most common products in the Moscow region, sources of indole glucosinolates. It was found that 44% of the respondents didn't include cruciferous vegetables in the diet, and of those who consumed sources of indoles (56% of respondents), only about half received them in the recommended amount. It should also be noted that as in men, in women the most commonly used in the diet product as a source of indoles was cabbage, it was included in the diet of 68% of the respondents who used cruciferous vegetables, rarely pekin cabbage was used (16.3%) and broccoli (16.3%). Cauliflower, radishes, Kale and horseradish was included in the diet of 7.8-14.9% of the students. Less often turnip was consumed - only by 2.1% of the students. No significant differences in the consumption of indoles in the student with deficient, normal or overweight was revealed. Also, there was no correlation between excess weight and the consumption of various indoles sources. The obtained results testify to the extremely low level of alimentary intake of indole-3-carbinol.

Analysis of survival of patients treated with vemurafenib, ipilimumab and dabrafenib for advanced skin melanoma in daily clinical practice (Real-World Data): retrospective analysis of patients treated under drug/reimbursement programmes in Poland in 2013-2016.

Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of advanced skin melanoma pursuant to the results of randomized phase III clinical trials. Real-world data on survival time for patients treated with those drugs in daily clinical practice are so far limited. Patients with advanced skin melanoma treated under reimbursement programmes (drug programmes), for which they were qualified pursuant to uniform inclusion criteria in force in all oncology centres in Poland. Data were obtained from the electronic databases of the national payer (NFZ) responsible for the implementation and monitoring of reimbursement (drug) programmes. The analysis included all patients included for treatment with vemurafenib (since March of 2013), ipilimumab (since March of 2014) and dabrafenib (since July of 2015) until December 2016. The end date of the observation was set to 31 December 2016. The total survival analysis was performed using the Kaplan-Meier estimator. Until 31 December 2016, 759 patients were treated with vemurafenib, 370 with ipilimumab and 181 with dabrafenib. The overall survival (OS) median was 9.8 months for patients treated with vemurafenib (95% confidence interval: 8.8-10.6) and 6.9 months for patients treated with ipilimumab (95% confidence interval: 5.7-9.2). For patients treated with dabrafenib, the OS median was not reached because of an overly short observation period. The probability of surviving 12 months in the group of patients treated with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The probability of surviving 24 and 36 months in the group of patients treated with vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS of patients with advanced melanoma treated in daily clinical practice may be comparable to the ones achieved in registration trials. The use of appropriate treatment inclusion criteria may affect the obtained OS.

Clinical and Economic Outcomes in Elderly Advanced Renal Cell Carcinoma Patients Starting Pazopanib or Sunitinib Treatment: A Retrospective Medicare Claims Analysis.

INTRODUCTION: Studies indicate similar survival and toxicity between pazopanib and sunitinib, but few have examined real-world outcomes among elderly patients with advanced renal cell carcinoma (RCC). The purpose of this retrospective claims analysis was to assess real-world overall survival (OS), healthcare resource utilization (HRU), and healthcare costs (both all-cause and associated with RCC diagnosis) among elderly advanced RCC patients starting pazopanib or sunitinib treatment. METHODS: Advanced RCC patients aged 65 years or older who started first-line treatment with pazopanib or sunitinib (index drug; the initiation date was the index date) were identified from the 100% Medicare database plus Part D linkage (January 1, 2006 to December 31, 2014). Patients were stratified by index drug and matched 1:1 with use of propensity scores based on baseline characteristics. OS was assessed from the index date to death and compared by Kaplan-Meier analyses and univariable Cox models; patients were censored at the end of eligibility/data. Monthly HRU and costs from an intent-to-treat perspective were compared by Wilcoxon signed-rank tests. RESULTS: Baseline characteristics were balanced after matching (both N = 522). Treatment with pazopanib was associated with significantly longer median OS compared with treatment with sunitinib (18.2 months vs 14.6 months, respectively; log-rank p = 0.015). Pazopanib was associated with significantly lower monthly all-cause costs compared with sunitinib ($8845 vs $10,416, respectively), as well as lower inpatient costs associated with RCC diagnosis ($1542 vs $2522), fewer monthly inpatient admissions (0.179 vs 0.262), and shorter length of inpatient stay (1.375 days vs 1.883 days; all p ≤ 0.004). CONCLUSIONS: Among elderly Medicare patients with advanced RCC, first-line pazopanib tretament was associated with significantly longer OS, as well as lower healthcare costs and HRU, compared with first-line sunitinib treatment.

Treatment-free interval as a metric of patient experience and a health outcome of value for advanced multiple myeloma: the case for the histone deacetylase inhibitor panobinostat, a next-generation novel agent.

BACKGROUND: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions. METHODS: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population. RESULTS: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline. CONCLUSIONS: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

Real-world costs and outcomes in metastatic renal cell carcinoma patients treated with targeted therapies: a cohort study from the French health insurance database.

OBJECTIVES: The objective of this study was to describe treatment patterns, survival, healthcare use and costs in patients with metastatic renal cell carcinoma (mRCC) in a real-world setting. RESEARCH DESIGN AND METHODS: We used the National Health Insurance (NHI) claims database for the Ile-de-France region to perform a retrospective cohort analysis of patients with mRCC treated by a first-line targeted therapy. Treatment naïve patients were identified combining the 10th revision of the International Classification of Diseases (ICD-10) codes (C64 & C77-C79) and a first prescription of targeted therapies. Descriptive analyses were performed on treatment patterns and patients' characteristics. Progression free survival (PFS) and overall survival (OS) were determined using Kaplan-Meier actuarial survival analysis. All healthcare resource use and costs were estimated on a per patient per month (PPPM) basis (€2016). RESULTS: A total of 327 treatment naïve patients with mRCC were included. Median follow-up was 13.4 months. Sunitinib accounted for 73% of first-line treatments. The most frequently observed treatment sequence for the first two lines was sunitinib-everolimus (16%; n = 137) and for the first three lines sunitinib-everolimus-axitinib (20%; n = 49). First-line PFS for sunitinib, everolimus, pazopanib, sorafenib and other was 8.7, 6.2, 10.7, 5.7 and 11.2 months, respectively. Median OS for patients treated by first-line sunitinib, everolimus, pazopanib, sorafenib and other was respectively 14.7, 8.1, 21.1, 8.9 and 14.0 months. From the NHI's perspective, the mean PPPM was €5546. The average PPPM in pre-progression was €5597 compared to €5541 beyond progression of the disease. Oral targeted therapies accounted for 53% of the total PPPM. CONCLUSION: This descriptive study showed that the economic burden of mRCC is substantial with oral targeted therapies accounting for 53% of the PPPM. OS and PFS in real life are poorer than observed in clinical trials.

Cost-effectiveness of pazopanib versus sunitinib for metastatic renal cell carcinoma in the United Kingdom.

BACKGROUND: Sunitinib and pazopanib are the only two targeted therapies for the first-line treatment of locally advanced or metastatic renal cell carcinoma (mRCC) recommended by the United Kingdom's National Institute for Health and Care Excellence. Pazopanib demonstrated non-inferior efficacy and a differentiated safety profile versus sunitinib in the phase III COMPARZ trial. The current analysis provides a direct comparison of the cost-effectiveness of pazopanib versus sunitinib from the perspective of the United Kingdom's National Health Service based on data from COMPARZ and other sources. METHODS: A partitioned-survival analysis model with three health states (alive with no progression, alive with progression, or dead) was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib over five years (duration of follow-up for final survival analysis in COMPARZ). The proportion of patients in each health state over time was based on Kaplan-Meier distributions for progression-free and overall survival from COMPARZ. Utility values were based on EQ-5D data from the pivotal study of pazopanib versus placebo. Costs were based on medical resource utilisation data from COMPARZ and unit costs from secondary sources. Probabilistic and deterministic sensitivity analyses were conducted to assess uncertainty of model results. RESULTS: In the base case, pazopanib was estimated to provide more QALYs (0.0565, 95% credible interval [CrI]: -0.0920 to 0.2126) at a lower cost (-£1,061, 95% CrI: -£4,328 to £2,067) versus sunitinib. The probability that pazopanib yields more QALYs than sunitinib was estimated to be 76%. For a threshold value of £30,000 per QALY gained, the probability that pazopanib is cost-effective versus sunitinib was estimated to be 95%. Pazopanib was dominant in most scenarios examined in deterministic sensitivity analyses. CONCLUSIONS: Pazopanib is likely to be a cost-effective treatment option compared with sunitinib as first-line treatment of mRCC in the United Kingdom.

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov: NCT01689519.