Temporal Trends in Grade 3/4 Adverse Events and Associated Costs of Nivolumab Plus Cabozantinib Versus Sunitinib for Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND AND OBJECTIVES: Novel immunotherapy-based combination treatments have drastically improved clinical outcomes for previously untreated patients with advanced/metastatic renal cell carcinoma (aRCC). This study aimed to assess the temporal trends in grade 3/4 adverse event (AE) rates and associated costs of nivolumab plus cabozantinib combination therapy versus sunitinib monotherapy in previously untreated patients with aRCC. METHODS: Individual patient data from the CheckMate 9ER trial (nivolumab plus cabozantinib: N = 320; sunitinib: N = 320) were used to calculate the proportion of patients experiencing grade 3/4 AEs. AE unit costs were obtained from the United States (US) 2017 Healthcare Cost and Utilization Project (HCUP) and inflated to 2020 US dollars. Per-patient-per-month (PPPM) all-cause and treatment-related grade 3/4 AE costs over 18-months, temporal trends, and top drivers of AE costs were evaluated in both treatment arms. RESULTS: Overall, the proportion of patients experiencing grade 3/4 AEs decreased over time, with the highest rates observed in the first 3 months for the nivolumab plus cabozantinib and sunitinib arms. Compared with sunitinib, nivolumab plus cabozantinib was associated with consistently lower average all-cause AE costs PPPM [month 3: $2021 vs. $3097 (p < 0.05); month 6: $1653 vs. $2418 (p < 0.05); month 12: $1450 vs. $1935 (p > 0.05); month 18: $1337 vs. $1755 (p > 0.05)]. Over 18 months, metabolism and nutrition disorders ($244), laboratory abnormalities ($182), and general disorders and administration site conditions ($122) were the costliest all-cause PPPM AE categories in the nivolumab plus cabozantinib arm, and laboratory abnormalities ($443), blood and lymphatic system disorders ($254), and metabolism and nutrition disorders ($177) were the costliest in the sunitinib arm. Trends of treatment-related AE costs were consistent with all-cause AE costs. CONCLUSIONS: Nivolumab plus cabozantinib was associated with lower costs of grade 3/4 AE management PPPM than sunitinib, which accumulated over the 18-month study period.

Real-world assessment and treatment of locally advanced basal cell carcinoma: Findings from the RegiSONIC disease registry.

BACKGROUND: Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States. METHODS: This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings. RESULTS: Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment. CONCLUSIONS: This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.

Vismodegib (ERIVEDGE) pregnancy prevention programme: assessment of risk awareness.

INTRODUCTION: Vismodegib (Erivedge; Roche), a Hedgehog pathway inhibitor (HPI), is indicated for the treatment of symptomatic metastatic basal cell carcinoma (BCC) and locally advanced BCC inappropriate for surgery or radiotherapy. Due to the known risk of HPI teratogenicity, the Erivedge Pregnancy Prevention Program (PPP) was introduced at approval (2013) as part of the EU Risk Management Plan. METHODS: Structured, quantitative Web-based surveys were conducted in 2015 (Wave 1), 2016 (Wave 2), and 2017/2018 (Wave 3) among prescribing oncologists and dermato-oncologists in Austria, France, Germany, Hungary, and the United Kingdom to assess the effectiveness of the Erivedge PPP. RESULTS: Overall, 95%, 87%, and 91% of respondents in Waves 3 (N = 181), 2 (N = 214), and 1 (N = 207), respectively, were vismodegib prescribers. The surveys consistently showed a high awareness about the risk of teratogenicity associated with vismodegib (98%, Wave 3; 95%, Wave 2) and that a high proportion of prescribing physicians took appropriate precautions to minimize this risk (95%, Wave 3; 92%, Wave 2; 88%, Wave 1). Physicians were also highly aware of the Erivedge PPP (70%, Wave 3; 67%, Wave 2; 71%, Wave 1). CONCLUSION: Survey data suggest that the risk of teratogenicity with vismodegib has been effectively communicated to the prescribing community.

Analysis of Longitudinal-Ordered Categorical Data for Muscle Spasm Adverse Event of Vismodegib: Comparison Between Different Pharmacometric Models.

Longitudinal-ordered categorical data, common in clinical trials, can be effectively analyzed with nonlinear mixed effect models. In this article, we systematically evaluated the performance of three different models in longitudinal muscle spasm adverse event (AE) data obtained from a clinical trial for vismodegib: a proportional odds (PO) model, a discrete-time Markov model, and a continuous-time Markov model. All models developed based on weekly spaced data can reasonably capture the proportion of AE grade over time; however, the PO model overpredicted the transition frequency between grades and the cumulative probability of AEs. The influence of data frequency (daily, weekly, or unevenly spaced) was also investigated. The PO model performance reduced with increased data frequency, and the discrete-time Markov model failed to describe unevenly spaced data, but the continuous-time Markov model performed consistently well. Clinical trial simulations were conducted to illustrate the muscle spasm resolution time profile during the 8-week dose interruption period after 12 weeks of continuous treatment.

Cost-Effectiveness of Cabozantinib in the Second-Line Treatment of Advanced Hepatocellular Carcinoma.

BACKGROUND: Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective. PATIENTS AND METHODS: Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC. RESULTS: In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63-0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario. CONCLUSIONS: At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.

Patterns of Bicalutamide Use in Prostate Cancer Treatment: A U.S. Real-World Analysis Using the SEER-Medicare Database.

INTRODUCTION: Bicalutamide (BIC), a non-steroidal anti-androgen, is FDA-indicated for use in combination with a luteinizing hormone-releasing hormone (LHRH) analog for treatment of Stage D2 metastatic carcinoma of the prostate. Lack of consensus exists regarding the clinical benefit of BIC use, either alone or combined use of BIC with an LHRH analog or antagonist (combined androgen blockade or CAB), versus treatment with androgen deprivation therapy (ADT) alone. METHODS: The SEER-Medicare database was used to identify prostate cancer patients aged ≥ 66 years diagnosed between 2007 and 2011 and who filled at least one prescription for BIC. Duration of BIC treatment was assessed in relation to ADT use; either alone (monotherapy), as part of CAB only, and as part of CAB followed by monotherapy. Additionally, we assessed use of BIC during or outside a potential testosterone flare prevention period (initiation within 2 months of an LHRH agonist). RESULTS: A total of 7521 prostate cancer patients who filled a prescription for BIC were identified. Eighteen percent of the cohort used BIC alone, over half the patients (54%) used BIC as part of CAB and 27% used BIC as part of CAB followed by monotherapy. Among men treated with BIC as part of CAB, 58% received BIC only within the potential flare period. CONCLUSIONS: Although there is no FDA indication for BIC use as monotherapy, > 44% of patients in this study used BIC alone or as part of CAB followed by monotherapy. Further research is necessary to understand the outcomes of BIC utilization in these settings, particularly compared with newer second-generation anti-androgens. FUNDING: Medivation LLC, a Pfizer company, and Astellas, Pharma, Inc.

Safety assessment in Child A cirrhotic patients treated with Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin.

BACKGROUND: In our country, the national program for hepatitis C virus treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir was approved for patients with stage four of liver fibrosis and stage three associated with specific comorbidities. Our aim was to analyze the characteristics associated with the presence of adverse events in patients receiving this antiviral regimen, with ribavirin in cirrhotic patients. METHODS: We prospectively studied a cohort of adults with hepatitis C virus infection with Child A cirrhosis, treated for 12 weeks with ombitasvir/paritaprevir/ritonavir/dasabuvir and ribavirin, which have been followed in an infectious diseases tertiary-care hospital. RESULTS: We included 137 adult patients diagnosed with compensated cirrhosis, hepatitis C virus genotype 1b infected, 82 (60%) previously treated. We recorded 201 adverse events in 98 (71.5%) patients, with a median number of events per patient of one. The intensity of adverse events was classified as mild, moderate and severe in 50%, 36% and 14% of cases, respectively. Forty-five (22%) episodes required medical intervention. The most frequently reported adverse events were pruritus 34(35%), asthenia 22(22%) and insomnia 15(15%). The presence of severe adverse events was associated with the presence of comorbidities (p = 0.01, OR : 9.5, 95% CI : 1.2-74.3) and with the presence of associated medication (p = 0.02, OR : 3.9, 95% CI : 1.08-14.2). At the end of current treatment, 136 (99.2%) patients had undetectable viral load. CONCLUSION: We found a high number of adverse events, but most of them were mild or moderate and only one quarter of them required medical intervention. Only severe adverse events were associated with comorbidities and associated medication.

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study.

Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.

Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes.

PURPOSE: This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). METHODS: Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. RESULTS: Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. CONCLUSIONS: Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

Clinical benefit assessment of vismodegib therapy in patients with advanced basal cell carcinoma.

PURPOSE: Vismodegib was approved for the treatment of advanced basal cell carcinoma (aBCC) based on the pivotal ERIVANCE BCC study. The primary endpoint (objective response rate [ORR]) was assessed 9 months after the last patient was enrolled. To confirm the clinical benefit of vismodegib, an additional analysis was performed 12 months after the primary analysis. MATERIALS AND METHODS: ERIVANCE BCC was a multicenter, nonrandomized, two-cohort study of 104 patients with histologically confirmed aBCC. Patients received 150 mg oral vismodegib daily until disease progression, intolerable toxicity, or withdrawal. An independent review panel comprising three expert clinicians reviewed patient photographs individually and as a consensus panel to evaluate baseline disease severity and clinical benefit after vismodegib treatment in 71 patients with locally advanced BCC (laBCC). RESULTS: Sixty-three patients were efficacy evaluable; baseline and postprogression photographs for 61 were available for review. Baseline disease severity was judged as 5 or 4 (very severe or moderately severe) in 71.4%. Clinical benefit was observed in 76.2% (significant: 65.1%; some: 11.1%). Interpanelist agreement (maximum difference ≤1 point among panelists' scores in 65.1% and 87.3% of patients for clinical benefit and baseline disease severity, respectively) and correlation between individual and panel reviews were strong. Clinical benefit scores showed good concordance with the protocol-specified ORR obtained by an independent review facility and with investigator-assessed response. CONCLUSION: Clinical benefit assessed by independent review based on expert clinical judgment provides strong evidence that treatment with vismodegib results in clinically meaningful and durable responses in patients with laBCC.

Vismodegib for the treatment of basal cell skin cancer.

PURPOSE: The pharmacology, clinical efficacy, adverse effects, cost, and place in therapy of vismodegib are reviewed. SUMMARY: Vismodegib, the first oral treatment for basal cell carcinoma (BCC), was recently approved for the treatment of patients with locally advanced or metastatic BCC whose cancer is refractory to standard treatments or who are not candidates for surgery or radiation. Vismodegib is a small molecule that potently inhibits signal transduction in the hedgehog signaling pathway, demonstrates nonlinear pharmacokinetics, and has a half-life of 13 days. Agents that increase gastrointestinal pH may reduce the solubility and bioavailability of vismodegib. It is effective in both locally advanced and metastatic BCCs, with response rates ranging from 30% to 60% in two clinical trials. Vismodegib is available as a 150-mg capsule, and the approved dosage is 150 mg orally once daily. The most common adverse effects of vismodegib include mild-to-moderate hair loss, muscle cramps, taste disturbance, and weight loss. The estimated cost of one month of treatment with vismodegib is $7500. CONCLUSION: Vismodegib was recently approved for the treatment of locally advanced or metastatic BCC that is refractory to standard treatments or if patients are not candidates for surgery or radiation. Vismodegib may have little effect on the treatment of BCC, given its high cost, the high cure rates achieved with standard therapies, and its unacceptable toxicity profile in patients with a non-life-threatening disease. However, vismodegib's novel mechanism of action, oral dosage form, preliminary efficacy, and tolerability compared with cytotoxic chemotherapy may make it an attractive candidate for the treatment of other cancers.

Maximal androgen blockade for advanced prostate cancer.

Maximal androgen blockade (MAB) refers to the combination of medical (gonadotrophin-releasing hormone agonist) or surgical castration with an anti-androgen for the treatment of advanced prostate cancer. A substantial body of basic research has improved our understanding of the interactions between the anti-androgens, the androgen receptor, and androgen response elements in the genome. Anti-androgens act by two primary mechanisms: inhibition of ligand (androgen) binding to the androgen receptor, and inhibition of androgen-independent activation of the receptor. The latter mechanism occurs via several pathways, including inhibiting nuclear co-activators, activating co-suppressors, and inhibiting transcription of a variety of androgen-regulated genes. It is more accurate to refer to these compounds as androgen-receptor antagonists, since they inhibit activation whether this is androgen-mediated or not. Within the class of non-steroidal anti-androgens, there is variation in the degree to which ligand-independent activation is inhibited. Over the last 25 years, approximately 30 clinical trials have addressed the benefit of MAB versus monotherapy. Most of these trials have evaluated flutamide or nilutamide. Several meta-analyses suggest a modest survival benefit of these drugs, amounting to an 8% mortality reduction at 5 years. Preclinical data and two randomized trials -- one historic and one current -- suggest that bicalutamide may be a more effective drug in this respect. This requires confirmation pending further maturity of the current trial, which is the only one directly comparing bicalutamide plus castration to castration alone. In prostate cancer patients at high risk for mortality (based on extent of disease or prostate-specific antigen kinetics), combination therapy with bicalutamide should be considered in preference to monotherapy.

Eliciting patient preferences for hormonal therapy options in the treatment of metastatic prostate cancer.

Treatment choices for metastatic prostate cancer are complex and can involve men balancing survival versus quality of life. The present study aims to elicit patient preferences with respect to the attributes of treatments for metastatic prostate cancer through a discrete choice experiment (DCE) questionnaire. Men with recently diagnosed localized prostate cancer were asked to envisage that they had metastatic disease when completing a survey. As expected, men with prostate cancer placed considerable importance on gains in survival; however, avoiding side effects of treatment was also clearly important. Survival gains should be considered alongside side effects when discussing treatment options in metastatic disease.

Tolerability assessment of maximal androgen blockade with 50 mg daily of bicalutamide and castration in patients with advanced prostate cancer.

BACKGROUND: Androgen is the most important growth factor for the development and growth of prostatic adenocarcinomas. For patients with advanced prostate cancer, hormonal manipulation including castration and antiandrogen therapy is a well-established mode of treatment. The choice of hormonal therapy for prostate cancer depends not only on the desired progression-free and overall survival, but also on the patient's quality of life, treatment costs, and treatment toxicities. METHODS: This was an open, non-comparative trial to determine the tolerability of 50 mg bicalutamide (Casodex) in combination with castration; we also investigated whether the prostate-specific antigen (PSA) rates of change at weeks 4 and 12 were indicative of an increased risk of progression. RESULTS: Thirty-seven patients were enrolled in the study from December 1996 to June 1999 in Chang Gung Memorial Hospital, Taoyuan. The overall incidence rate of adverse events was 27%. The most frequent adverse event was hot flushes (5.4%). The rate of overall disease response was 85.3%. No evidence was found for any predictive relationship between serum PSA concentration and risk of progression. CONCLUSION: The overall results indicate that bicalutamide administered as a 50-mg daily dosage in combination with castration is a well-tolerated therapy for the treatment of patients with advanced prostate cancer.

Treatment of frequent ventricular arrhythmia with encainide: assessment using serial ambulatory electrocardiograms, intracardiac electrophysiologic studies, treadmill exercise tests, and radionuclide cineangiographic studies.

The effects of encainide on ventricular arrhythmia and left ventricular function were studied in 21 patients with chronic, high-grade ventricular arrhythmia using a prospective, 3-month, placebo-controlled, single-blind trial design. Encainide caused a 96% decrease in the average hourly frequency of ventricular premature complexes (VPCs) and comparable reductions in salvos of nonsustained ventricular tachycardia (VT) and episodes of sustained VT. Intracardiac electrophysiologic testing showed prolonged intraatrial and intraventricular conduction times and increased atrial, atrioventricular nodal, and ventricular refractory periods with both i.v. and oral encainide without His-Purkinje block, despite marked prolongation of HV and QRS intervals. Induced repetitive ventricular beating after ventricular extrastimuli in 15 patients showed persistent repetitive ventricular beating with chronic oral encainide in seven patients, four of whom had sustained VT within 2 months of treatment on encainide. Encainide did not reduce exercise capacity or left ventricular ejection fraction at rest or during supine exercise. Minor adverse effects of encainide in 11 of 21 patients included dose-related visual disturbances, dizziness and sinus pauses (less than 3 seconds). Major adverse effects included the new appearance of sustained VT in three of 20 patients (15%). Oral encainide effectively reduces the frequency and grade of VPCs, prolongs intracardiac conduction times, and does not impair left ventricular performance. However, it is associated with frequent minor side effects and uncommon but potentially severe major side effects (sustained VT), both of which apparently have a direct relationship to the size of the dose.