Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.

Abiraterone acetate to treat metastatic castration-resistant prostate cancer in combination with prednisone.

Prostate cancer is one of the most common cancers in the United States, with an estimated incidence of 164,690 cases, accounting for 9.5% of all new cancer diagnoses. The mainstay of therapy for metastatic prostate cancer involves suppressing testosterone production through androgen deprivation therapy. However, nearly all patients on androgen deprivation therapy will develop resistance to hormone therapy. An improved understanding of the biology of castration resistance has allowed for the development of novel inhibitors of the androgen axis. Agents such as abiraterone acetate, which provides additional androgen suppression by inhibiting cytochrome P450 17A (CYP17A), have improved survival outcomes of patients with advanced prostate cancer. The longest experience with abiraterone acetate is in the metastatic castration-resistant setting. However, more recent trials have demonstrated that abiraterone acetate is an option for treatment earlier in the prostate cancer paradigm. This review will cover the current use of abiraterone acetate in combination with prednisone for the treatment of castration-resistant prostate cancer.

Cabozantinib use in renal cell carcinoma.

In the last several years, many new drugs have been approved to treat metastatic renal cell carcinoma (RCC). Cabozantinib is a novel multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR), proto-oncogene tyrosine-protein kinase receptor Ret and other kinases that recently joined this impressive list of approved agents. Cabozantinib is an active agent in the preclinical and clinical setting, having recently demonstrated superiority over everolimus in a blinded, randomized phase III study of patients with progressive RCC after at least one prior line of antiangiogenic therapy. This agent's toxicity profile is similar to those of other multikinase inhibitors approved to treat RCC. This review will explore cabozantinib's pharmacologic and safety profile and its preclinical and clinical activity in RCC.

Axitinib, a new therapeutic option in renal cell carcinoma.

Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit. Improved knowledge of kidney cancer development, and specifically mutations in the VHL gene, has supported the targeting of angiogenesis pathways. Axitinib is the most recently approved agent for use in metastatic renal cell carcinoma. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical activity of this agent, and describe its place in the current treatment of renal cell carcinoma.

Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib).

XL-184 (cabozantinib) is a novel, small-molecule, multitargeted receptor tyrosine kinase inhibitor with particular activity against hepatocyte growth factor receptor (tyrosine-protein kinase Met), vascular endothelial growth factor receptor 2 (VEGFR-2) and proto-oncogene tyrosine-protein kinase receptor Ret. There is ample evidence of Met, VEGFR-2 and Ret signaling in several tumor types. Preclinical data suggest that XL-184 has activity in tumors derived from both epithelial and mesenchymal origins. Phase I and II clinical studies support significant antitumor activity, particularly in medullary thyroid cancer and cancers metastatic to the bone. This review will evaluate XL-184's preclinical pharmacology, pharmacokinetics, drug interactions and clinical activity in phase I through phase III studies.

Time to treatment and cost of thrombolysis: a multicenter comparison of tPA and rPA.

STUDY OBJECTIVE: This study reports a comparison of the time to treatment and cost of administration of alteplase (tPA) and reteplase (rPA) in patients with acute myocardial infarction (MI). DESIGN: Retrospective chart review. SETTING: Hospital emergency department. INTERVENTIONS: A retrospective chart review of 500 MI patients who received alteplase or reteplase was performed. A comparison of time from presentation in the emergency department to start of treatment was performed, and the cost of administration of drugs, including cost of supplies, monitoring time, and IV line complications, was calculated for each drug. RESULTS: The time from presentation to start of treatment was significantly shorter for reteplase than alteplase (51 vs 34 min). This difference resulted from a shorter decision to treat to start of treatment time for reteplase (11 min) compared to alteplase (31 min). The cost of administration of alteplase ranged from $136 to $184 per patient, while the cost of administration of reteplase ranged from $87 to $120 per patient. DISCUSSION: Given the similar safety and efficacy profiles of these thrombolytic agents, the advantages of reteplase in speed of administration and the reduction in cost should be considered when making formulary and drug product selection decisions.). Abbreviated Abstract. Alteplase (tPA) and reteplase (rPA) were compared in a retrospective review of 500 patients. rPA was associated with 17 minute time savings from presentation-to-treatment compared to tPA. rPA was also associated with a per patient cost savings $49 to $64 compared to tPA. The time and cost advantages of rPA should be considered when making drug product selection decisions.

Vaccine-preventable diseases in health care.

It cannot be overemphasized that good preventive measures such as universal precautions, good hand-washing techniques, and appropriate personal protection is the mainstay of reducing the risk of nosocomial infections to other patients and HCWs. Vaccines that are safe and effective in reducing risks of nosocomial infections must be promoted through educational campaigns and made easily available to all employees, including those on night and weekend shifts. Extended hours and onsite vaccination programs help to increase acceptance of vaccines at certain times, such as during the annual influenza vaccine campaign. When more than one vaccine is recommended, consideration must be given to an appropriate vaccine schedule. Table 2 lists the interactions and contraindications of the vaccines most commonly administered to health care workers. Certain vaccines, such as rubella, should be required for susceptible employees when working in an area of a health care facility where exposure and consequent transmission to patients could have life-threatening consequences.

Comparison of intravenous and oral routes of theophylline loading in acute asthma.

In a prospective, randomized clinical trial, 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV (n = 10) or oral route (n = 9) of administration following treatment with epinephrine. Plasma concentrations of theophylline were measured prior to giving the loading dose, and one, two, three, and 24 to 48 hours later. Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose, and one, three, and 24 to 48 hours later. Side effects also were recorded. In the IV group, the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading, and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading. There was no correlation between theophylline concentrations and normalized change in spirometric values. There was no significant difference in spirometric values between the IV and oral groups. Nausea was slightly more common in the IV group. We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine.

Use of orally administered diazepam in the reduction of dental anxiety.

A double-blind randomized clinical trial of the effectiveness of orally administered diazepam in reducing dental anxiety was conducted. Forty-one subjects were assigned to a diazepam or placebo group and tested, using the Dental Fear Survey and State-Trait Anxiety Inventory. Diazepam was effective in reducing anxiety scores but not dental fear scores.