Fruquintinib Prolongs Survival in Metastatic Colorectal Cancer
Nealy 50% of patients with colorectal cancer will develop distant metastases, and the overall survival rate for these patients is about 15%. An international, randomized, double-blind, placebo-controlled, phase 3 study published in The Lancet demonstrated that fruquintinib, a selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 is effective as a treatment for such metastatic colorectal cancer.
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FRESCO-2 was conducted at 124 hospitals and cancer centers across 14 countries. It enrolled 691 patients with documented metastatic colorectal adenocarcinoma who had progressed on or been intolerant to cytotoxic and targeted therapies. They were randomly assigned to fruquintinib 50 mg (n = 461) or placebo (n = 230) once daily on days 1 to 21 in 28-day cycles. The patients had received a median of four lines of previous systemic therapy for the disease; 73% of patients had received more than three lines of therapy.
The use of fruquintinib resulted in meaningful improvements in overall and progression-free survival among patients who had progressed or been intolerant to multiple previous therapies. At 6 months, 24% of the patients in the treatment group demonstrated progression-free survival, compared to 1% in the placebo group. The treatment group also had longer overall survival than the placebo group, with a 34% reduced risk of death. The median survival of patients in the fruquintinib group was 7.4 months, compared with 4.8 months in the placebo group (hazard ratio, 0.66).
Adverse events were generally manageable, with minimal discontinuation due to treatment-related toxicity. Grade 3 or worse adverse events occurred in 286 (63%) who received fruquintinib and 116 (50%) who received placebo. The most common of these were hypertension (n = 62 [14%]), asthenia (n = 35 [8%]), and hand-foot syndrome (n = 29 [6%]). One treatment-related death occurred in each group.
These data support the use of fruquintinib as a treatment option for patients with refractory metastatic colorectal cancer. Future research is needed, both to assess patient quality of life after fruquintinib therapy and the safety of the drug, and to determine the optimal sequencing strategy for patients with metastatic colorectal cancer who have failed at least two lines of therapy. (Dasari, A., et al. (2023). Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): An international, multicentre, randomised, double-blind, phase 3 study. The Lancet, 402(10395): 41–53. Retrieved June 2023 from – https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/fulltext#%20; Norris, J. (2023). New therapy may be on the horizon for metastatic colorectal cancer. Medical News Today. Retrieved June 2023 from https://www.medicalnewstoday.com/articles/new-therapy-may-be-on-the-horizon-for-metastatic-colorectal-cancer
Released: July 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Examining Possible Association between Menopausal Hormone Therapy and Dementia
In a Danish nationwide, nested case-control study, exposure to menopausal hormonal therapy with estrogen and progestin was positively associated with development of all-cause dementia and Alzheimer disease, even with short-term usage around the age of menopause onset. The study identified 5,589 incident cases of dementia and 55,890 age-matched controls in Danish women ages 50 to 60 with no history of dementia or contraindications for menopausal hormone therapy. For all included participants, researchers assessed the history of menopausal hormone therapy in each patient starting from ages 45 to 55 up to 2 years before study initiation or dementia diagnosis. Using the program Medicin Macro, they were able to calculate probable daily dose and duration of medication use.
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The study examined the cohort for development of dementia, defined by first-time diagnosis or first-time use of dementia-specific medications. Compared with people who had never used estrogen-progestin therapy, those who did had an increased rate of all-cause dementia (hazard ratio [HR], 1.24). Increasing duration of use produced higher HRs, ranging from 1.21 for 1 year or less of use to 1.74 for more than 12 years of hormonal therapy. Both continuous (HR, 1.31) and cyclical (HR, 1.24) treatment regimens were associated with the development of dementia. This association persisted in women who received estrogen-progestin therapy at age 55 or younger (HR, 1.24); for those who initiated therapy at ages 45 to 50, HR was 1.26 and for those who initiated therapy at ages 51 to 60 years, HR was 1.21. It also held for either late-onset (HR, 1.21) or Alzheimer disease (HR, 1.22).
Before the index date, 1,782 (31.9%) of patients with dementia and 16,154 (28.9%) of those in the control group had received menopausal treatment with estrogen-progestin. Among all users of estrogen-progestin, 66.2% had their last treatment day more than 8 years before the index date; 8.7% were still users at diagnosis or matching. Median age at initiation of estrogen-progestin was 53 years for both case and control groups; the median duration of use was 3.8 years for cases and 3.6 years for controls. Among those in the case group, 25.7% received continuous progestin, 38.9% received cyclical progestin, and 30.4% received both continuous and cyclical treatment before the index date. In the control group, among those who received hormonal therapy, 24.3% received continuous progestin, 38.9% received cyclical progestin, and 31.5% received both continuous and cyclical progestin.
Further studies are necessary to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk or whether they reflect an underlying predisposition in women in need of these therapies. In addition, the effect of short-term use of hormone therapy around the age of menopause remains to be fully explained. (Kantarci, K., & Manson, J. E. (2023). Menopausal hormone therapy and dementia. BMJ, 381, 1404. Retrieved June 2023 from https://www.bmj.com/content/381/bmj.p1404; Pourhadi, N., et al. (2023). Menopausal hormone therapy and dementia: Nationwide, nested case-control study. BMJ, 381, Article e072770. Retrieved June 2023 from https://www.bmj.com/content/bmj/381/bmj-2022-072770.full.pdf)
Released: July 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Tezepelumab Effective in a Range of Severe Asthma Types
Post hoc pooled analysis of two studies of patients with severe asthma suggest that treatment with tezepelumab resulted in clinically meaningful reductions in asthma exacerbations, including those associated with hospitalization or an emergency department (ED) visit, across patient subgroups. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, which is released by airway epithelial cells in response to allergens or other triggers and drives airway inflammation. The two studies analyzed were PATHWAY, a phase 2 dose-finding study of tezepelumab in adults with inadequately controlled severe asthma, and NAVIGATOR, a phase 3 study of subcutaneous tezepelumab in adults and adolescents with severe asthma.
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The pooled analysis included patients ages 18 to 75 years in PATHWAY and ages 12 to 80 years in NAVIGATOR who had received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Overall, 1,334 patients were included (665 tezepelumab, 669 placebo). All patients had experienced at least two exacerbations of their asthma in the year before enrollment. The annualized asthma exacerbation rate (AAER) over 52 weeks was calculated both in the overall population and in subgroups defined by inflammatory biomarkers or clinical characteristics. To examine the reduction of AAER in patients across the spectrum of T2 inflammation, AAER reduction was assessed in patients grouped by combinations of baseline blood eosinophil counts (BEC), functional exhaled nitric oxide (FENO) levels, and perennial allergy status. Patients were grouped by combinations of low and high BEC (less than 150 cells/microliter, or greater than or equal to 150 cells/microliter) and low and high FENO levels (less than 25 ppb, or greater than or equal to 26 ppb).
In both studies, treatment with tezepelumab reduced the AAER; in the pooled population, tezepelumab reduced AAER by 60% compared with placebo; clinically meaningful reductions in exacerbations were observed in patients with type 2-low disease, defined by low (less than 300 cells/microliter) or very low (less than 150 cells/microliter) baseline BEC, low FENO levels (less than 25 ppb), and negative perennial allergy status in the absence of maintenance corticosteroid use at baseline. Reductions in exacerbations ranged from 37% in type 2-low disease (BEC less than 300 cells/microliter, FENO levels less than 25 ppb) to 77% in type 2-high disease (BEC greater than or equal to 300 cells/microliter, FENO levels greater than or equal to 25 ppb). In the triple T2-low subgroup (BEC less than 150 cells/microliter, FENO levels less than 25 ppb, no perennial allergies), the AAER over 52 weeks was 34% lower with tezepelumab compared with placebo. Use of tezelepumab reduced rate of exacerbations requiring hospitalization or ED visit by 79% in the total population and by 60% in type 2-low disease and by 91% in type 2-high disease subgroups. The AAER among these patients remained consistent across baseline BECs but increased as baseline FENO levels increased. Exacerbations associated with hospitalizations or ED visit was decreased by 80% in patients with perennial allergies and by 74% in those without.
Tezepelumab also improved lung function, asthma control, and asthma-related quality of life. In the overall population, the incidence of adverse events was similar between the two groups: in 75% of patients receiving tezepelumab and in 77% of patients receiving placebo. Serious adverse events were seen in 9% of patients receiving tezepelumab and in 13% of patients receiving placebo.
Capturing a clear picture of the efficacy of tezepelumab in different subgroups is important as it represents the first in a new class of asthma medications. Real-world studies are warranted to further illuminate the drug's safety and its optimal use. (Brusselle, G., & Riemann, S. (2023). Is efficacy of Tezepelumab independent of severe asthma phenotype. Am J Respir Crit Care Med, 208(1), 1–3. Retrieved June 2023 from https://www.atsjournals.org/doi/epdf/10.1164/rccm.202304-0700ED?role=tab; Corren, J., et al. (2023). Efficacy of tezepelumab in severe, uncontrolled asthma: Pooled analysis of the PATHWAY and NAVIGATOR clinical trials. Am J Respir Crit Care Med, 208(1): 13–24. Retrieved June 2023 from https://www.atsjournals.org/doi/full/10.1164/rccm.202210-2005OC)
Released: July 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer