Meta-analysis and indirect treatment comparison of lipegfilgrastim with pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia-related events

Background: Granulocyte colony-stimulating factors are effective at reducing the risk and duration of neutropenia. The current meta-analysis compared the neutropenia-related efficacy and safety of lipegfilgrastim to those of pegfilgrastim and filgrastim. Methods: Embase was searched for trials examining the efficacy/safety of lipegfilgrastim, pegfilgrastim, or filgrastim. Outcomes included febrile neutropenia, severe neutropenia, duration of severe neutropenia, time to recovery of absolute neutrophil count, and incidence of bone pain. Direct comparisons were made using random-effects models. No trials directly compared lipegfilgrastim and filgrastim. Indirect comparisons were made between lipegfilgrastim and filgrastim with pegfilgrastim as the common comparator. Results: This meta-analysis included a total of 5769 patients from 24 studies. Over all cycles, lipegfilgrastim showed a lower, nonsignificant risk of febrile neutropenia compared with pegfilgrastim. Lipegfilgrastim has a lower risk of febrile neutropenia versus filgrastim but was also not statistically significant. The risk ratio for severe neutropenia in cycle 1 was 0.80, a 20% reduction in favor of lipegfilgrastim. For cycles 2–4, the risk ratio was 0.53 (0.35, 0.79) for lipegfilgrastim versus pegfilgrastim. The risk of severe neutropenia in cycles 2–4 was also significantly lower for lipegfilgrastim (risk ratio 0.45, 0.27, 0.75, respectively). No significant differences were found for febrile neutropenia and severe neutropenia in cycle 1. However, in cycles 2–4, lipegfilgrastim was associated with significant and clinically meaningful reductions in risk of severe neutropenia versus either pegfilgrastim or filgrastim. Conclusions: Compared with pegfilgrastim or filgrastim, lipegfilgrastim has a statistically significantly lower absolute neutrophil count recovery time; however, differences in duration of severe neutropenia and bone pain were nonsignificant.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Ovarian Function Suppression: A Deeper Consideration of the Role in Early Breast Cancer and its Potential Impact on Patient Outcomes: A Consensus Statement from an International Expert Panel

It has been suggested that the benefit of adjuvant chemotherapy (CT) in premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) early breast cancer may be related, at least in part, to CT-induced ovarian function suppression (OFS) in this subgroup of patients. Although this hypothesis has not been directly tested in large randomized clinical trials, the observations from prospective studies have been remarkably consistent in showing a late benefit of CT among the subgroup of patients who benefit (ie, women who were close to menopause). The hypothesis has important clinical implications, as it may be possible to spare the associated adverse effects of adjuvant CT in a select group of women with early breast cancer, in favor of optimizing OFS and endocrine therapy (ET), without compromising clinical outcomes. Such an approach has the added benefit of preserving the key quality of life outcomes in premenopausal women, particularly by preventing the irreversible loss of ovarian function that may result from CT use. For this reason, we convened an international panel of clinical experts in breast cancer treatment to discuss the key aspects of the available data in this area, as well as the potential clinical implications for patients. This article summarizes the results of these discussions and presents the consensus opinion of the panel regarding optimizing the use of OFS for premenopausal women with HR+, HER2- early breast cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining .0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed $ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of .2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): A randomised, open-label, multicentre, phase 3 trial

Background: New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. Methods: In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m2 as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. Findings: Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock). Interpretation: This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. Funding: Nektar Therapeutics.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Mobilization of hematopoietic stem and progenitor cells in mice

Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components) are critical to the process. The increasing availability of recombinant proteins (growth factors, cytokines, chemokines), antibodies, drugs (agonists and antagonists), and mutant and genetically modified animal models [gene knock-in (KI) and knock-out (KO)] continue to add to the tools available to better understand and manipulate mobilization processes.</p