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The Lancet. Oncology Dec 2023Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated... (Randomized Controlled Trial)
Randomized Controlled Trial
Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial.
BACKGROUND
Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains.
METHODS
TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m cyclophosphamide intravenously on days 1 and 8 or 100 mg/m orally on days 1-14; 40 mg/m methotrexate intravenously on days 1 and 8; and 600 mg/m fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m capecitabine (1250 mg/m given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1-3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925.
FINDINGS
From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6-95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months.
INTERPRETATION
Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer.
FUNDING
Cancer Research UK, Amgen, Pfizer, and Roche.
Topics: Humans; Male; Female; Breast Neoplasms; Capecitabine; Epirubicin; Methotrexate; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Cyclophosphamide; Chemotherapy, Adjuvant; Fatigue; United Kingdom
PubMed: 37926100
DOI: 10.1016/S1470-2045(23)00460-6 -
Drug Safety Dec 2023Biosimilars are additional treatment options that are approved based on robust analytical and clinical comparisons with their reference biologic. At the time of initial... (Review)
Review
Long-Term Real-World Post-approval Safety Data of Multiple Biosimilars from One Marketing-Authorization Holder After More than 18 Years Since Their First Biosimilar Launch.
BACKGROUND
Biosimilars are additional treatment options that are approved based on robust analytical and clinical comparisons with their reference biologic. At the time of initial approval, the full safety profile of a biosimilar is inferred from the reference biologic. Nonetheless, there are still lingering concerns related to the long-term safety of biosimilars. Therefore, we reviewed the post-approval pharmacovigilance data for eight marketed biosimilars from one Marketing Authorization Holder (MAH) to summarize their safety experience in a real-world setting for up to 18 years since their first biosimilar launch.
METHODS
Post-approval cumulative patient exposure and safety experience for eight Sandoz biosimilars [adalimumab (Hyrimoz), epoetin alfa (Binocrit), etanercept (Erelzi), filgrastim (Zarzio), infliximab (Zessly), pegfilgrastim (Ziextenzo), rituximab (Rixathon), and somatropin (Omnitrope)] was summarized based on the available pharmacovigilance data from Periodic Safety Update Reports (PSURs) and the corresponding health authority-authored PSUR assessment reports, where available, as of 31 January 2023. Exposure to all biosimilars was calculated in patient treatment days (PTD) except for rituximab, which was expressed in number of patient doses (PD).
RESULTS
The combined post-approval cumulative exposure to seven out of the eight marketed Sandoz biosimilars was more than 1.3 billion PTD and for rituximab more than 1.8 million PD. Overall, a critical analysis of the cumulative safety data of all eight Sandoz biosimilar PSURs concluded that the overall benefit-risk profile of each remains favorable and is consistent with the respective reference biologics.
CONCLUSIONS
This is one of the largest reviews of post-approval biosimilar pharmacovigilance data to date by one MAH. The real-world experience of all eight marketed Sandoz biosimilars for up to 18 years demonstrates that Sandoz biosimilars can be used as safely as their respective reference biologics. Therefore, patients and healthcare providers can be confident in the clinical benefit and safety of Sandoz biosimilars. It is reasonable to believe that similar conclusions about safety may be reached for other biosimilars developed and approved to the high standards as are already in place by major health authorities such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The long-term safety of biosimilars demonstrated here provides strong support for the concept of biosimilarity.
Topics: Humans; Biosimilar Pharmaceuticals; Rituximab; Infliximab; Adalimumab; Epoetin Alfa; Marketing; Drug Approval
PubMed: 37902937
DOI: 10.1007/s40264-023-01371-8 -
Case Reports in Oncology 2023With the increased use of granulocyte colony-stimulating factor (G-CSF) preparations, there is concern about the increase in G-CSF-associated large-vessel vasculitis;...
Recurrence of Large-Vessel Vasculitis Induced by Multiple Types of Granulocyte Colony-Stimulating Factor Preparation in Patient with Large-Cell Neuroendocrine Lung Carcinoma: A Case Report.
With the increased use of granulocyte colony-stimulating factor (G-CSF) preparations, there is concern about the increase in G-CSF-associated large-vessel vasculitis; however, there have been no previous reports of vasculitis caused by multiple types of G-CSF preparations. We experienced a case of drug-induced large-vessel vasculitis caused by two different G-CSF products, which was difficult to diagnose. When treating patients with a history of large-vessel vasculitis caused by pegfilgrastim, we need to pay attention to its recurrence when using other G-CSF preparations.
PubMed: 37900825
DOI: 10.1159/000533375 -
Thoracic Cancer Dec 2023Amrubicin (AMR) regimens have shown efficacy as second-line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia...
BACKGROUND
Amrubicin (AMR) regimens have shown efficacy as second-line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P-PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P-PEG as second-line chemotherapy for SCLC.
METHODS
We retrospectively reviewed patients with SCLC who received AMR as second-line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P-PEG in their regimen, patients (n = 60) were divided into P-PEG (n = 21) and non-P-PEG groups, and their clinical outcomes were evaluated.
RESULTS
Median of AMR treatment cycles was five (range: 1-39 cycles) in P-PEG group and four (range: 1-15 cycles) in non-P-PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P-PEG group than in the non-P-PEG group. The objective response rates were 52.4% and 30.8%, and median progression-free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P-PEG and non-P-PEG groups, respectively.
CONCLUSIONS
AMR with P-PEG as second-line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P-PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Retrospective Studies; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37873674
DOI: 10.1111/1759-7714.15140 -
Cancer Medicine Oct 2023Pegfilgrastim is indicated to decrease the incidence of chemotherapy-induced febrile neutropenia. It is the first granulocyte-colony stimulating factor approved for...
INTRODUCTION
Pegfilgrastim is indicated to decrease the incidence of chemotherapy-induced febrile neutropenia. It is the first granulocyte-colony stimulating factor approved for prophylactic use regardless of carcinoma type and is marketed in Japan as G-LASTA (Kyowa Kirin Co., Ltd., Tokyo, Japan). MD-110 is a biosimilar of pegfilgrastim. This phase III, multicenter, open-label, single-arm study investigated the efficacy and safety of MD-110 in early-stage breast cancer patients receiving neoadjuvant or adjuvant myelosuppressive chemotherapy.
METHODS
A total of 101 patients received the study drug. Each patient received docetaxel 75 mg/m and cyclophosphamide 600 mg/m (TC) for four cycles on day 1 of each cycle. MD-110 (3.6 mg) was administered subcutaneously on day 2 of each cycle. The primary efficacy endpoint was the duration of severe neutropenia during cycle 1 (days with absolute neutrophil count < 500/mm ). The safety endpoints were adverse events and the presence of antidrug antibodies.
RESULTS
The mean (SD) duration of severe neutropenia for MD-110 was 0.2 (0.4) days. The upper limit of the two-sided 95% confidence interval for the mean duration of severe neutropenia was 0.2 days, below the predefined threshold of 3.0 days. The incidence of febrile neutropenia, the secondary efficacy endpoint, was 6.9% (7/101). Adverse events, occurring in more than 50% of patients, were alopecia, constipation, and malaise, which are common side effects of TC chemotherapy. Antidrug antibodies were negative in all patients.
CONCLUSION
MD-110 was effective against chemotherapy-induced neutropenia. No additional safety concern, compared with the originator, was observed in patients with breast cancer receiving TC chemotherapy.(JapicCTI-205230).
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Breast Neoplasms; Filgrastim; Granulocyte Colony-Stimulating Factor; Neutropenia; Polyethylene Glycols
PubMed: 37824431
DOI: 10.1002/cam4.6519 -
Breast (Edinburgh, Scotland) Dec 2023Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving... (Observational Study)
Observational Study
An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer.
PURPOSE
Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support.
MATERIALS AND METHODS
This was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE.
RESULTS
Pegfilgrastim administration reduced FN by 11.8-1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%.
CONCLUSION
The use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.
Topics: Humans; Female; Breast Neoplasms; Incidence; Prospective Studies; Febrile Neutropenia; Pain; Republic of Korea
PubMed: 37802015
DOI: 10.1016/j.breast.2023.103585 -
Supportive Care in Cancer : Official... Sep 2023Clinical practice guidelines recommend the use of all approved granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, as primary...
PURPOSE
Clinical practice guidelines recommend the use of all approved granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, as primary febrile neutropenia (FN) prophylaxis in patients receiving high- or intermediate-risk regimens (in those with additional patient risk factors). Previous studies have examined G-CSF cost-effectiveness by cancer type in patients with a high baseline risk of FN. This study evaluated patients with breast cancer (BC), non-small cell lung cancer (NSCLC), or non-Hodgkin's lymphoma (NHL) receiving therapy who were at intermediate risk for FN and compared primary prophylaxis (PP) and secondary prophylaxis (SP) using biosimilar filgrastim or biosimilar pegfilgrastim in Austria, France, and Germany.
METHODS
A Markov cycle tree-based model was constructed to evaluate PP versus SP in patients with BC, NSCLC, or NHL receiving therapy over a lifetime horizon. Cost-effectiveness was evaluated over a range of willingness-to-pay (WTP) thresholds for incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty.
RESULTS
Results demonstrated that using biosimilar filgrastim as PP compared to SP resulted in incremental cost-effectiveness ratios (ICERs) well below the most commonly accepted WTP threshold of €30,000. Across all three countries, PP in NSCLC had the lowest cost per QALY, and in France, PP was both cheaper and more effective than SP. Similar results were found using biosimilar pegfilgrastim, with ICERs generally higher than those for filgrastim.
CONCLUSIONS
Biosimilar filgrastim and pegfilgrastim as primary prophylaxis are cost-effective approaches to avoid FN events in patients with BC, NSCLC, or NHL at intermediate risk for FN in Austria, France, and Germany.
Topics: Humans; Female; Filgrastim; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Biosimilar Pharmaceuticals; Lung Neoplasms; Granulocyte Colony-Stimulating Factor; Breast Neoplasms; Lymphoma, Non-Hodgkin; Febrile Neutropenia; Granulocytes
PubMed: 37728795
DOI: 10.1007/s00520-023-08043-4 -
Federal Practitioner : For the Health... May 2023Granulocyte colony-stimulating factor prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and febrile neutropenia and is...
BACKGROUND
Granulocyte colony-stimulating factor prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and febrile neutropenia and is recommended for at-risk patients receiving chemotherapy. Within the South Texas Veterans Health Care System, daily filgrastim injections remain the preferred formulation of granulocyte colony-stimulating factor for primary prophylaxis of febrile neutropenia.
METHODS
This retrospective, single-center cohort study included 59 patients who received daily filgrastim as primary prophylaxis with a curative cancer diagnosis and a chemotherapy regimen at the South Texas Veterans Health Care System from September 1, 2015 to September 24, 2020. Patients had either a high risk for febrile neutropenia or a chemotherapy regimen with an intermediate risk for febrile neutropenia and additional risk factors. The primary outcome was the incidence of neutropenia/febrile neutropenia leading to treatment delays. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia/febrile neutropenia.
RESULTS
Patients received a median (IQR) of 7 (5-10) doses of filgrastim for primary prophylaxis. Overall, 10 patients (17%) experienced treatment delays due to neutropenia/febrile neutropenia. Fifteen patients (25%) were hospitalized with a median (IQR) length of stay of 5 (4-7) days, 9 patients (15%) had documented infections, and 2 patients (3%) required a chemotherapy dose reduction. Additionally, 9 patients (15%) required an additional median (IQR) of 2 (2-5) doses of filgrastim, and 9 (15%) patients were transitioned to pegfilgrastim.
CONCLUSIONS
These results suggest that additional measures such as tracking postnadir absolute neutrophil counts should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia/febrile neutropenia.
PubMed: 37727832
DOI: 10.12788/fp.0327 -
Advances in Therapy Nov 2023Pegfilgrastim-cbqv (UDENYCA; Coherus BioSciences, Redwood City, CA, USA) is a pegfilgrastim (Neulasta; Amgen, Thousand Oaks, CA, USA) biosimilar approved for... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Pegfilgrastim-cbqv (UDENYCA; Coherus BioSciences, Redwood City, CA, USA) is a pegfilgrastim (Neulasta; Amgen, Thousand Oaks, CA, USA) biosimilar approved for administration by prefilled syringe (PFS). The recently approved pegfilgrastim-cbqv prefilled autoinjector (AI) was developed as another method of self-administration and to aid in-office use, providing flexibility in drug delivery. The objectives of the study were to assess the pharmacokinetics (PK) and pharmacodynamics (PD) to determine bioequivalence of the prefilled AI and the PFS for administration of pegfilgrastim-cbqv and to assess the safety profile of the prefilled AI.
METHODS
During this open-label, two-period crossover study, healthy adult males (N = 155) were randomly assigned (1:1 ratio) to receive a subcutaneous injection of pegfilgrastim-cbqv using a prefilled AI (n = 76) or a PFS (n = 79) in period 1. During period 2, participants received an injection using the other method. Primary PK and secondary PD parameters were calculated to assess the bioequivalence of the treatment as administered by the two delivery methods. Safety and immunogenicity were also assessed.
RESULTS
The 90% CIs of the geometric mean ratios for the PK and PD parameters were within the required range (80-125%), demonstrating bioequivalence between the pegfilgrastim-cbqv prefilled AI and PFS. Treatment-emergent adverse events (TEAEs) were reported by 75% and 74.1% of participants in the prefilled AI and PFS groups, respectively. The most common TEAEs in both treatment groups were myalgia, bone pain, and headache. AI-device-related TEAEs were injection site pain (1.4%) and injection site bruising (0.7%). The incidence of antidrug antibodies and neutralizing antibodies was low and was similar in both treatment sequences.
CONCLUSIONS
The bioequivalence of pegfilgrastim-cbqv administered using a prefilled AI and a PFS was established. The safety, including immunogenicity profiles, of pegfilgrastim-cbqv administered using the prefilled AI and the PFS were similar, with no new safety findings.
Topics: Adult; Humans; Male; Therapeutic Equivalency; Syringes; Cross-Over Studies; Injections, Subcutaneous; Healthy Volunteers; Biosimilar Pharmaceuticals; Injection Site Reaction; Pain
PubMed: 37707674
DOI: 10.1007/s12325-023-02636-5