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PloS One 2024To evaluate the impact of the entry of biosimilars on the pricing of eight biologic products in 57 countries and regions.
OBJECTIVE
To evaluate the impact of the entry of biosimilars on the pricing of eight biologic products in 57 countries and regions.
METHODS
We utilized an interrupted time series design and IQVIA MIDAS® data to analyze the annual sales data of eight biologic products (adalimumab, bevacizumab, epoetin, etanercept, filgrastim, infliximab, pegfilgrastim, and trastuzumab) across 57 countries and regions from January 1, 2012, to December 31, 2019. We examined the immediate and long-term changes in biologics ex-manufacturer pricing following the entry of biosimilars to the market.
RESULTS
Following the entry of biosimilars, the average price per dose of biologic product was immediately reduced by $438 for trastuzumab, $112 for infliximab, and $110 for bevacizumab. The persistent effect of biosimilars' market entry led to further reductions in price per dose every year: by $49 for adalimumab, $290 for filgrastim, $21 for infliximab, and $189 for trastuzumab. Similarly, we analyzed the impact of biosimilars on four biologics' prices in the US, where the prices of three biologics significantly decreased every year, with filgrastim, pegfilgrastim, and infliximab decreasing by $955, $753, and $104, respectively.
CONCLUSIONS
The introduction of biosimilars has significantly reduced the prices of biologics both globally and in the US. These findings not only demonstrate the economic benefits of increasing biosimilar utilization, but also emphasize the importance of biosimilars in controlling healthcare costs. Policies should aim to expand the availability of biosimilars to counteract the exponential growth of medical spending caused by the use of biologics.
Topics: Biosimilar Pharmaceuticals; Humans; Infliximab; Filgrastim; Biological Products; Drug Costs; Adalimumab; Etanercept; Trastuzumab; Costs and Cost Analysis; Polyethylene Glycols
PubMed: 38843282
DOI: 10.1371/journal.pone.0304851 -
PloS One 2024Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous...
Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.
Topics: CD47 Antigen; Animals; Receptors, Immunologic; Humans; Mice; Immunoconjugates; Antigens, Differentiation; Cell Line, Tumor; Female; Trastuzumab; Topoisomerase I Inhibitors; Immunotherapy; Mice, Inbred BALB C
PubMed: 38843278
DOI: 10.1371/journal.pone.0304985 -
Internal Medicine (Tokyo, Japan) Jun 2024Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive...
Sustained Clinical Complete Response after Discontinuation of Trastuzumab-deruxetecan Due to Interstitial Pneumonia for HER2-positive Gastric adenocarcinoma with Enteroblastic Differentiation (GAED): A Case Report.
Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.
PubMed: 38839335
DOI: 10.2169/internalmedicine.3155-23 -
Oncology and Therapy Jun 2024Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse...
INTRODUCTION
Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice.
METHODS
We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form.
RESULTS
Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced.
CONCLUSION
Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources.
GOV REGISTRATION
NCT03892655.
PubMed: 38836997
DOI: 10.1007/s40487-024-00284-5 -
Scientific Reports Jun 2024Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel...
Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel approaches are required to improve patient outcomes. We have evaluated patient-derived explants (PDEs) as a novel preclinical platform for breast cancer (BC) and implemented cutting-edge digital pathology and multi-immunofluorescent approaches for investigating biomarker changes in both tumour and stromal areas at endpoint. Short-term culture of intact fragments of BCs as PDEs retained an intact immune microenvironment, and tumour architecture was augmented by the inclusion of autologous serum in the culture media. Cell death/proliferation responses to FET chemotherapy in BC-PDEs correlated significantly with BC patient progression-free survival (p = 0.012 and p = 0.0041, respectively) and cell death responses to the HER2 antibody therapy trastuzumab correlated significantly with HER2 status (p = 0.018). These studies show that the PDE platform combined with digital pathology is a robust preclinical approach for informing clinical responses to chemotherapy and antibody-directed therapies in breast cancer. Furthermore, since BC-PDEs retain an intact tumour architecture over the short-term, they facilitate the preclinical testing of anti-cancer agents targeting the tumour microenvironment.
Topics: Humans; Breast Neoplasms; Female; Tumor Microenvironment; Trastuzumab; Receptor, ErbB-2; Cell Proliferation; Antineoplastic Agents; Middle Aged; Biomarkers, Tumor; Antineoplastic Agents, Immunological
PubMed: 38834809
DOI: 10.1038/s41598-024-63170-0 -
Scientific Reports Jun 2024The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence... (Randomized Controlled Trial)
Randomized Controlled Trial
The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin. Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin similarly secreted IL-6, TNF-α, IL-1β, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin, strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.
Topics: Humans; Trastuzumab; Biosimilar Pharmaceuticals; Male; Therapeutic Equivalency; Adult; Cytokines; Cross-Over Studies; Double-Blind Method; Leukocytes, Mononuclear; Immunomodulation; Young Adult
PubMed: 38834577
DOI: 10.1038/s41598-024-61265-2 -
ESMO Open Jun 2024In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired...
BACKGROUND
In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control.
PATIENTS AND METHODS
Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant.
RESULTS
Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months.
CONCLUSIONS
PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
PubMed: 38833970
DOI: 10.1016/j.esmoop.2024.103465 -
Heliyon Jun 2024The significance of novel anti-tumor pharmaceuticals in the treatment of gynecological tumors is growing, but there is no consensus regarding the optimal drug delivery...
OBJECTIVE
The significance of novel anti-tumor pharmaceuticals in the treatment of gynecological tumors is growing, but there is no consensus regarding the optimal drug delivery strategy for gynecological tumors. This study seeks to investigate the treatment models of novel anti-tumor drugs in patients with gynecological cancer in China over the past five years, with a particular emphasis on the trend and rationality of their use.
METHOD
We conducted a cross-sectional analysis of data from a China Medical Association-supervised hospital prescription analysis cooperation initiative. The data was derived from prescriptions written for patients diagnosed with cancer between January 2017 and December 2021. The required information for patients was extracted. Our study included 2308 patients that were diagnosed as gynecological tumors which were treated with novel antineoplastic targeted drugs. Patients were categorized by age and region. Then, the selection, application, and indications of the most essential treatment pharmaceuticals were investigated. We evaluated anti-tumor prescription information based on the recommended drug labeling protocol and the most recent domestic and international guidelines.Excel 2013 and SPSS (version 25; SPSS Inc., Chicago, IL, United States) were utilized to conduct statistical analysis.In addition,we also used Sankey diagram to evalute the relation between novel antineoplastic targeted drugs and corresponding diagnoses.
RESULT
The top three cities for the 2308 patients included in this study were Guangzhou (28.51%), Hangzhou (21.79%), and Beijing (20.06%). In the past five years, the average age of medication patients was 55.61-year-old, with 37.86% of women aged of 51-60. Each patient's primary treatment regimens were statistically analyzed, yielding a total of 16 single-drug and combination-drug primary treatment regimens. Bevacizumab, Olaparib, Trastuzumab, Apatinib, and Arotinib were the top five treatment strategies. The maximum proportion, up to 0.74%, was attributed to the combination of human epidermal growth factor receptor-2 inhibitor (HER2i), including Trastuzumab and Parostuzumab. Vascular endothelial growth factor receptor inhibitor (VEGFRi), including Bevacizumab and Apatinib was the most frequently prescribed medication for outpatients in major cities across the country. According to the 5-year change in time, poly adenosine diphosphate ribose polymerase inhibitor (PARPi) rated first in terms of usage, with Olaparib ranking first with the highest concentration of 33.44% and Niraparib ranking second overall with the fastest growth in 2021. The quantity of VEGFRi variants utilized was the greatest, and their proportion of total usage increased annually. The top five drugs by total drug costs were Bevacizumab, Carelizumab, Olaparib, Trastuzumab, and Apatinib. However, the top five drugs by per capita drug cost were Olaparib + Bevacizumab, Bevacizumab + Sidilimab, Arrotinib + Olaparib, Olaparib, and Patuzumab + Trastuzumab.
CONCLUSION
The incidence rate of gynecological tumor patients rises with age, and the cost of drug treatment has risen annually over the past five years, which is also related to the rising incidence rate of tumors in recent years. Bevacizumab rates first in the drug treatment scheme for the application of novel anti-tumor targeted drugs, which may be related to the widespread use of VEGFRi drugs in gynecological and reproductive tumors. Breast cancer and adenocarcinoma are at the top of the female cancer incidence spectrum, which may explain why HER2i multi-drug combination regimen rates highest among multi-drug combination regimens. Future research may concentrate on how novel anti-tumor targeted drugs can minimize the economic burden and maximize the benefits of patient treatment for patients with gynecological cancer.
PubMed: 38832281
DOI: 10.1016/j.heliyon.2024.e31371 -
Cureus May 2024Chemotherapy-related cardiotoxicity can exhibit several patterns of functional, structural, and vascular complications. This study aims to identify the patterns and the...
BACKGROUND
Chemotherapy-related cardiotoxicity can exhibit several patterns of functional, structural, and vascular complications. This study aims to identify the patterns and the factors associated with cardiotoxicity in cancer patients.
METHOD
A retrospective cross-sectional analysis of 96 adult cancer patients undergoing anticancer therapy was investigated at King Khalid Hospital in Najran, Saudi Arabia, from May 2022 to April 2023. The data on patient and cancer characteristics, treatment, and outcomes were collected and analyzed. Factors associated with cardiotoxicity were investigated through univariate analyses using odds ratio (OR) and 95% confidence interval (CI).
RESULTS
Among the 96 cancer patients in the study, cardiotoxicity occurred in 12 individuals (12.5%). The mean age was 57.0 ± 13.3 years (range: 32-81 years), with 32 (33.3%) being above 65 years. The most common comorbidities were diabetes (n=48; 50%), followed by hypertension (n=32; 33.3%), and dyslipidemia (n=20; 20.8%). The most common cancers were gastrointestinal cancer (n=32; 33.3%), followed by breast cancer (n=22; 22.9%) and lymphoma (n=14; 14.6%). Females were disproportionately affected (64.6%), with 57.3% of them in the metastatic stage. The majority of patients (90.6%) had normal ejection fraction before chemotherapy initiation. In univariate analysis, current smoking (OR: 7.00; 95%CI: 1.94-25.25, p= 0.003), history of percutaneous cardiac intervention (OR: 40.24; 95%CI: 1.80-896.26, p= 0.019), diabetes (OR: 6.05; 95%CI: 1.24-29.32, p= 0.025), renal failure (OR: 8.20; 95%CI: 0.91-74.88, p= 0.046), dyslipidemia (OR: 5.00; 95 CI: 1.38-18.32, p=0.012), anthracycline use (OR: 18.33; 95%CI: 4.36-126.55, p <0.001), trastuzumab use (OR: 25.00; 95%CI: 6.25-129.86, p < 0.001), and increased chemotherapy cycles number (> 10 cycles) (OR: 73.00; 95%CI: 8.56- 622.36, p < 0.001) were associated with cardiotoxicity. Additionally, beta-blocker use was associated with lower rates of cardiotoxicity (OR: 0.17; 95%CI: 0.036-0.84, p= 0.029).
CONCLUSIONS
The incidence of cardiotoxicity among cancer patients treated with chemotherapy is modest, difficult to predict, and independent of baseline cardiac systolic functions. Factors associated with cardiotoxicity include smoking, history of percutaneous cardiac intervention, diabetes, renal failure, dyslipidemia, anthracycline or trastuzumab use, and increased chemotherapy cycle numbers. A combination of various anticancer drugs and chemotherapy may dramatically raise the risk of cardiotoxicity in cancer patients. As a result, patients receiving high-risk cardiotoxic drugs should be monitored with caution to avoid drug-related cardiotoxicity. Furthermore, proactive treatment techniques aiming at reducing the possible cardiotoxic effects of anticancer therapy are critical.
PubMed: 38832203
DOI: 10.7759/cureus.59608 -
Orphanet Journal of Rare Diseases Jun 2024Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration...
BACKGROUND
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape.
METHODS
Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed.
RESULTS
Notable copy number gains (logFC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (logFC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event.
CONCLUSION
Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.
Topics: Humans; Paget Disease, Extramammary; Whole Genome Sequencing; Male; Receptor, ErbB-2; Aged; DNA Copy Number Variations
PubMed: 38831459
DOI: 10.1186/s13023-024-03169-y