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Lancet (London, England) Oct 2023Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated,... (Randomized Controlled Trial)
Randomized Controlled Trial
Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.
BACKGROUND
Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables.
METHODS
In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339.
FINDINGS
At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment.
INTERPRETATION
Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer.
FUNDING
Gilead Sciences.
Topics: Humans; Female; Breast Neoplasms; Quality of Life; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37633306
DOI: 10.1016/S0140-6736(23)01245-X -
Cancers Aug 2023Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This... (Review)
Review
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% ( = 0.056) and overall survival of 85.0% vs. 72.4% ( = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.
PubMed: 37568826
DOI: 10.3390/cancers15154012 -
Journal of Immunology (Baltimore, Md. :... Jul 2023Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2)...
Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
Topics: Humans; Female; Animals; Epitopes; Vinorelbine; Receptor, ErbB-2; Breast Neoplasms; Immunotherapy; Mammary Neoplasms, Animal; Peptides; Dendritic Cells; Trastuzumab
PubMed: 37204246
DOI: 10.4049/jimmunol.2300077 -
International Journal of Molecular... Dec 2023Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of...
Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of rapamycin/sirolimus (mTOR) and microtubules are prominent druggable targets for HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine yielded results superior to those of the monotherapies in HCC PDX models. Our research showed that the vinorelbine arrests cells at the mitotic phase, induces apoptosis, and normalizes tumor blood vessels but upregulates survivin and activates the mTOR/p70S6K/4EBP1 pathway. The addition of the everolimus significantly improved the tumor response to the vinorelbine, leading to improved overall survival (OS) in most tested orthotopic HCC PDX models. The mechanistic investigation revealed that this marked antitumor effect was accompanied by the downregulations of mTOR targets (p-p70S6K, p-4EBP1, and p-S6K); several key cell-cycle regulators; and the antiapoptotic protein survivin. These effects did not compromise the normalization of the blood vessels observed in response to the vinorelbine in the vinorelbine-sensitive PDX models or to the everolimus in the everolimus-sensitive PDX models. The combination of the everolimus and vinorelbine (everolimus/vinorelbine) also promoted apoptosis with minimal toxicity. Given the cost-effectiveness and established effectiveness of everolimus, and especially sirolimus, this strategy warrants further investigation in early-phase clinical trials.
Topics: Humans; Everolimus; Carcinoma, Hepatocellular; Vinorelbine; Survivin; Ribosomal Protein S6 Kinases, 70-kDa; Liver Neoplasms; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 38203186
DOI: 10.3390/ijms25010017 -
Aging Jul 2023In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to...
Comparative analyses of the prognosis, tumor immune microenvironment, and drug treatment response between left-sided and right-sided colon cancer by integrating scRNA-seq and bulk RNA-seq data.
BACKGROUND
In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to predict outcomes in patients with LCC and RCC.
METHODS
Based on identified differentially expressed genes and using single-cell RNA sequencing data, we constructed and validated a prognostic model for LCC and RCC patients in the TCGA-COAD cohort and GSE103479 cohort. Moreover, we compared the differences of TIM characteristics and drug treatment response between LCC and RCC patients.
RESULTS
We constructed and validated a five-gene prognostic model for LCC patients and a four-gene prognostic model for RCC patients, and both showed excellent performance. The RCC patients with higher risk scores were significantly associated with greater metastasis ( = 2.6×10), N stage ( = 0.012), advanced pathological stage ( = 1.4×10), and more stable microsatellite status ( = 0.007) but not T stage ( = 0.200). For LCC patients, the risk scores were not significantly associated with tumor stage and microsatellite status ( > 0.05). Additionally, immune infiltration by CD8 and regulatory T cells and M0, M1, and M2 macrophages differed significantly between LCC and RCC patients ( < 0.05). and mutations were significantly more common in LCC patients ( < 0.05). In contrast, , , and mutations were significantly more common in RCC patients ( < 0.05). In addition, tumor mutation burden values were significantly higher in RCC patients than in LCC patients ( = 5.9×10). Moreover, the expression of immune checkpoint targets was significantly higher in RCC patients than in LCC patients ( < 0.05), indicating that RCC patients maybe more sensitive to immunotherapy. However, LCC and RCC patients did not differ significantly in their sensitivity to eight selected chemicals or target drugs ( > 0.05). The average half-maximal inhibitory concentrations for camptothecin, teniposide, vinorelbine, and mitoxantrone were significantly lower in low-risk than in high-risk RCC patients ( < 0.05), indicating that the lower risk score of RCC patients, the more sensitive they were to these four drugs.
CONCLUSIONS
We investigated the differences in prognosis, TIM, and drug treatment response between LCC and RCC patients, which may contribute to accurate colon cancer prognosis and treatment of colon cancer.
Topics: Humans; Carcinoma, Renal Cell; RNA-Seq; Single-Cell Gene Expression Analysis; Prognosis; Colonic Neoplasms; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37480572
DOI: 10.18632/aging.204894 -
Frontiers in Oncology 2023Pediatric classical Hodgkin lymphoma (CHL) is a curable disease; however, the optimal salvage regimen is unclear for relapsed/refractory (R/R) disease. This study aimed...
Outcome and toxicity of ifosfamide, carboplatin, and etoposide versus gemcitabine and vinorelbine regimen for pediatric patients with relapsed or refractory Hodgkin's lymphoma.
BACKGROUND
Pediatric classical Hodgkin lymphoma (CHL) is a curable disease; however, the optimal salvage regimen is unclear for relapsed/refractory (R/R) disease. This study aimed to compare response rates, toxicity, event-free survival (EFS), and overall survival (OS) of ifosfamide, carboplatin, and etoposide (ICE) with gemcitabine and vinorelbine (GV) regimen after first-line doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in pediatric patients with R/R CHL.
METHODS
This is a retrospective cohort study of 132 pediatric patients with R/R CHL treated from July 2012 to December 2020 with ICE (n = 82) or GV (n = 50).
RESULTS
The median age at relapse was 13.9 years, and 68.2% were men. Rates of complete response, partial response, and progressive disease before consolidation were 50.6%, 3.7%, and 45.7% for ICE and 28.5%, 0%, and 71.5% for GV (P = 0.011). By multivariate analysis, regimen (P = 0.002), time to relapse (P = 0.0001), and B-symptoms (P = 0.002) were independent factors to lower response rates. Hematological toxicity, electrolyte disturbance, hemorrhagic cystitis, infectious complications, and hospital admission for fever neutropenia were statistically significant higher for the ICE regimen. Treatment-related mortalities were 2.4% for ICE and 2% for GV (P = 0.86). The 3-year EFS was 39.3% ± 11.4% for ICE and 24.9% ± 12.5% for GV (P = 0.0001), while 3-year OS was 69.3% ± 10.6% and 74% ± 12.9% (P = 0.3), respectively. By multivariate analysis, regimen (P = 0.0001), time to relapse (P = 0.011), B-symptoms (P = 0.001), and leukocytosis (P = 0.007) were significant for EFS, while anemia (P = 0.008), and progressive disease on early response evaluation (P = 0.022) were significant for OS.
CONCLUSIONS
The ICE regimen had a better overall response rate and EFS, but higher toxicity, than GV; however, OS and mortality were similar.
PubMed: 37441423
DOI: 10.3389/fonc.2023.1153128 -
Frontiers in Pharmacology 2023Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them... (Review)
Review
Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them eventually progress to advanced stages. Currently, chemotherapy is the first-line treatment for advanced STSs. There are difficulties in selecting appropriate drugs for multiline chemotherapy, or for combination treatment of different STS histological subtypes. In this study, we first comprehensively reviewed the efficacy of various chemotherapeutic drugs in the treatment of STSs, and then described the current status of sensitive drugs for different STS subtypes. anthracyclines are the most important systemic treatment for advanced STSs. Ifosfamide, trabectedin, gemcitabine, taxanes, dacarbazine, and eribulin exhibit certain activities in STSs. Vinca alkaloid agents (vindesine, vinblastine, vinorelbine, vincristine) have important therapeutic effects in specific STS subtypes, such as rhabdomyosarcoma and Ewing sarcoma family tumors, whereas their activity in other subtypes is weak. Other chemotherapeutic drugs (methotrexate, cisplatin, etoposide, pemetrexed) have weak efficacy in STSs and are rarely used. It is necessary to select specific second- or above-line chemotherapeutic drugs depending on the histological subtype. This review aims to provide a reference for the selection of chemotherapeutic drugs for multi-line therapy for patients with advanced STSs who have an increasingly long survival.
PubMed: 37637411
DOI: 10.3389/fphar.2023.1199292 -
Thoracic Cancer Aug 2023This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in...
A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2-negative metastatic breast cancer.
BACKGROUND
This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China.
METHODS
The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status.
RESULTS
Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and ≥second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%).
CONCLUSIONS
The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup.
Topics: Humans; Female; Breast Neoplasms; Capecitabine; Vinorelbine; East Asian People; Prospective Studies; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2; Triple Negative Breast Neoplasms; Neoplasm Metastasis; Treatment Outcome
PubMed: 37402471
DOI: 10.1111/1759-7714.15011 -
BMC Medical Genomics Aug 2023To screen the possible potential signaling pathways related to enhancer of zeste homolog 2 (EZH2) based on ceRNA mechanism, and to analyze the correlation between E2H2...
OBJECTIVE
To screen the possible potential signaling pathways related to enhancer of zeste homolog 2 (EZH2) based on ceRNA mechanism, and to analyze the correlation between E2H2 and depths of various immune cell infiltration depths. The relationship between different immune checkpoints were also analyzed.
METHODS
First, the expression of EZH2 in pan-cancer (18 malignancies) was analyzed with the TCGA database. Hepatocellular carcinoma (HCC) tissues of 374 cases and normal tissues of 50 cases were analyzed in terms of the differential expression, overall survival (OS) and progression-free-survival (PFS). Then, we conducted GO and KEGG enrichment analysis on target gene. We also analyzed mRNA-miRNA and MicroRNA (miRNA)- long non-coding RNA (lncRNA) correlation with starbase databse, so as to determine the potential ceRNA mechanism associated with EZH2. Finally, immunoassay and drug-sensitivity analysis of EZH2 was performed.
RESULTS
Seven potential EZH2-related ceRNA pathways were screened out, namely lncRNA: Small Nucleolar RNA Host Gene 1 (SNHG1), SNHG 3, and SNHG 6-miR-101-3p-EZH2; and lncRNA: Long Intergenic Non-Protein Coding RNA 1978 (LINC01978), SNHG12, Ring Finger Protein 216 Pseudogene 1 (RNF216P1), and Coiled-coil Domain Containing 18 Antisense RNA 1 (CCDC18-AS1)-let-7c-5p-EZH2. Finally, 4 potential EZH2-related ceRNA pathways were identified through qPCR.According to immune correlation analysis, EZH2 may be positively correlated with T cells follicular helper, T cells Cluster of differentiation (CD)4 memory activated, Macrophages M0, and B cells memory (P < 0.05, cof > 0.2); while be negatively correlated with T cells CD4 + memory resting (P < 0.05, cof < -0.2). And EZH2 is positively correlated with Programmed Cell Death 1 (PDCD1) (R = 0.22), CD274 (R = 0.3) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) (R = 0.23). According to drug sensitivity analysis, patients in the high expression group were more susceptible to the effects of various drugs including Sorafenib, 5-Fluorouracil, Doxorubicin, Etoposide, Paclitaxel, and Vinorelbine than those with low expression.
CONCLUSION
This study revealed seven potential pathways of Enhancer of Zeste Homolog 2 (EZH2)-related ceRNA mechanisms: lncRNA (SNHG3, 6) -Mir-101-3P-ezh2; lncRNA (SNHG12, RNF216P1)-let-7c-5p-EZH2. We also analyzed the immunity and drug sensitivity of EZH2. Our study proves that EZH2 still has great research prospects in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Enhancer of Zeste Homolog 2 Protein; RNA, Long Noncoding; Liver Neoplasms; MicroRNAs; Immunoassay
PubMed: 37626362
DOI: 10.1186/s12920-023-01594-9