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Journal of Clinical Oncology : Official... Dec 2023JCO The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Lung Neoplasms; Neoplasm Staging; Pemetrexed; Survival Analysis; Vinorelbine
PubMed: 37656928
DOI: 10.1200/JCO.23.00179 -
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 -
Journal of Biomolecular Structure &... Nov 2023Vinorelbine, a vinca alkaloid, is an antimitotic drug that inhibits polymerisation process of tubulins to microtubules, and is widely used in cancer chemotherapy. Due to...
Vinorelbine, a vinca alkaloid, is an antimitotic drug that inhibits polymerisation process of tubulins to microtubules, and is widely used in cancer chemotherapy. Due to the importance of the structure-activity relationship, in this work the conformational preferences of the vinorelbine molecule were surched by PM3 method. The obtained lowest energy conformer was then optimized at DFT/B3LYP/6-31G(d,p) level of theory and the structural characteristics were determined. Frontier orbital (HOMO, LUMO) and molecular electrostatic potential (MEP) analyses were performed for the optimized structure. The experimental FT-IR, Raman and UV-VIS spectral data of vinorelbine along with the theoretical DFT/B3LYP/6-31G(d,p) calculations were investigated in detail. The vibrational wavenumbers were assigned based on the calculated potential energy distribution (PED) of the vibrational modes. To shed light into the anticancer property of vinorelbine as microtubule destabilizer, the most favourable binding mode and the interaction details between vinorelbine and tubulin were revealed by molecular docking studies of vinorelbine into the α,β-tubulin (PDB IDs: 4O2B; 1SA0; 7CNN) and binding free energies were calculated by the combination of Molecular Mechanics/Generalized Born Surface Area (MMGBSA) and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methods {MM/PB(GB)SA}. The calculated vinorelbine-7CNN binding free energy, using by MM/PB(GB)SA approach, was found to be the best (-50.39 kcal/mol), and followed by vinorelbine-4O2B (-28.5 kcal/mol) and vinorelbine-1SA0 (-17.59 kcal/mol) systems. Moreover, the interaction of vinorelbine with the cytochrome P450 enzymes (CYP), which are known to help in the metabolism of many drugs in the body, was investigated by docking studies against CYP2D6 and CYP3A4 targets.Communicated by Ramaswamy H. Sarma.
Topics: Molecular Docking Simulation; Vinorelbine; Vinca; Spectroscopy, Fourier Transform Infrared; Molecular Conformation; Vibration; Spectrum Analysis, Raman; Quantum Theory; Spectrophotometry, Ultraviolet; Thermodynamics
PubMed: 36369834
DOI: 10.1080/07391102.2022.2145369 -
Technology in Cancer Research &... 2023Immune checkpoint (ICP) expression in tumor cells could directly or indirectly affect the results of immunotherapy. ICP ligands on tumor cells usually bind their immune...
Immune checkpoint (ICP) expression in tumor cells could directly or indirectly affect the results of immunotherapy. ICP ligands on tumor cells usually bind their immune cell receptors to inhibit the activity, resulting in tumor immune escape. Thus, the purpose of this study was to ascertain the impact of various chemotherapeutic drugs on ICP expression in non-small cell lung cancer (NSCLC) cell lines with different pathological subtypes to provide a basis for the development of a superior regimen of chemotherapy combined with ICP blockade. Several first-line chemotherapy agents (cisplatin, carboplatin, paclitaxel, gemcitabine, vinorelbine, and pemetrexed) were selected to treat different NSCLC cell lines (squamous carcinoma H1703, adenocarcinoma A549, and large cell cancer H460) for 72 hours, and then the changes in ICP expression in the tumor cells were observed through flow cytometry. Cisplatin, carboplatin, and paclitaxel upregulated the expressions of programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) in A549 and H460 cell lines. Meanwhile, vinorelbine and pemetrexed upregulated PD-L1 and PD-L2 in H1703, A549, and H460 cell lines. Paclitaxel, gemcitabine, vinorelbine, and pemetrexed significantly upregulated the expressions of both galectin-9 and high-mobility group box protein 1 (HMGB1) in the A549 cell line. Cisplatin and paclitaxel significantly upregulated the expressions of major histocompatibility complex-II (MHC-II), galectin-3, α-synuclein, and fibrinogen-like protein 1 (FGL1) in A549 and H460 cell lines. In addition, cisplatin and vinorelbine significantly upregulated the expressions of both CD155 and CD112 in the H460 cell line. Vinorelbine upregulated MHC-I in all three cell lines. Chemotherapy agents have different effects on the expression of ICP ligands in tumor cells with different pathological types, and this may affect the efficacy of combined immunotherapy. These results provide a theoretical basis for further selection and optimization of the combination of chemotherapy and immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cisplatin; Vinorelbine; Lung Neoplasms; Carboplatin; Pemetrexed; B7-H1 Antigen; Ligands; Deoxycytidine; Antineoplastic Agents; Gemcitabine; Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Fibrinogen
PubMed: 37728201
DOI: 10.1177/15330338231202307 -
Expert Opinion on Pharmacotherapy Aug 2014Originally formulated as an intravenous (i.v.) agent, vinorelbine is also currently available as an oral chemotherapeutic agent. Oral vinorelbine has demonstrated... (Review)
Review
INTRODUCTION
Originally formulated as an intravenous (i.v.) agent, vinorelbine is also currently available as an oral chemotherapeutic agent. Oral vinorelbine has demonstrated significant activity in different settings for NSCLC, including adjuvant treatment for resected disease, concurrent chemoradiation for locally advanced NSCLC and palliative chemotherapy for recurrent/metastatic NSCLC, as part of combination schedules or as a single-agent treatment.
AREAS COVERED
The authors explored the available data describing the use of oral vinorelbine in NSCLC. PubMed articles and abstracts presented at international conferences were analysed, and relevant trials were reported and discussed. Specific settings, including the treatment of elderly and unfit patients and metronomic schedules including oral vinorelbine, were evaluated. Available pharmacoeconomic data were also assessed.
EXPERT OPINION
Oral vinorelbine is an appealing agent, particularly as part of combination regimens containing platinum derivatives, although it can have a role as a single-agent treatment as well. Its safety profile is generally favourable and its route of administration is generally preferred by patients receiving chemotherapy. Compared to i.v. vinorelbine and other antineoplastic agents, oral vinorelbine has been reported to be advantageous in terms of cost savings.
Topics: Administration, Oral; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome; Vinblastine; Vinorelbine
PubMed: 24972635
DOI: 10.1517/14656566.2014.934224 -
The Lancet. Oncology Apr 2022Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.
METHODS
In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.
FINDINGS
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).
INTERPRETATION
Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.
FUNDING
Bayer Healthcare Pharmaceuticals.
Topics: Adolescent; Adult; Humans; Arthrogryposis; Immunoconjugates; Maytansine; Mesothelin; Mesothelioma, Malignant; Neoplasm Recurrence, Local; Vinorelbine
PubMed: 35358455
DOI: 10.1016/S1470-2045(22)00061-4 -
Experimental & Molecular Medicine Nov 2020Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits....
Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Synergism; Fibroblast Growth Factors; Gene Expression; Humans; Immunohistochemistry; Liver Neoplasms; Mice; Piperazines; Pyridines; Receptor, Fibroblast Growth Factor, Type 4; Vinorelbine; Xenograft Model Antitumor Assays
PubMed: 33235319
DOI: 10.1038/s12276-020-00524-4 -
Cancer Chemotherapy and Pharmacology Sep 2014Over the last decade, metronomic chemotherapy has been increasingly considered as an attractive strategy for treating cancer in a variety of settings. Beside... (Review)
Review
Over the last decade, metronomic chemotherapy has been increasingly considered as an attractive strategy for treating cancer in a variety of settings. Beside pharmaco-economic considerations making metronomics a unique opportunity in low- or middle-income countries, revisiting dosing schedules using continuous low doses of cytotoxics should theoretically permit to reduce the incidence of treatment-related toxicities, while offering unexpected novel mechanisms of actions such as antiangiogenic or immuno-stimulating properties. Consequently, a number of clinical trials sought to evaluate to what extent switching to metronomic schedules could actually impact indeed on the efficacy/toxicity balance of a variety of anticancer drugs in both adults and pediatric oncology. Vinorelbine is a vinca-alcaloïd that remains the backbone of several regimens to treat patients with metastatic breast cancer or non-small cell lung cancer. Additionally, vinorelbine is widely used to treat a variety of solid tumors in children such as rhabdomyosarcomas and acute leukemia. The recent approval of an oral formulation of vinorelbine has open the way to developing alternative metronomic schedules with this drug. Consequently, a number of clinical trials investigating on metronomic vinorelbine have been performed over the last few years, with seemingly inconsistent results to date. Of note, all the studies published thus far were based upon empirical determination of the metronomic schedule, both in terms of doses, drug-free intervals and repartition of the administrations throughout time. Because the very concept of «low, repeated doses with little or no drug-free interval» covers numerous possible combinations, determining the optimal protocol using traditional under-powered empirical design looks like an unreachable goal. In this context, mathematical modeling offers invaluable in silico tools to help determining the optimal metronomic schedule among a variety of possibilities. This review covers the latest clinical trials investigating on metronomic vinorelbine and proposes alternative strategies for developing computational decision support to make metronomics a scientific-grounded strategy, rather than an empirical practice at the bedside. In particular, mathematical simulations using an original pharmacokinetics/pharmacodynamics constraint models provide clues for exploring new paths in the way metronomic vinorelbine could be scheduled in patients with lung cancer.
Topics: Administration, Metronomic; Administration, Oral; Angiogenesis Inhibitors; Antineoplastic Agents; Child; Clinical Trials as Topic; Decision Support Systems, Clinical; Humans; Lung Neoplasms; Vinblastine; Vinorelbine
PubMed: 25082520
DOI: 10.1007/s00280-014-2546-1 -
Cancer Biotherapy & Radiopharmaceuticals Oct 2023This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic...
This study investigated the loadability and releasing profiles of vinorelbine and raltitrexed from CalliSpheres Beads (CB) , and further explored the pharmacokinetic features of vinorelbine and raltitrexed eluting CB Ten milligrams vinorelbine and 0.2 mg raltitrexed were mixed with 0.15 g CB at two sizes (100-300 and 300-500 μm) for 24 h, respectively, to measure the loadability. Then vinorelbine/raltitrexed loading CBs were placed in 20% phosphate-buffered saline for 24 h to measure the release profiles. Transcatheter arterial chemoembolization (TACE) with 1 mg vinorelbine eluting CBs (two sizes respectively) and transcatheter arterial hepatic infusion (TAI) with 1 mg vinorelbine were performed in 9 rabbits (3 rabbits in each group). The above experiments were repeated with 0.2 mg raltitrexed. Vinorelbine loading efficiency quickly reached 90% within 10 min with maximum loadability >90% by CB with both two sizes, and vinorelbine release rate gradually increased to ∼100% within 1 h. Raltitrexed loading efficiency gradually increased to >40% within 15 min, then slowly increased to >60% within 24 h, with maximum loadability <70% by CB with both sizes, and raltitrexed release rate gradually increased to >90% within 1 h. Besides, vinorelbine/raltitrexed eluting CB showed greatly decreased maximum serum concentration (Cmax) of the drug compared with TAI in rabbits with similar area under the curve (0-t), mean residence time (0-t), and half-time (T1/2). CB exhibits good loadability and an acceptable releasing profile for eluting vinorelbine and raltitrexed, and shows lower Cmax and numerically stable concentration than TAI.
Topics: Animals; Rabbits; Vinorelbine; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic
PubMed: 32614660
DOI: 10.1089/cbr.2019.3360 -
Advances in Experimental Medicine and... 2016Despite a growing interest in development of non-cytotoxic targeted agents, systemic chemotherapy is still the mainstay of treatment for both non-small cell lung cancer... (Review)
Review
Despite a growing interest in development of non-cytotoxic targeted agents, systemic chemotherapy is still the mainstay of treatment for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). However, chemotherapy resistance limits our ability to effectively treat advanced lung cancer. Some lung tumors are intrinsically resistant to chemotherapy, and in virtually all cases, even the initial responders rapidly develop acquired resistance. While targeting histology could result in enhanced tumor sensitivity to a particular chemotherapeutic agent, better understanding of molecular determinants of chemotherapy sensitivity/resistance would be critically important. Development of predictive biomarkers to personalize chemotherapeutic agents and combining novel agents targeting specific resistance pathways with standard chemotherapy could be some promising strategies to overcome chemotherapy resistance in lung cancer. In this chapter, we will discuss some key mechanisms of resistance for commonly used chemotherapeutic agents in lung cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B; Deoxycytidine; Drug Resistance, Neoplasm; Etoposide; Humans; Lung Neoplasms; Pemetrexed; Taxoids; Vinblastine; Vinorelbine; Gemcitabine
PubMed: 26667345
DOI: 10.1007/978-3-319-24223-1_10