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Web Resources: Vinorelbine
Recent Research Publications

Web Resources: Vinorelbine (6 links)

Recent Research Publications

Merdin A, İskender D, Ulu BU, et al.
Pralatrexate induced durable response in a relapsed/refractory peripheral T-cell lymphoma patient with a history of autologous stem cell transplantation: Case report of a patient followed-up over 3 years under pralatrexate treatment.
Medicine (Baltimore). 2019; 98(30):e16482 [PubMed] Related Publications
RATIONALE: Relapsed or refractory peripheral T-cell lymphomas are aggressive diseases. Pralatrexate is an antimetabolite. Hereby, we are reporting a pralatrexate induced durable response in a relapsed/refractory peripheral T-Cell lymphoma patient with a history of autologous stem cell transplantation.
PATIENT CONCERNS: A male patient born in February 1947 was diagnosed with lymphoma based on his cervical lymph node excisional biopsy.
DIAGNOSES: He was diagnosed with PTCL-NOS on February 19, 2013.
INTERVENTIONS: The patient received 6 cycles of CHOP (Cyclophosphamide, doxorubicine, vincristine, methylprednisolone) chemotherapy, which achieved a complete remission. The patient underwent autologous stem cell transplantation in December 2013. After relapse was detected in the third month of the transplantation, the patient was treated with 2 cycles of ViGePP (vinorelbine, gemcitabine, procarbazine, prednisone/ methylprednisolone) chemotherapy. The patient was considered refractory to treatment after the ViGePP chemotherapy, and he was given brentuximab vedotin. Once a full response to treatment was achieved after 2 cycles, the patient received 6 cycles of brentuximab vedotin treatment. After 6 cycles, a skin biopsy was performed and the patient was diagnosed with relapsed/refractory PTCL-NOS. Pralatrexate therapy was then started on February 1, 2016 at a dose of 30 mg/m once weekly for 6 weeks in 7-week cycles.
OUTCOMES: The patient responded to pralatrexate treatment. And he has been under pralatrexate treatment over 3 years.
LESSONS: Pralatrexate should also be kept in mind as a treatment alternative in relapsed or refractory peripheral T-cell lymphoma patients.

Drąg-Zalesińska M, Saczko J, Choromańska A, et al.
Cisplatin and Vinorelbine -Mediated Electrochemotherapeutic Approach Against Multidrug Resistant Small Cell Lung Cancer (H69AR)
Anticancer Res. 2019; 39(7):3711-3718 [PubMed] Related Publications
BACKGROUND/AIM: Small cell lung cancer (SCLC) originates from neuroendocrine branchial cells (15-20%). It is regarded as distinct from other lung cancers due to its biological and clinical features. In most cases of SCLC, surgery or radiotherapy alone is not an effective cure. The aim of our study was to examine the cytotoxic effects of chemotherapy supported by electroporation (EP) on a resistant SCLC model, in vitro.
MATERIAL AND METHODS: The multidrug resistant small lung cell line H69AR was used to evaluate the cytotoxic effects of cisplatin (CPPD) and vinorelbine (Navirel®; NAV) at lower doses when used with EP. Cells were treated with different concentrations of CPPD and NAV, alone or in combination with the following EP parameters: 400-1200 V/cm, 8 pulses of 100 μs duration, at 1Hz. The cell viability was estimated by MTT assay after 24 and 48 h. Apoptotic cells were detected by neutral comet assay and immunofluorescence assay with PARP-6.
RESULTS: CPPD and NAV alone showed a dose-dependent effect on cell viability. Cytostatic drugs combined with EP revealed increased anticancer activity. Lower doses of CPPD or NAV delivered by EP were as effective as higher doses of these drugs without EP. The electrochemotherapeutic protocols increased the number of apoptotic cells and increased immunoreactivity of PARP-6. Our results indicated higher sensitivity of H69AR cells to NAV supported by EP.
CONCLUSION: In SCLC cells, an increased anticancer activity was potentiated by exposure of cells to high intensity electric pulses and low drug doses. It is suggested that this method could be effectively applied in the treatment of lung cancer.

Stravodimou A, Voutsadakis IA
A Systematic Review and Meta-analysis of the Combination of Vinorelbine and Lapatinib in Patients With Her2-positive Metastatic Breast Cancer.
Anticancer Res. 2019; 39(7):3295-3301 [PubMed] Related Publications
The development of effective human epidermal growth factor receptor 2 (HER2)-targeted therapies has been heralded as a significant milestone in breast cancer treatment, resulting in improvement of the outcome for those with HER2-positive metastatic breast cancer. Despite these advantages, metastatic breast cancer is still regarded as an incurable disease. In heavily pretreated patients with increasingly limited options for palliative management, ensuring control of disease and maintenance of quality of life is an important goal. Vinorelbine and lapatinib is a combination used in later-line treatment of metastatic HER2-positive breast cancer. The current article presents a systematic review and meta-analysis of prospective series of the vinorelbine/lapatinib doublet for efficacy and toxicity in metastatic HER2-positive breast cancer. Altogether seven prospective trials involving 235 evaluable patients were retrieved for analysis. Pooled estimates of response rate and disease control rate were 24.4% and 63.3% respectively. Furthermore, overall survival was 20.1 months and progression-free survival was 5.44 months. The most common grade 3 and 4 toxicities were seen in fewer than 10% of cases. Vinorelbine/ lapatinib combination regimen may serve as an option for pre-treated patients with metastatic HER2-positive breast cancer.

Roviello G, Corona SP, Conca R, et al.
Is there still a place for vinorelbine in advanced metastatic castration resistant prostate cancer?
Medicine (Baltimore). 2019; 98(26):e16249 [PubMed] Free Access to Full Article Related Publications
The aim of this paper was to evaluate the activity and tolerability of oral vinorelbine in patients with advanced castration resistant prostate cancer (CRPC) who progressed after a minimum of three lines including: abiraterone acetate, docetaxel, cabazitaxel, and enzalutamide.Treatment consisted of weekly oral vinorelbine 60 mg/m. Chemotherapy was administered until disease progression or unacceptable toxicity.Twenty-six patients received vinorelbine: their median age was 74 years (range 58-84 years). Twenty-four (92.3%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in 2 patients (7.7%). Among the subjects who were symptomatic at baseline, pain was reduced in 3 patients (13.6%) with a significant decrease in analgesic use. Median progression-free survival was 9 weeks (95% CI: 7 to 11) and median overall survival was 17 weeks (95% CI: 12 to 22). Treatment was well tolerated, and no grade 4 toxicities were observed.Our findings do not suggest the use of oral vinorelbine on a weekly schedule, in CRPC heavily pre-treated.

Yan Y, Li XQ, Duan JL, et al.
Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene.
Int J Nanomedicine. 2019; 14:3645-3667 [PubMed] Free Access to Full Article Related Publications

Kwon BS, Park JH, Kim S, et al.
Survival benefit of first-generation epidermal growth factor receptor-tyrosine kinase inhibitors in female with advanced lung cancer.
Tumori. 2019; 105(3):216-224 [PubMed] Related Publications
BACKGROUND: This study aimed to estimate therapeutic effects of first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in real-world practice, by analyzing survival outcomes in an unselected, Korean female population with advanced lung cancer based on the National Health Insurance Service database.
METHODS: We identified women with newly diagnosed advanced lung cancer from January 2004 to December 2013. For progression-free survival (PFS) and overall survival (OS) analyses, patients were defined into the following subgroups: group A, treated with first-generation EGFR-TKI ⩾6 months; group B, treated with EGFR-TKIs <6 months but at least >1 month; and group C, treated with cytotoxic chemotherapy as follows: monotherapy or combination therapy with gemcitabine or pemetrexed; or monotherapy with docetaxel, paclitaxel, or vinorelbine.
RESULTS: Among 11,045 enrolled patients, 6170 (55.8%) were treated with first-generation EGFR-TKIs for at least 1 month. The median OS for patients treated with EGFR-TKIs was significantly longer than that of EGFR-TKI-naive patients (19.1 months [95% confidence interval (CI) 18.5-19.7] vs 9.5 months [95% CI 9.1-9.8],
CONCLUSIONS: Our analysis demonstrates that EGFR-TKIs confer significant PFS and OS benefits in the real-world practice for Korean female with advanced lung cancer.

Qi K, Li Y, Huang K, et al.
Pre-application of arsenic trioxide may potentiate cytotoxic effects of vinorelbine/docetaxel on neuroblastoma SK-N-SH cells.
Biomed Pharmacother. 2019; 113:108665 [PubMed] Related Publications
BACKGROUND: Arsenic trioxide is effective in the treatment of acute promyelocytic leukemia and is currently in use in clinical trials for the treatment of solid tumor types. Given that arsenic trioxide is able to arrest neuroblastoma cell cycle in the G2/M phase, the present study is, to the best of our knowledge, the first to investigate whether the combination of arsenic trioxide with mitosis-phase-specific antineoplastic agents (vinorelbine or docetaxel) or non-mitosis-phase-specific antineoplastic agents (etoposide or cisplatin) exert synergistic effects in cytotoxicity on the human SK-N-SH neuroblastoma cell line.
METHODS: Neuroblastoma cells were either incubated with one of the four drugs individually, or preincubated with arsenic trioxide and then followed by another drug when cell cycle was arrested at the G2/M phase with the highest proportion.
RESULTS: The results of the present study revealed that arsenic trioxide potentiated the apoptotic rate of neuroblastoma cells induced by chemotherapeutic drugs. The present study further demonstrated that preincubation with arsenic trioxide followed by a mitosis-phase-specific antineoplastic agent result in a higher cytotoxicity effect compared with a non mitosis-phase-specific antineoplastic agent. Along with the enhanced cytotoxicity in combination group, the cell cycle distribution demonstrated a decreased proportion of G2/M phase in the combination group.
CONCLUSION: The in vitro study revealed that the pre-application of arsenic trioxide followed by mitosis-phase-specific antineoplastic agents potentiate the cytotoxic effects on neuroblastoma cells, therefore arsenic trioxide may be a promising therapeutic option for treating neuroblastoma.

Holleman MS, Uyl-de Groot CA, Goodall S, van der Linden N
Determining the Comparative Value of Pharmaceutical Risk-Sharing Policies in Non-Small Cell Lung Cancer Using Real-World Data.
Value Health. 2019; 22(3):322-331 [PubMed] Related Publications
BACKGROUND: Risk-sharing arrangements (RSAs) can be used to mitigate uncertainty about the value of a drug by sharing the financial risk between payer and pharmaceutical company. We evaluated the projected impact of alternative RSAs for non-small cell lung cancer (NSCLC) therapies based on real-world data.
METHODS: Data on treatment patterns of Dutch NSCLC patients from four different hospitals were used to perform "what-if" analyses, evaluating the costs and benefits likely associated with various RSAs. In the scenarios, drug costs or refunds were based on response evaluation criteria in solid tumors (RECIST) response, survival compared to the pivotal trial, treatment duration, or a fixed cost per patient. Analyses were done for erlotinib, gemcitabine/cisplatin, and pemetrexed/platinum for metastatic NSCLC, and gemcitabine/cisplatin, pemetrexed/cisplatin, and vinorelbine/cisplatin for nonmetastatic NSCLC.
RESULTS: Money-back guarantees led to moderate cost reductions to the payer. For conditional treatment continuation schemes, costs and outcomes associated with the different treatments were dispersed. When price was linked to the outcome, the payer's drug costs reduced by 2.5% to 26.7%. Discounted treatment initiation schemes yielded large cost reductions. Utilization caps mainly reduced the costs of erlotinib treatment (by 16%). Given a fixed cost per patient based on projected average use of the drug, risk sharing was unfavorable to the payer because of the lower than projected use. The impact of RSAs on a national scale was dispersed.
CONCLUSIONS: For erlotinib and pemetrexed/platinum, large cost reductions were observed with risk sharing. RSAs can mitigate uncertainty around the incremental cost-effectiveness or budget impact of drugs, but only when the type of arrangement matches the setting and type of uncertainty.

Pedro PI, Canário D, Lopes M, Argyropoulou D
Rare cause of lung atelectasis in a young woman.
BMJ Case Rep. 2019; 12(1) [PubMed] Related Publications
Pulmonary mucoepidermoid carcinoma is an extremely rare intrathoracic malignancy, comprising less than 1% of all lung tumours. These are very slow growing and are classified into low grade and high grade based on histological features. Surgical resection is the primary treatment with excellent outcomes, while chemotherapy or radiotherapy effectiveness is not known. Preoperative fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) is useful for predicting tumour grade and postsurgical prognosis.A clinical case of a 31-year-old woman who presented with dyspnoea on exertion, cough and wheezing is reported. Imaging studies revealed a mass involving the left lower lobe bronchus and atelectasis. 18F-FDG PET/CT showed uptake in the described mass with a maximum standardised uptake value of 9.7. Complete surgical resection was performed, and pathological examination revealed a high-grade mucoepidermoid carcinoma with tumour-free margins. Adjuvant chemotherapy was given and there is no evidence of tumour recurrence.

Kim JH, Yoon YS, Kim JC, Kim YM
Assessment of the Applicability of Integrative Tumor Response Assays in Advanced Epithelial Ovarian Cancer.
Anticancer Res. 2019; 39(1):313-318 [PubMed] Related Publications
AIM: To prospectively correlate clinical responses to second-line chemotherapy for recurrent epithelial ovarian cancer (EOC) with in vitro integrative tumor-response assay (ITRA) results.
PATIENTS AND METHODS: Forty-four patients with advanced EOC were enrolled from 2015-2017 at the Asan Medical Center, Seoul, Korea. ITRA comprised of two sequential histoculture drug response assays (HDRAs) of the tumor tissues. The first stage was HDRA with paclitaxel-carboplatin, paclitaxel, and carboplatin chemotherapy. The second stage was performed with surviving tumor cells from the first stage using topotecan, belotecan, gemcitabine, doxorubicin, ifosfamide, vinorelbine, and etoposide.
RESULTS: The median follow-up period was 23.35 (range=4-35.35) months. Eighteen patients (40.9%) completed the second-line chemotherapy, based on the ITRA results. The objective response rate was 38.9%. The clinical response rate was 50%; two patients (11.1%) had stable disease. The sensitivity of ITRA for predicting response was 85.7% (specificity=18.2%; accuracy=44.44%).
CONCLUSION: ITRAs had acceptable applicability and may help choose second-line chemotherapy for patients with advanced EOC.

Washio I, Nakanishi T, Ishiguro N, et al.
Effect of endogenous multidrug resistance 1 and P-glycoprotein expression on anticancer drug resistance in colon cancer cell lines.
Biopharm Drug Dispos. 2019; 40(1):32-43 [PubMed] Related Publications
P-glycoprotein (P-gp, multidrug resistance 1 (MDR1)) overexpression confers multidrug resistance to cancer cells, and P-gp in cell lines transfected with MDR1 or selected with chemotherapeutics significantly affect the anticancer drug efficacy. Although human cancer cell line panels consisting of defined tumor cell lines expressing endogenous P-gp have been used to screen drugs in pharmaceutical industries, endogenous P-gp affecting in vitro anticancer drug efficacy is unclear. The impact of P-gp expression on anticancer drug efficacy was assessed by using five colon cancer cell lines expressing varying endogenous P-gp levels and by selecting from the Cancer Cell Line Encyclopedia (CCLE). mRNA expression of MDR1 was considered as a surrogate of the protein expression of its gene product, P-gp, in CL-11, C2BBe1 and RKO cells, whereas P-gp protein expression in plasma membranes or crude membrane fractions was lower than expected from mRNA expression in CW-2 and CL-40 cells. The EC

Mavrogiannis AV, Kokkinopoulou I, Kontos CK, Sideris DC
Effect of Vinca Alkaloids on the Expression Levels of microRNAs Targeting Apoptosis-related Genes in Breast Cancer Cell Lines.
Curr Pharm Biotechnol. 2018; 19(13):1076-1086 [PubMed] Related Publications
BACKGROUND: Treatment of cancer with natural chemotherapeutic agents induces apoptosis along with remarkable alterations in the expression of apoptosis-related genes. Deregulation of microRNA (miRNA) expression is implicated in several human malignancies. Vinca alkaloids compose a class of antimitotic drugs preventing cancer cells from dividing, leading to apoptosis. They are commonly used in clinical practice for breast cancer treatment.
OBJECTIVE: The present study focused on the effects of vinca alkaloids (vincristine, vinblastine, and vinorelbine) on miRNA expression of treated breast cancer cells.
METHODS: We investigated the effect of vincristine, vinblastine, and vinorelbine on the expression of oncogenic and tumor-suppressive miRNAs (miR-15a-5p, miR-16-5p, miR-21-5p, miR-25-3p, miR- 29b-3p, miR-125b-5p, miR-148a-3p, miR-214-3p, miR-221-3p, miR-222-3p, and miR-421), as well as on the expression of the apoptosis-related genes BAX, BCL2, TP53, and CDKN1B in BT-20 and SKBR- 3 breast adenocarcinoma cells.
RESULTS: Treatment of BT-20 cells with vincristine, vinblastine, and/or vinorelbine resulted in upregulation of TP53 expression. However, no alterations in the mRNA levels of the pivotal BCL2 family members BAX and BCL2 were observed. On the other hand, treatment of SK-BR-3 cells with any of these vinca alkaloids led to an increase in the BAX/BCL2 mRNA ratio, implying the activation of the intrinsic apoptotic pathway. No concomitant alteration in TP53 expression was observed in treated SKBR- 3 cells. Regarding the miRNAs examined in this study, miR-222-3p expression exhibited the most remarkable modulations in both treated cell lines.
CONCLUSION: This study suggests the possible involvement of miR-222-3p expression in breast cancer cell apoptosis, triggered by vincristine, vinblastine, and vinorelbine.

Qin RS, Zhang ZH, Zhu NP, et al.
Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma.
BMC Cancer. 2018; 18(1):967 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar).
METHODS: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (
RESULTS: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (
CONCLUSION: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.

Blancas I, Aguirre E, Morales S, et al.
Real-world data on the efficacy and safety of weekly oral vinorelbine in breast cancer patients previously treated with anthracycline or taxane-based regimens.
Clin Transl Oncol. 2019; 21(4):459-466 [PubMed] Related Publications
PURPOSE: To evaluate the efficacy and safety of oral weekly vinorelbine 60 mg/m
MATERIALS AND METHODS: Fifty-five patients were enrolled in a prospective multicentre study conducted in Spain. Women ≥ 18 years of age with locally advanced breast cancer who were not candidates for surgical treatment with a radical intention or patients with stage IV disease, and who had received a prior taxane or anthracycline regimen were eligible for participation.
RESULTS: Median age was 67 years. Median progression-free survival was 3.7 months (95% CI 2.5-4.9), median overall survival 10 months (95% CI 6.6-13.5), and overall response rate and clinical benefit rate were 29.1% and 49.1%, respectively. Main grade 3 and 4 toxicities were neutropenia 9.1%, febrile neutropenia 3.6% and constipation 3.6%. In total, 86% of the patients received complete treatment without delays or dose reduction. Moreover, HER2-positive patients who received oral vinorelbine concomitantly with trastuzumab showed better response (complete response: HER2-positive 14.3% vs. HER2-negative 0%; partial response: HER2-positive 42.9% vs. HER2-negative 25.6%; p = 0.008), better disease control rate (HER2-positive 100% vs. HER2-negative 46.2%; p = 0.011), and better values for the remaining analysed variables than HER2-negative patients.
CONCLUSION: Our study provides real-world data on the use of oral weekly vinorelbine, which proves an effective and well-tolerated regimen for MBC patients previously treated with taxanes or anthracyclines. Patients with HER2-positive disease could also benefit from this treatment in combination with trastuzumab.

D'Ascanio M, Pezzuto A, Fiorentino C, et al.
Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer.
Biomed Res Int. 2018; 2018:6278403 [PubMed] Free Access to Full Article Related Publications
Background: Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC).
Methods: From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0.
Results: Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules.
Conclusions: This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients.

Sasaki T, Seto T, Yamanaka T, et al.
A randomised phase II trial of S-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for unresectable, locally advanced non-small cell lung cancer: WJOG5008L.
Br J Cancer. 2018; 119(6):675-682 [PubMed] Related Publications
BACKGROUND: Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy.
METHODS: Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UMIN000002420).
RESULTS: From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm.
CONCLUSIONS: The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.

Lesueur P, Martel-Laffay I, Escande A, et al.
Oral vinorelbine-based concomitant chemoradiotherapy in unresectable stage III non-small cell lung cancer: a systematic review.
Expert Rev Anticancer Ther. 2018; 18(11):1159-1165 [PubMed] Related Publications
INTRODUCTION: Cisplatin-based chemotherapy administered concomitantly to thoracic radiotherapy is the treatment recommended by the European guidelines for fit patients with unresectable stage III non-small cell lung cancer (NSCLC). Cisplatin may be combined with etoposide, vinorelbine or other vinca alkaloids, which act also as radiation sensitizers. Initially administered intravenously, vinorelbine is also available as oral formulation and is the only orally available microtubule-targeting agent. In addition, the oral formulation avoids the risk of extravasation and phlebitis. Areas covered: A literature search has been performed for articles reporting phase II-III trials aimed to evaluate efficacy and safety of oral vinorelbine-based chemoradiotherapy in unresectable locally advanced NSCLC. Expert commentary: In a series of trials with various protocols published from 2008 to 2018, mostly phase II studies, oral vinorelbine demonstrated a significant activity in concomitant chemoradiotherapy for unresectable locally advanced NSCLC typically as part of combination schedules with cisplatin. Main toxicities were hematologic (neutropenia and anemia); non-hematological toxicities included esophagitis and gastro-duodenal adverse events. Large prospective phase III trials are needed to confirm the role of vinorelbine-based chemotherapy associated to thoracic radiotherapy in unresectable stage III NSCLC and more particularly trials with metronomic oral vinorelbine.

Rath EM, Cheng YY, Pinese M, et al.
BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state.
PLoS One. 2018; 13(8):e0203003 [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

Yue D, Xu S, Wang Q, et al.
Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial.
Lancet Respir Med. 2018; 6(11):863-873 [PubMed] Related Publications
BACKGROUND: Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC.
METHODS: In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m
FINDINGS: Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported.
INTERPRETATION: Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC.
FUNDING: National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.

Yuan C, Xu XH, Luo SW, et al.
Which neoadjuvant chemotherapy regimen should be recommended for patients with advanced nasopharyngeal carcinoma?: A network meta-analysis.
Medicine (Baltimore). 2018; 97(34):e11978 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The clinical application has widespread disagreement on the different regimens of neoadjuvant chemotherapy (NCT) in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). We conducted a network meta-analysis (NMA) to evaluate the efficacy of the different NCT regimens in the treatment of NPC.
METHODS: A systematic literature search was performed using PubMed, Embase, and Cochran Library. Totally, 31 randomized controlled trials (RCTs) (n = 4062) met study selection criteria and were incorporated in this NMA study.
RESULTS: Our study showed that certain NCT regimens improved the prognosis of patients, and found out the relative best solution for each endpoint, such as paclitaxel, carboplatin, and gemcitabine for 1-year overall survival (OS) rate, cisplatin, calcium folinate, and 5-fluorouracil for 2-year OS rate, vinorelbine and cisplatin (NP) for 3-year OS rate, cyclophosphamide, cisplatin, and 5-fluorouracil for 5-year OS rate, NP for complete remission rate, cisplatin and gemcitabine for overall remission rate of the primary tumor. In addition, for certain grade 3 and above toxicity, the results of the NMA reflected certain NCT regimens can reduce toxicity of chemoradiotherapy (CRT) to a minimum, such as NP for anemia, mucositis, and thrombocytopenia, paclitaxel, epirubicin, and cisplatin for neutropenia and skin toxicity.
CONCLUSION: Our NMA showed that certain cisplatin-based NCT regimens improved the prognosis of patients with NPC and reduced the toxicity of CRT. However, in view of survival rate and response rate, the best NCT regimen is not entirely consistent. Therefore, which NCT regimen will benefit most patients will need further explored.

Martino E, Casamassima G, Castiglione S, et al.
Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead.
Bioorg Med Chem Lett. 2018; 28(17):2816-2826 [PubMed] Related Publications
Cancer still represents a "nightmare" worldwide, causing annually millions of victims. Several antiproliferative molecules are currently used as drugs market and offer a pharmaceutical opportunity for attenuating and treating tumor manifestations. In this context, natural sources have a relevant role, since they provide the 60% of currently-used anticancer agents. Among the numerous natural products, acting via different mechanisms of action, microtubule-targeting agents (MTAs) have a high therapeutic potential, since they disrupt the abnormal cancer cell growth, interfering with the continuous mitotic division. Vinca alkaloids (VAs) are the earliest developed MTAs and approved for clinical use (Vincristine, Vinblastine, Vinorelbine, Vindesine, and Vinflunine) as agents in the treatment of hematological and lymphatic neoplasms. Here, we review the state-of-art of VAs, discussing their mechanism of action and pharmacokinetic properties and highlighting their therapeutic relevance and toxicological profile. Additionally, we briefly disclosed the technological approaches faced so far to ameliorate the pharmacological properties, as well as to avoid the drug resistance. Lastly, we introduced the recent advances in the discovery of new derivatives.

Litton JK, Rugo HS, Ettl J, et al.
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
N Engl J Med. 2018; 379(8):753-763 [PubMed] Related Publications
BACKGROUND: The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2).
METHODS: We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.
RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed.
CONCLUSIONS: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775 .).

Sakane T, Okuda K, Hattori H, et al.
Blastomatoid pulmonary carcinosarcoma: A rare case report and review of the literature.
Thorac Cancer. 2018; 9(10):1323-1326 [PubMed] Free Access to Full Article Related Publications
A 65-year-old never-smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X-ray. Computed tomography (CT) revealed a 5-cm tumor in segment 6 of her right lung and an enlarged subcarinal lymph node, suggesting metastasis. The lung tumor was diagnosed as adenocarcinoma by a CT-guided percutaneous needle biopsy. She was referred to our hospital and underwent right lower lobectomy with lymph node dissection (ND2a-2). A histopathological examination of the tumor showed a biphasic proliferation made of carcinomatous and sarcomatous components. The carcinomatous component consisted of glandular structures of atypical cells that possessed chromatin-rich nuclear and clear cytoplasm, confirming high-grade fetal adenocarcinoma. The sarcomatous component consisted of immature spindle cells that differentiated into chondrosarcoma. Immunohistochemically, the glandular structures expressed membranous beta-catenin, and the ultimate diagnosis was blastomatoid variant of pulmonary carcinosarcoma. She received four courses of cisplatin plus vinorelbine as adjuvant chemotherapy and remained alive with neither recurrence nor distant metastasis at two and a half years after the operation. We experienced a rare case of blastomatoid pulmonary carcinoasarcoma.

Kristensen A, Solheim TS, Fløtten Ø, Grønberg BH
Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.
Acta Oncol. 2018; 57(11):1574-1579 [PubMed] Related Publications
BACKGROUND: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.
MATERIAL AND METHODS: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).
RESULTS: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).
CONCLUSIONS: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

Daniels B, Girosi F, Tervonen H, et al.
Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: A national population-based observational study (2001-2016).
PLoS One. 2018; 13(7):e0198152 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions.
PATIENTS AND METHODS: Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001-2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence.
RESULTS: Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further sub-clusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment.
CONCLUSIONS: Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging.

Sharif-Askari B, Amrein L, Aloyz R, Panasci L
PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines.
Breast Cancer Res Treat. 2018; 172(1):23-32 [PubMed] Related Publications
PURPOSE: PARP-3 is member of the PARP family of poly (ADP-ribose) polymerases involved in ADPribosylation. PARPs are involved in the basic mechanisms of DNA repair. PARP3, a critical player for efficient mitotic progression, is required for the stabilization of the mitotic spindle by regulation of the mitotic components, NuMA and Tankyrase 1.
METHODS: The sensitization effect of vinorelbine on PARP3 inhibition-induced cytotoxicity was assessed by the SRB assay. The contribution of programed cell death and cell cycle arrest to the sensitization effect were determined by assessing changes in Annexin V, a marker of apoptosis. Alterations in cell cycle progression were assessed by cell cycle analysis. We used immunofluorescence to assess the effect of vinorelbine and/or PARP3 inhibitors on tubulin and microtubule depolarization. The PARP3 chemiluminescent assay kit was used for PARP3 activity.
RESULTS: PARP3 inhibitors sensitize breast cancer cells to vinorelbine, a vinca alkaloid used in the treatment of metastatic breast cancer. Olaparib which was originally described as a PARP1 and 2 inhibitor has recently been shown to be a potent PARP3 inhibitor while ME0328 is a more selective PARP3 inhibitor. The combination of vinorelbine with nontoxic concentrations of ME0328 or olaparib reduces vinorelbine resistance by 10 and 17 fold, respectively, potentiating vinorelbine-induced arrest at the G2/M boundary. In addition, PARP3 inhibition potentiates vinorelbine interaction with tubulin. Furthermore, olaparib or ME0328 potentiates vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis.
CONCLUSION: Our results indicated this approach with PARP3 inhibitors and vinorelbine is unique and promising for breast cancer patients with metastases. This combination could significantly increase the survival of breast cancer patients with metastases.

Hallqvist A, Bergström S, Björkestrand H, et al.
Dose escalation to 84 Gy with concurrent chemotherapy in stage III NSCLC appears excessively toxic: Results from a prematurely terminated randomized phase II trial.
Lung Cancer. 2018; 122:180-186 [PubMed] Related Publications
OBJECTIVES: Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease. To investigate whether radiation dose escalation based on individual normal tissue constraints can improve outcome, the Swedish lung cancer study group launched this randomized phase II trial.
MATERIALS AND METHODS: NSCLC patients with stage III disease, good performance status (0-1) and adequate lung function (FEV1 > 1.0 L and CO diffusion capacity > 40%) received three cycles of cisplatin (75 mg/m
RESULTS: A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in arm B compared to the encouraging results of 28 and 45 months in the standard arm. The 1- and 3-year survival rates were 56% and 33% (B) and 72% and 56% (A), respectively. There were seven toxicity-related deaths due to esophageal perforations and pneumonitis: five in the escalated group and two with standard treatment.
CONCLUSION: Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 3-year survival of 56% (NCT01664663).

Altinoz MA, Ozpinar A, Alturfan EE, Elmaci I
Vinorelbine's anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas.
J Chemother. 2018; 30(4):203-212 [PubMed] Related Publications
Vinorelbine is a very potent chemotherapeutic agent which is used to treat a number of cancers including breast and non-small cell lung tumors. Vinorelbine mainly acts via blocking microtubules and induces a specific type of cell death called 'mitotic catastrophe/apoptosis' subsequent to mitotic slippage, which is the failure of cells to stay in a mitotic arrested state and replicating their DNA without cytokinesis. Glial tumor cells are especially sensitive to mitotic slippage. In recent years, vinorelbine demonstrated potency in pediatric optic and pontine gliomas. In this manuscript, we propose that vinorelbine's anti-tumor actions involve mitotic apoptosis, autophagy and inflammation. Intravenous infusion of vinorelbine induces a peculiar severe pain in the tumor site and patients with highly vascularized, oedematous and necrotic tumors are particularly vulnerable to this pain. Severe pain is a sign of robust inflammation and anti-inflammatory agents are used in treatment of this side effect. However, no one has questioned whether inflammation contributes to anti-tumor effects of vinorelbine, despite the existing data that vinorelbine induces Toll-Like Receptor-4 (TLR4), cytokines and cell death in endothelial cells especially under hypoxia. Robust inflammation may contribute to tumor necrosis such as seen during immunotherapy with lipopolysaccharides (LPS). Evidence also emerges that enhanced cyclooxygenase activity may increase cancer cell death in certain contexts. There are data indicating that non-steroidal anti-inflammatory drugs (NSAIDs) could block anti-tumor efficacy of taxanes, which also work mainly via anti-microtubule actions. Further, combining vinorelbine with immunostimulant cytokines provided encouraging results in far advanced melanoma and renal cell carcinoma, which are highly antigenic tumors. Vinorelbine also showed potential in treatment of inflammatory breast cancer. Finally, pontine gliomas - where partial activity of vinorelbine is shown by some studies - are also tumors which partially respond to immune stimulation. Animal experiments shall be conducted whether TLR4-activating molecules or immune-checkpoint inhibitors could augment anti-tumor actions of vinorelbine. Noteworthy, TLR4-activation seems as the most promising way of cancer immunotherapy, as a high percentage of molecules which demonstrated clinical benefits in cancer treatment are activators of TLR4, including BCG vaccine, monophosphoryl lipid A and picibanil (OKT-432). The provided data would be meaningful for the oncological practice.

Pasini F, Barile C, Caruso D, et al.
Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world.
Invest New Drugs. 2018; 36(5):927-932 [PubMed] Related Publications
Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.

Van Swearingen AED, Siegel MB, Deal AM, et al.
LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.
Breast Cancer Res Treat. 2018; 171(3):637-648 [PubMed] Related Publications
PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.
PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.
RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.
CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted.

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