RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative, Locally Recurrent or Metastatic Breast Cancer

Robert, Nicholas J.; Dièras, Véronique; Glaspy, John A.; Brufsky, Adam; Bondarenko, Igor; Lipatov, Oleg; Perez, Edith A.; Yardley, Denise A.; Chan, Stephen Y.; Zhou, Xian; Phan, See; O’Shaughnessy, Joyce

doi:10.1200/jco.2010.28.0982

Cited by 866 publications

(556 citation statements)

References 19 publications

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“…It should be noted, however, that for some indications for use in our cohort there were no survival gains even in the absence of crossover 750 74 75 76 …”

Section: Discussionmentioning

confidence: 67%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

462

404

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Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

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“…It should be noted, however, that for some indications for use in our cohort there were no survival gains even in the absence of crossover 750 74 75 76 …”

Section: Discussionmentioning

confidence: 67%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

462

404

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“…These results suggest that ARHGAP17 mediated by VEGF–NRP1 interaction partly contributed to DFS in HR(−) BCs. As shown in Supporting Information Table S10, the association between HR status and bevacizumab treatment efficacy in clinical trials has been inconsistent 9, 41, 42, 43, 44, 45, 46, 47. Our findings demonstrated that there are bevacizumab‐independent VEGF signals in HR(−) BC tumors.…”

Section: Discussionmentioning

confidence: 67%

“…5.9 months, hazard ratio: 0.60, p < 0.001), although it did not have a significant impact on overall survival (OS). Two other bevacizumab‐related randomized trials for metastatic BC, the AVADO trial8 and the RIBBON‐1 trial,9 confirmed the E2100’s findings that bevacizumab prolonged PFS but not OS.…”

Section: Introductionmentioning

confidence: 60%

Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network

Kiso

Tanaka

Toi

et al. 2018

Intl Journal of Cancer

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VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF‐related molecular mechanisms on breast cancer cells. VEGF‐knocked‐out MDA‐MB‐231 cells (231VEGFKOex3) showed rounded morphology and shorter perimeter (1.6‐fold, p < 0.0001). The 231VEGFKOex3 cells also showed impaired cell migration (2.6‐fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin‐1 overexpressing MDA‐MB‐231 cells (231sNRP1) exhibited rounded morphology and shorter perimeter (1.3‐fold, p < 0.0001). The 231sNRP1 cells also showed impaired cell migration (1.7‐fold, p = 0.003). These changes were similar to that of 231VEGFKOex3 cells. As MDA‐MB‐231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP‐binding domain regulates the morphology and migration ability of MDA‐MB‐231 cells. Genome‐wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone‐receptor‐negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab‐independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer.

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“…Studies that demonstrate decreased tumor uptake of small molecule chemotherapeutics following bevacizumab administration and a lack of a survival benefit typically dose above 10 mg/ kg. [27][28][29] Others have demonstrated decreased tumor uptake using radiolabelled antibodies with and without a 5 mg/kg dose of bevacizumab dosed once one day prior to and 2 additional bevacizumab treatments following antibody therapy. 30 Timing of bevacizumab therapy may limit the vascular remodeling required to improve therapeutic delivery.…”

Section: Discussionmentioning

confidence: 99%

Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies

Chung

Warram²,

Day

et al. 2015

Cancer Biology & Therapy

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RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative, Locally Recurrent or Metastatic Breast Cancer

Abstract: The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

Cited by 866 publications

References 19 publications

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network

Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies

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