Phase II Study of Bevacizumab in Combination with Trastuzumab and Capecitabine as First-Line Treatment for HER-2-positive Locally Recurrent or Metastatic Breast Cancer

Martín, Miguel; Махсон, А. Н.; Gligorov, J.; Lichinitser, Mikhail; Lluch, Aña; Семиглазов, Владимир; Scotto, Nana; Mitchell, Lada; Tjulandin, Sergei

doi:10.1634/theoncologist.2011-0344

Cited by 49 publications

(25 citation statements)

References 27 publications

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“…This hypothesis is consistent with the finding that targeting both HER2 and VEGF in orthotopic breast cancer xenografts results in better growth delay than targeting either agent alone (21,22). Furthermore, the phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER2-positive locally recurrent or metastatic breast cancer showed an overall response rate of 73% (16).…”

supporting

confidence: 87%

“…In patients with metastatic breast cancer, the anti-VEGF antibody bevacizumab (Genentech/Roche), in combination with paclitaxel, prolonged progression-free survival but not overall survival compared with paclitaxel alone (15). In addition, the use of bevacizumab with trastuzumab and chemotherapy in HER2-positive metastatic breast cancer has shown some promise in phase II trials (16). However, there remain no data on the efficacy of bevacizumab in the context of brain metastases because these patients have often been excluded from clinical trials due to fear of an increased risk of cerebral hemorrhage after anti-VEGF therapy.…”

mentioning

confidence: 99%

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Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

106

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Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.treatment resistance | tumor-stroma interaction | targeted therapy | tumor microenvironment | antiangiogenesis

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supporting

confidence: 87%

mentioning

confidence: 99%

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

106

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“…Another phase II study is evaluating neoadjuvant trastuzumab and chemotherapy with or without bevacizumab (NCT01367028). In the locally recurrent and MBC setting, a single-arm phase II study combined bevacizumab with trastuzumab/capecitabine as first-line therapy, with an RR of 73% and median PFS of 14.4 months [109]. In a phase II study of bevacizumab with trastuzumab/vinorelbine in HER2-positive MBC, the RR was 73% as first-line therapy and 71% as second-line therapy; median PFS durations were 9.9 and 7.8 months, respectively [110].…”

Section: Other Targetsmentioning

confidence: 99%

Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer

2014

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Purpose. Chemotherapy has been tested extensively in conjunction with standard therapy in the treatment of head and neck cancer, primarily in the form of neoadjuvant chemotherapy, but few trials have shown a survival benefit. Although a few studies have suggested that adjuvant chemotherapy given after standard treatment may improve survival, to date these trials have been troubled by various problems in design and dosing. The purpose of our trial was to determine the feasibility of giving moderately intensive chemotherapy exclusively after standard therapy, and to determine whether survival appeared to be improved as measured against historical data. Methods. We used adjuvant chemotherapy in two groups of patients with squamous cell carcinoma of the head and neck: group A consisted of 46 patients with newly diagnosed stage III and IV disease, and group B consisted of 46 patients with relapsed disease having been treated with salvage surgery. In all patients, the intended adjuvant chemotherapy consisted of two cycles of combination cisplatin, bleomycin, and infusional 5‐fluorouracil (5‐FU) given three weeks apart, followed by four cycles of bolus methotrexate, 5‐FU, and bleomycin given every two weeks. Results. In group A, the two‐year survival was 72%. In group B, the two‐year survival was 58%. Conclusion. Compared to the vast majority of similarly staged patients with head and neck cancer reported in the literature, the survival of our group seemed considerably better, suggesting that a definitive randomized study testing this schedule of adjuvant chemotherapy is warranted.

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“…[65][66][67] In contrast, in advanced colorectal cancers, the combination of chemotherapy and bevacizumab with anti-EGFR antibodies (cetuximab and panitumumab) failed to improve patient survival [68][69][70] and exhibited adverse effects to an extent of significantly reducing survival. 70 To determine the underlying cause of these diverse clinical observations, two recent studies determined the impact of anti-VEGF antibodies on the tumor uptake of radiolabeled antibodies in experimental breast cancer models.…”

Section: Jain Et Almentioning

confidence: 99%

Emerging Trends for Radioimmunotherapy in Solid Tumors

Jain

Gupta

Kaur

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting shortrange, high energy a-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed.

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Phase II Study of Bevacizumab in Combination with Trastuzumab and Capecitabine as First-Line Treatment for HER-2-positive Locally Recurrent or Metastatic Breast Cancer

Abstract: ABSTRACT

Cited by 49 publications

References 27 publications

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Human Epidermal Growth Factor Receptor Family-Targeted Therapies in the Treatment of HER2-Overexpressing Breast Cancer

Emerging Trends for Radioimmunotherapy in Solid Tumors

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