Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study

Corrie, Pippa; Marshall, Andrea; Dunn, Janet A.; Middleton, Mark R.; Nathan, Paul; Gore, Martin; Davidson, N.; Nicholson, Steve; Kelly, Charles; Marples, Maria; Danson, Sarah; Marshall, Ernest; Houston, Stephen; Board, Ruth; Waterston, Ashita; Nobes, Jenny; Harries, Mark; Kumar, Satish; Young, Gareth T.; Lorigan, Paul

doi:10.1016/s1470-2045(14)70110-x

Cited by 95 publications

(73 citation statements)

References 27 publications

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“…A combination of bevacizumab with interferon alpha (IFN-α) immunotherapy prolonged PFS and is now a standard of care in metastatic renal cell carcinoma [76]. In the majority of cancers (melanoma, breast, pancreatic and prostate cancer), bevacizumab failed to increase survival when combined with chemotherapy [77–79]. A VEGF receptor chimera, VEGF-Trap or aflibercept, was developed as a blocker of multiple VEGF family members, VEGF, VEGF-B and PlGF, and more broadly inhibit VEGFR-2 kinase activity.…”

Section: Anti-angiogenic Therapy For Solid Tumors: Anti-vegf Agentsmentioning

confidence: 99%

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

2017

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Angiogenesis is defined as the formation of new blood vessels from pre-existing vessels, and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients, and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time-window. However, anti-angiogenics may excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.

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Section: Anti-angiogenic Therapy For Solid Tumors: Anti-vegf Agentsmentioning

confidence: 99%

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

2017

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“…The results of a preplanned interim analysis of the phase III adjuvant bevacizumab study in patients with high risk melanoma at (AVAST-M) trial were reported by Corrie et al [83]. This trial tested adjuvant bevacizumab versus observation in stage II/III resected melanoma patients (N = 1343).…”

Section: News On Immunotherapymentioning

confidence: 99%

Future perspectives in melanoma research

et al. 2016

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The sixth “Melanoma Bridge Meeting” took place in Naples, Italy, December 1st–4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin’s disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various loc...

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“…For phase II, the patients were allowed no more than one previous regimen containing cytotoxic chemotherapy for advanced disease. 53 ULN in the presence of liver metastasis, and international normalized ratio ,1.5 and activated partial thromboplastin time within normal limits). Patients were excluded if they had received chemotherapy, radiation therapy, or immunotherapy within 4 weeks, nitrosoureas or mitomycin Cwithin 6weeks, ora monoclonal antibodywithin8 weeks of study entry.…”

Section: Patientsmentioning

confidence: 94%

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

et al. 2015

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Background. Vascular endothelial growth factor and plateletderived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks

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Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study

Abstract: Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Cited by 95 publications

References 27 publications

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

Future perspectives in melanoma research

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

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