Westmead Institute for Cancer Research

Sydney, Australia

Westmead Institute for Cancer Research

Sydney, Australia
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Menzies A.M.,Melanoma Institute Australia | Long G.V.,Melanoma Institute Australia | Long G.V.,Westmead Institute for Cancer Research | Murali R.,Sloan Kettering Cancer Center
Drug Design, Development and Therapy | Year: 2012

The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAFmut) protein in melanomas with BRAFV600E and BRAFV600K genotypes. BRAFV600E metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAFV600K patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy. © 2012 Menzies et al, publisher and licensee Dove Medical Press Ltd.

Wilmott J.S.,Melanoma Institute Australia | Wilmott J.S.,University of Sydney | Wilmott J.S.,Royal Prince Alfred Hospital | Long G.V.,Melanoma Institute Australia | And 26 more authors.
Clinical Cancer Research | Year: 2012

Purpose: To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment. Experimental Design: Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. Results: Tumor infiltration by CD4 + and CD8 + lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015). There was a correlation between the degree of tumor infiltration by CD8 + and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r=0.690 and ρ = 0.013). Increased intratumoral CD8 + lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r=-0.793, ρ= 0.011; and r = 0.761, ρ = 0.004, respectively). Conclusions: The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses. ©2011 AACR.

Sosman J.A.,Vanderbilt University | Kim K.B.,University of Texas M. D. Anderson Cancer Center | Schuchter L.,University of Pennsylvania | Gonzalez R.,University of Colorado at Denver | And 21 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.) Copyright © 2012 Massachusetts Medical Society.

Carlino M.S.,Westmead Institute for Cancer Research | Carlino M.S.,University of Sydney | Fogarty G.B.,Genesis Cancer Care Pty Ltd | Long G.V.,University of Sydney | Long G.V.,Genesis Cancer Care Pty Ltd
Cancer Journal | Year: 2012

Brain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors. Copyright © 2012 by Lippincott Williams &Wilkins.

McSharry B.P.,University of Sydney | Forbes S.K.,University of Sydney | Forbes S.K.,Westmead Millennium Institute | Cao J.Z.,University of Sydney | And 8 more authors.
Journal of Virology | Year: 2014

Regulation of the lectin galectin 9 (Gal-9) was investigated for the first time during human cytomegalovirus (HCMV) infection. Gal-9 transcription was significantly upregulated in transplant recipients with reactivated HCMV in vivo. In vitro, Gal-9 was potently upregulated by HCMV independently of viral gene expression, with interferon beta (IFN-β) identified as the mediator of this effect. This study defines an immunoregulatory protein potently increased by HCMV infection and a novel mechanism to control Gal-9 through IFN-β induction. © 2014, American Society for Microbiology.

Azer M.W.F.,Westmead Hospital | Azer M.W.F.,University of Sydney | Menzies A.M.,University of Sydney | Haydu L.E.,University of Sydney | And 5 more authors.
Cancer | Year: 2014

BACKGROUND Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib. METHODS Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed. RESULTS A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P =.416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P =.465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days. CONCLUSIONS IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progression, with ongoing dabrafenib treatment possible in a subset of patients. Cancer 2014;120:530-536. © 2013 American Cancer Society. Dabrafenib is highly active in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study demonstrates that in patients with melanoma brain metastases, intra- and extracranial metastases respond similarly to dabrafenib, the brain is not always the site of treatment failure, and most patients can receive effective salvage local treatment to the brain upon intracranial disease progression © 2013 American Cancer Society.

Menzies A.M.,Melanoma Institute Australia | Menzies A.M.,University of Sydney | Kefford R.F.,Melanoma Institute Australia | Kefford R.F.,University of Sydney | And 5 more authors.
Pigment Cell and Melanoma Research | Year: 2013

Summary: Cutaneous squamous cell carcinoma (cSCC) is a concerning toxicity with BRAF inhibitors in the treatment for melanoma. While the two drugs shown to improve survival, vemurafenib, and dabrafenib, have similar efficacy, the reported rates of cSCC are quite different. Drawing upon preclinical and clinical trial data, this article discusses the potential factors behind the different cSCC incidences reported with the two BRAF inhibitors and provides a strategic approach to understand this issue further. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Menzies A.M.,Melanoma Institute Australia | Menzies A.M.,University of Sydney | Long G.V.,Melanoma Institute Australia | Long G.V.,University of Sydney | Long G.V.,Westmead Institute for Cancer Research
European Journal of Cancer | Year: 2013

Metastatic melanoma has a poor prognosis and until recently systemic therapy was ineffective. Advances in the understanding of tumour biology and immune regulation have led to the development of targeted agents that have changed clinical practice, with further improvements expected with new compounds and combinations. The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab). These drugs proved vastly superior to conventional chemotherapy, however response, resistance and toxicity were limitations. The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes for patients with melanoma further, trials are underway examining the combination of MAPK inhibitors, immunotherapies and other pathway inhibitors and adjuvant studies of many of these agents have commenced. © 2013 Elsevier Ltd. All rights reserved.

Balleine R.L.,University of Sydney | Balleine R.L.,Westmead Institute for Cancer Research | Wilcken N.R.,University of Sydney
Molecular Diagnosis and Therapy | Year: 2012

The estrogen receptor (ER) has long been recognized as a key discriminative feature of breast cancer, which carries profound implications for management. However, recent advances in the understanding of breast cancer heterogeneity have demonstrated the importance of biologic context to the interpretation of ER as a prognostic and predictive factor. The use of tumor subtyping methods and prognostic indicators based on molecular profiling of tumor tissue is now helping to delineate high-risk ER-positive cancer types that have distinct risk and treatment response profiles. These new approaches to breast cancer classification will have a major impact on the conduct of clinical trials and individual patient assessment in the future. © 2012 Springer International Publishing AG. All rights reserved.

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