Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma.

Sharfman, William H.; Hodi, F. Stephen; Lawrence, Donald P.; Flaherty, K. T.; Amaravadi, Ravi K.; Kim, K. B.; Dummer, Reinhard; Gobbi, Silvia; Puzanov, Igor; Sosman, J. A.; Dohoney, Kathleen M.; Lam, Lucy; Kakar, Sumeet; Tang, Zhongwen; Krieter, Oliver; Atkins, Michael B.

doi:10.1200/jco.2011.29.15_suppl.8508

Cited by 42 publications

(38 citation statements)

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“…The earliest tested "RAF inhibitors," sorafenib and RAF265, were revealed as being multitargeted kinase inhibitors that had no real specificity for RAF, and were challenging to dose at levels high enough for efficient MAPK inhibition due to off-target toxicities related to the multiple other kinases that are inhibited by these agents. Not surprisingly, these agents never were associated with the dramatic effects of the more potent and specific BRAF inhibitors (72)(73)(74).…”

Section: Targeting Braf: From Target Identification To Effective Multmentioning

confidence: 99%

New Strategies in Melanoma: Entering the Era of Combinatorial Therapy

Sullivan

Flaherty

2015

Clinical Cancer Research

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The treatment of metastatic melanoma has been revolutionized over the past decade as effective molecularly targeted therapies and immunotherapies entered the clinic. It is hoped that deeper insights into the characteristics of patients and tumors that are most responsive will allow more precise patient selection for these therapies while understanding mechanisms of resistance will facilitate the develop of rational combinations or next-generation agents aimed at novel targets. Clin Cancer Res; 21(11); 2424-35. Ó2015 AACR. Disclosure of Potential Conflicts of InterestR.J. Sullivan is a consultant/advisory board member for Astex Pharmaceuticals. K.T. Flaherty is a consultant/advisory board member for GlaxoSmithKline, Novartis, and Roche. No other potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have an improved understanding of the standard treatment options for advanced (metastatic and unresectable) melanoma and the rationale for building "regimens" such as dual BRAF/MEK inhibitor therapy, combined immunotherapy (e.g., ipilimumab plus nivolumab), and the combination of molecular and immune-targeted therapy.

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Section: Targeting Braf: From Target Identification To Effective Multmentioning

confidence: 99%

New Strategies in Melanoma: Entering the Era of Combinatorial Therapy

Sullivan

Flaherty

2015

Clinical Cancer Research

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“…Lessons learned from BRAF-inhibitor clinical development and strategies for optimal patient selection The efficacy observed with vemurafenib and dabrafenib seems to be clearly related to the near-complete inhibition of the MAPK pathway achieved at tolerable doses. By comparison, sorafenib and RAF-265, 2 broad-spectrum kinase inhibitors (with BRAF being among the kinases inhibited), produced minimal evidence of tumor regression and achieved only modest MAPK pathway inhibition at their maximum tolerated doses (17,18). [For a discussion about the pitfalls encountered in the development of targeted therapies, see the article by Bates and colleagues (19) in this CCR Focus section.]…”

Section: Dabrafenibmentioning

confidence: 99%

BRAF Inhibitors for the Treatment of Metastatic Melanoma: Clinical Trials and Mechanisms of Resistance

Alcalá

Flaherty

2012

Clinical Cancer Research

117

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The efficacy of selective BRAF inhibitors has now been established in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations. However, for the vast majority of patients, responses persist for less than a year. In extensive preclinical investigations, researchers have focused on potential resistance mechanisms with the hope of identifying treatment strategies that can overcome resistance. Preliminary results suggest that reactivation of the mitogen-activated protein kinase (MAPK) pathway by several BRAF-independent mechanisms is the predominant pattern. However, MAPK pathway-independent mechanisms also seem to play a potential role. More definitive cataloging of resistance mechanisms in patients' tumor samples is needed as combination regimens are being readied for clinical evaluation.

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“…RAF265 may delay the development of tumor resistance to B-Raf inhibition and also have an increased anti-proliferative effect by blocking other driver pathways, such as VEGFR2 and RET. A phase I dose-escalation trial shown promising results, and phase II trials results are eagerly awaited (Sharfman et al, 2011).…”

Section: New Drugs In Clinical Developmentmentioning

confidence: 99%