Perioperative BRAF inhibitors in locally advanced stage III melanoma

Zippel, Douglas; Markel, Gal; Shapira-Frommer, Roni; Ben‐Betzalel, Guy; Goitein, David; Ben-Ami, Eytan; Nissan, Aviram; Schachter, Jacob; Schneebaum, Schlomo

doi:10.1002/jso.24744

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…(Fadaki et al, 2012;Kaidar-Person et al, 2014;Koers et al, 2013;Melnik et al, 2013;Rastrelli et al, 2014;Seremet et al, 2015) Two retrospective analyses of neoadjuvant BRAF-targeted therapy for unresectable stage III melanoma have also shown promising results, including clinical response enabling R0 resection in 12 of 13 patients following 6-8 weeks of BRAF-targeted therapy, with pCR in 31% of patients, and 2 of 6 patients with a pCR in another study after 6 months of neoadjuvant therapy. (Sloot et al, 2016;Zippel et al, 2017). Most recently, a randomized phase II trial comparing neoadjuvant/adjuvant dabrafenib+trametinib to surgery with the option of postoperative adjuvant immunotherapy was stopped early, after only 21 patients were accrued, when a planned interim analysis showed dramatically better relapse-free survival for the neoadjuvant arm.…”

Section: Introductionmentioning

confidence: 99%

Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Eroglu

Eatrides

Naqvi

et al. 2019

Pigment Cell Melanoma Res

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Background: Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible.Methods: A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging and clinical outcomes were evaluated.Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST-response based on preoperative imaging and pathologic response. After a median of 43 months follow-up, only 1 patient (10%) with a pCR recurred; while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapsefree (RFS) and overall survival (OS) compared to patients with residual tumor. Conclusion:Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

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Section: Introductionmentioning

confidence: 99%

Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Eroglu

Eatrides

Naqvi

et al. 2019

Pigment Cell Melanoma Res

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“…In such surgical challenges, targeted rational therapy can be used as a means for turning a tumor, whose upfront removal might result in disfigurement and functional impairment, into a smaller mass that can be completely and safely excised without damage to normal appearance and function. One of the hallmarks of BRAF targeted therapy is a rapid and significant clinical response, albeit sometimes tempered by a limited duration of response (Zippel et al, 2017). When such neoadjuvant bridging therapy is being considered for ameloblastoma, one should bear in mind that the impressive antitumor effect can be short lived and followed by regrowth.…”

Section: Discussionmentioning

confidence: 99%

Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration

Hirschhorn

Abebe-Campino

Vered

et al. 2021

J Tissue Eng Regen Med

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Ameloblastoma is a neoplasm arising in the craniofacial skeleton. Proliferating odontogenic epithelial cells comprise this benign, yet locally invasive tumor, often causing severe disfiguration. High recurrence rate entails ablative surgical resection, which is the current standard of care, resulting in subsequent critical size osteocutaneous defects. The high incidence of BRAF mutations in ameloblastoma, most notably the BRAF V600E mutation, enabled the use of BRAF inhibiting agent in a neoadjuvant setting. In this investigator-initiated, open-label study, three consecutive pediatric patients, with confirmed BRAF V600E ameloblastoma deemed marginally resectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The use of upfront BRAF inhibitor treatment resulted in substantial tumor regression, allowing for non-mutilating complete surgical removal, ad integrum bone regeneration and organ preservation. All patients showed a marked radiologic and clinical response to medical treatment, enabling successful conservative surgery. Microscopically, all patients showed evidence of minimal residual tumor with extensive tumor necrosis, fibrosis and generation of new bone. At a median follow-up of 31 months, all patients remained free of disease. Face preservation therapy was achieved in pediatric patients presenting with BRAF V600E mutated ameloblastoma. Our study demonstrates the translational potential of targeted therapy as a neoadjuvant agent. Patient-specific organ preservation therapy should be considered as the new standard of care in ameloblastoma, mainly for children and adolescents.

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“…Importantly, therapy was well-tolerated with no grade 4 adverse events 73 . Additionally, a recent study demonstrated that patients presenting with stage III, BRAF V600E-positive, non-resectable melanoma can be treated with BRAF inhibitors and achieve a successful R0 resection 74 . Questions that remain in the use of neoadjuvant targeted therapy include the optimal timing of therapy, the extent of surgery after therapy, and the use of pathologic response information to help guide post-operative therapy.…”

Section: Neoadjuvant Targeted Therapymentioning

confidence: 99%

Surgical Considerations and Systemic Therapy of Melanoma

Gamboa

Lowe

Yushak

et al. 2020

Surgical Clinics of North America

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dehydrogenase (LDH) levels. In this chapter, we outline available evidence supporting resection of metastatic disease for both stage III and IV melanoma in the context of currently available systemic therapeutic options. We additionally review the evidence supporting the use of adjuvant systemic therapies and other treatment modalities including radiotherapy, chemotherapy, and vaccines in advanced melanoma. Lastly, we highlight the effort of translating the success of these therapies to the neoadjuvant setting and summarize active clinical trials.

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Perioperative BRAF inhibitors in locally advanced stage III melanoma

Abstract: Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival.

Cited by 13 publications

References 31 publications

Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration

Surgical Considerations and Systemic Therapy of Melanoma

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