scholarly journals Atypical Melanocytic Proliferations and New Primary Melanomas in Patients With Advanced Melanoma Undergoing Selective BRAF Inhibition

2012 ◽  
Vol 30 (19) ◽  
pp. 2375-2383 ◽  
Author(s):  
Lisa Zimmer ◽  
Uwe Hillen ◽  
Elisabeth Livingstone ◽  
Mario E. Lacouture ◽  
Klaus Busam ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Mapk Signaling ◽  
Class I ◽  
Clinical Activity ◽  
Braf Inhibitors ◽  
Wild Type ◽  
Melanocytic Lesions ◽  
Inhibitor Treatment

Purpose Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. Patients and Methods In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment. Results Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. Conclusion Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy–induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

2015 ◽  
Vol 19 (8) ◽  
pp. 1027-1035 ◽  
Author(s):  
Rosamaria Pinto ◽  
Sabino Strippoli ◽  
Simona De Summa ◽  
Anna Albano ◽  
Amalia Azzariti ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Response Duration ◽  
Microrna Expression ◽  
Braf Inhibitors ◽  
Wild Type

Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9035-9035 ◽  
Author(s):  
Paolo Antonio Ascierto ◽  
Ester Simeone ◽  
Vanna Chiarion-Sileni ◽  
Paola Queirolo ◽  
Michele Del Vecchio ◽  
...  
Keyword(s):  
Overall Survival ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Median Overall Survival ◽  
Therapeutic Option ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Sequential Treatment ◽  
Braf Inhibitors ◽  
A Prospective Study

9035 Background: Ipilimumab and vemurafenib have recently been approved as single agents for the treatment of unresectable or metastatic melanoma. Currently, limited data exist on the sequential treatment with these agents in patients (pts) with the BRAF mutation; here we evaluate the efficacy outcomes of pts enrolled in the EAP in Italy who sequentially received a BRAF-inhibitor and ipilimumab, or vice versa. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were considered for this analysis if they tested positive for the BRAF mutation and had received a BRAF-inhibitor before or after ipilimumab treatment. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. Out of 173 BRAF positive pts, 93 (53.7%) were treated sequentially with both treatments: 48 pts received a BRAF inhibitor upon disease progression with ipilimumab and 45 pts received ipilimumab upon disease progression with a BRAF inhibitor. As of December 2012, median overall survival was 14.5 months (11.1-17.9) and 9.7 months (4.6-14.9) for the two groups, respectively (p=0.01). Among the 45 BRAF inhibitors pretreated pts, 18 (40%) had rapid disease progression (median overall survival: 5.8 months) and were unable to complete all four induction doses of ipilimumab, while the remaining 27 (60%) pts had slower disease progression (median overall survival: 19.3 months) and were able to complete the therapy with ipilimumab. Conclusions: These preliminary results suggest that, in BRAF-mutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence. These findings deserve confirmation in a prospective study.

Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9048-9048
Author(s):  
Tulasi Gummadi ◽  
Roxana Stefania Dronca ◽  
Chul Kim ◽  
Lisa A. Kottschade ◽  
Rajendar K Mittapalli ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Retrospective Analysis ◽  
Braf Mutation ◽  
Braf Inhibitor ◽  
Preclinical Studies ◽  
Braf Inhibitors ◽  
Intracranial Disease ◽  
Extracranial Disease ◽  
The Brain

9048 Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.

scholarly journals Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

2017 ◽  
Vol 7 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Jessica C. Hassel ◽  
Kristina Buder-Bakhaya ◽  
Carolin Bender ◽  
Lisa Zimmer ◽  
Benjamin Weide ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Treatment Beyond Progression ◽  
Inhibitor Treatment ◽  
Progression Patterns

scholarly journals Granulomatous Reactions from Tattoos Following BRAF Inhibitor Therapy

2019 ◽  
Vol 11 (1) ◽  
pp. 101-107 ◽  
Author(s):  
Gabrielle Giet ◽  
Eve Lebas ◽  
Andrée Rorive ◽  
Jorge E. Arrese ◽  
Arjen F. Nikkels
Keyword(s):  
Squamous Cell Carcinoma ◽  
Adverse Effects ◽  
Cell Carcinoma ◽  
Metastatic Melanoma ◽  
Squamous Cell ◽  
Actinic Keratosis ◽  
Braf Inhibitor ◽  
Inhibitor Therapy ◽  
Topical Steroids ◽  
Braf Inhibitors

BRAF inhibitors may present several cutaneous adverse effects, including actinic keratosis, squamous cell carcinoma, keratoacanthoma, rashes, increased photosensitivity, panniculitis, palmoplantar and capillary involvement, pruritus and xerosis as well as granulomatous reactions. A 30-year-old patient with multiple tattoos received dabrafenib and trametinib for metastatic melanoma. After 4 months, he developed an induration and thickening strictly limited to several tattoos. Histopathology revealed nonnecrotizing granulomas in the dermis. Topical steroids relieved pruritus but not the granulomatous aspect of the tattoos. As far as we know, this is the first description of granulomatous reactions restricted to preexisting tattoos following BRAF inhibitor therapy.

Combination Therapies Building on the Efficacy of CTLA4 and BRAF Inhibitors for Metastatic Melanoma

2012 ◽  
pp. 675-678 ◽  
Author(s):  
Antoni Ribas
Keyword(s):  
Metastatic Melanoma ◽  
Mechanism Of Action ◽  
Treatment Options ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Current Treatment ◽  
Additional Treatment ◽  
Significant Advance ◽  
Braf Inhibitors ◽  
Combination Therapies

Overview: The demonstration of improved survival with the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib in patients with metastatic melanoma is arguably the most significant advance in the treatment for these patients in the last 30 years. However, the majority of patients will either not experience response, or will experience response and then progression, when receiving these therapies, so additional treatment options are required. Since these agents have been developed with a refined understanding of their mechanism of action and mechanisms leading to resistance are being elucidated, then combination therapies building on these single-agent therapies can be designed rationally. Such combinations are being tested both preclinically and in the clinic, and provide a strong promise to improve on the current treatment approaches for patients with metastatic melanoma.

Complete remission of metastatic melanoma upon BRAF inhibitor treatment – what happens after discontinuation?

2015 ◽  
Vol 25 (4) ◽  
pp. 362-366 ◽  
Author(s):  
Henrike Tolk ◽  
Imke Satzger ◽  
Peter Mohr ◽  
Lisa Zimmer ◽  
Benjamin Weide ◽  
...  
Keyword(s):  
Complete Remission ◽  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Inhibitor Treatment

Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

2013 ◽  
Vol 31 (26) ◽  
pp. 3205-3211 ◽  
Author(s):  
Paolo A. Ascierto ◽  
David Minor ◽  
Antoni Ribas ◽  
Celeste Lebbe ◽  
Anne O'Hagan ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Mutation Status ◽  
Free Survival

Purpose Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAFV600E/K mutation–positive metastatic melanoma (mut+ MM). Patients and Methods Histologically confirmed patients with stage IV BRAFV600E/K mut+ MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAFV600E mut+ MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. Results Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study. In the BRAFV600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAFV600K mut+ MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAFV600E mut+ MM patients. Conclusion Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a useful prognostic and response marker in future studies.

scholarly journals Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1950 ◽  
Author(s):  
Austin Greco ◽  
Danish Safi ◽  
Umang Swami ◽  
Tim Ginader ◽  
Mohammed Milhem ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Randomized Clinical Trials ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Mek Inhibitors

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.

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