BRAF inhibitor activity in V600R metastatic melanoma

Purpose: To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors.Experimental Design: Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n ¼ 28) or combination of BRAF and MEK inhibitors (Combi; n ¼ 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome.Results: Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P ¼ 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P ¼ 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4 þ , CD8þ , and PD-1 þ lymphocytes from PRE to EDT (P ¼ 0.001, P ¼ 0.001, P ¼ 0.017, respectively), and Combi-treated patients showed similar increases in CD4 þ and CD8 þ lymphocytes from PRE to EDT (P ¼ 0.017, P ¼ 0.021).Conclusions: The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.

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“…The BRAF mutation status was determined as previously described (26,27). The dosages and durations of treatment are described in Table 1.…”

Section: Methodsmentioning

confidence: 99%

PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor–Treated Melanoma Patients

Kakavand

Wilmott

Menzies

et al. 2015

Clinical Cancer Research

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124

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“…A small proportion of patients with BRAF-mutant melanomas (3-5%) have other V600 amino acid substitutions, for example, V600M, V600D, or V600R 5,6,22 . Clinical evidence is currently insufficient to quote the likelihood that such patients will respond to the available BRAF inhibitors, although good response rates have been documented in case studies 24 . An additional 3-5% of melanomas harbour other forms of genetic alteration in BRAF that are also considered to be oncogenic 5 .…”

Section: Genetic and Immune Landscape Of Melanomamentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…Neither drug has, therefore, been prospectively studied in patients with BRAF V600K melanoma in a randomized trial, but sufficient data exist to suggest that both drugs are active, and likely equally active, in BRAF V600K melanoma. Both drugs are also active in patients with BRAF V600R melanoma and there is a case report of response to vemurafenib in BRAF L597R melanoma (18,19). It, therefore, seems that patients with all forms of BRAF V600 mutations are likely to benefit from BRAF inhibition.…”

Section: Comparisons With Vemurafenibmentioning

confidence: 99%

Dabrafenib and Trametinib, Alone and in Combination for BRAF-Mutant Metastatic Melanoma

Menzies

Long

2014

Clinical Cancer Research

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140

101

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Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF V600E metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-na€ ve patients with BRAF V600Eor BRAF V600K also showed benefit with a prolonged median PFS and OS compared with chemotherapy.Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.

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BRAF inhibitor activity in V600R metastatic melanoma

Cited by 101 publications

References 19 publications

PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor–Treated Melanoma Patients

PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor–Treated Melanoma Patients

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Dabrafenib and Trametinib, Alone and in Combination for BRAF-Mutant Metastatic Melanoma

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