New Treatments for Cutaneous Metastatic Melanoma: MAPK Pathway-Targeted and Immune Based Therapies

2015 ◽  
Vol 15 (4) ◽  
pp. 461-467 ◽  
Author(s):  
F. Ranchon ◽  
A. Boespflug ◽  
C. Rioufol ◽  
V. Schwiertz ◽  
L. Thomas ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
New Treatments

scholarly journals Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Bilgen Gençler ◽  
Müzeyyen Gönül
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Case Reports ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Cutaneous Side Effects ◽  
Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

Preclinical activity of cobimetinib alone or in combination with chemotherapy and targeted therapies in renal cell carcinoma

2021 ◽  
Author(s):  
Lichen Zhang ◽  
Deqiong Xie ◽  
Yonghua Lei ◽  
Aoli Na ◽  
Lei Zhu
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mapk Pathway ◽  
Standard Of Care ◽  
Underlying Mechanism ◽  
Mek Inhibitor ◽  
Tumor Formation ◽  
Pathway Inhibition ◽  
New Treatments

Background: The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs. Methods: Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway. Results: Cobimetinib was active against RCC cells, with IC50 at 0.006–0.8μM, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition. Conclusion: Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.

Treating Metastatic Melanoma in 2014: What Just Happened and What Is Next?

2014 ◽  
pp. 16-19 ◽  
Author(s):  
Paul B. Chapman
Keyword(s):  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Program Committee ◽  
The Body ◽  
Driver Mutations ◽  
Cancer Center ◽  
Treatment Benefit ◽  
Medical College ◽  
Number Of Patients ◽  
Current Research Interest

INTRODUCTION In recent years the expectation related to treating patients with metastatic melanoma has changed. Three years ago, a diagnosis of metastatic melanoma was bleak; only a small number of patients would benefit from standard treatment and the reason for treatment benefit was often unknown, leaving physicians with limited options to help their patients. Today, just 3 years later, there are proven therapies that allow physicians to expect to shrink tumors and extend the lives of their patients after diagnosis. In this article, Paul B. Chapman, MD, Memorial Sloan Kettering Cancer Center, summarizes the recent advances in the field of metastatic melanoma and looks ahead to topics such as focusing on specificity, shutting down the ERK pathway, intermittent dosing, discovering driver mutations, individualizing checkpoint inhibition, and identifying rejection antigens to identify what should occur next in order to continue to improve outcomes for a larger population of patients with metastatic melanoma. Dr. Chapman's paper reminds us of the exciting progress that has been made while focusing on the work that is left in the field. Dr. Chapman is a physician-scientist who specializes in diagnosing and treating melanoma that has metastasized to other parts of the body. Dr. Chapman led a clinical trial that paved the way, in part, to the approval of vemurafenib—a drug that targets a BRAF mutation that is present in approximately 50% of patients with metastatic melanoma. Dr. Chapman is one of five Memorial Sloan Kettering scientists to be appointed to a melanoma “Dream Team” that focuses on identifying potential therapies for metastatic melanoma patients who do not have the mutated form of the BRAF gene. Dr. Chapman is also a professor of medicine at the Weill Cornell Medical College and is the chair of the Melanoma Research Alliance Medical Advisory Board. In addition to the above, Dr. Chapman is a sought-after mentor for medical oncology fellows and has a current research interest in identifying novel means to more durably block signaling in the MAPK pathway in melanoma cells. Jedd Wolchok, MD, PhD, Scientific Program Committee Chair

scholarly journals Current Advances in the Treatment of BRAF-Mutant Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 482 ◽  
Author(s):  
Hima Patel ◽  
Nour Yacoub ◽  
Rosalin Mishra ◽  
Aaron White ◽  
Long Yuan ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Individual Response ◽  
Term Survival ◽  
Mek Inhibitors ◽  
Development Of Resistance ◽  
Patient Responses ◽  
Braf Mutant

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9599-TPS9599 ◽  
Author(s):  
Jose A. Lopez-Martin ◽  
Alfonso Berrocal ◽  
María González-Cao
Keyword(s):  
Metastatic Melanoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Mapk Pathway ◽  
Locally Advanced ◽  
Advanced Melanoma ◽  
Drug Resistant ◽  
Randomized Phase Ii ◽  
Melanoma Patients ◽  
Resistant Cells

TPS9599 Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.

scholarly journals Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

2017 ◽  
Vol 16 (10) ◽  
pp. 2315-2323 ◽  
Author(s):  
Joo Ern Ang ◽  
Akos Pal ◽  
Yasmin J. Asad ◽  
Alan T. Henley ◽  
Melanie Valenti ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Plasma Metabolite

Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9587-9587 ◽  
Author(s):  
Jennifer Ann Wargo ◽  
Rodabe Navroze Amaria ◽  
Peter A. Prieto ◽  
Miles Cameron Andrews ◽  
Michael T. Tetzlaff ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Metastatic Melanoma ◽  
Response Rate ◽  
Mapk Pathway ◽  
Pathologic Complete Response ◽  
Stage Iv ◽  
Complete Response ◽  
Stage Iiib ◽  
Braf Mutant

9587 Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p < 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.

Plasma proteomic analyses and treatment predictive biomarker candidates in melanoma patients receiving immune checkpoint blockade or targeted therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9574-9574 ◽  
Author(s):  
Hanna Eriksson ◽  
Haris Babacic ◽  
Janne Lehtio ◽  
Maria Pernemalm
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Predictive Biomarkers ◽  
Cox Proportional Hazards ◽  
Protein Levels ◽  
Treatment Type ◽  
Melanoma Patients

9574 Background: The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Still, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs or MAPKis. Methods: We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis, respcetively. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used.We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models. Results: HiRIEFLC-MS/MS detected 1,835 proteins.We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p= 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient <0.05, pLRT<0.05, qLRT<0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient< 0.05, pLRT< 0.05, qLRT < 0.05). Conclusions: By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs or MAPKis. Our findings require further validation.

scholarly journals Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFV600E-Specific Inhibitor)

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 157 ◽  
Author(s):  
Antoni Torres-Collado ◽  
Jeffrey Knott ◽  
Ali Jazirehi
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Basic Research ◽  
Underlying Mechanism ◽  
Lessons Learned ◽  
Brafv600e Mutation ◽  
Braf Mutations ◽  
Immune Resistance

Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma.

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