Combination Immunotherapy and BRAF/MEK Inhibitor Therapy for BRAFV600-Mutated Advanced Melanoma: Are We There Yet?

Background: Retinopathy is a common adverse event with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors. Little is known about the pathophysiology of MEK inhibitor-associated retinopathy (MEKAR). Since MEKAR has many similarities to central serous chorioretinopathy (CSCR), they may share common risk factors. The aim of this study was to evaluate the association between baseline characteristics and MEKAR in melanoma patients initiating MEK inhibitor treatment. Methods: Data from patients treated with cobimetinib and vemurafenib for advanced melanoma in the coBRIM trial were subjected to secondary analysis. Consistent with CSCR risk factors, assessed baseline characteristics included: age, gender, past ocular disease, weight, hypertension, diabetes, dyslipidemia, glomerular filtration rate (eGFR) and corticosteroid use. Associations between characteristics and retinopathy events (any grade and symptomatic) were evaluated using univariate logistic regression and represented as odds ratios (OR). Results: A total of 247 patients were treated with cobimetinib and vemurafenib, of whom 72 (29%) had retinopathy of any grade and 33 (13%) had symptomatic retinopathy. Patients with a history of ocular disease were at significantly higher risk of retinopathy (any grade, 44%; symptomatic, 22%) than those with no ocular disease history (any grade, 22%; symptomatic, 10%). Individuals with a history of ocular inflammation or infection were at highest risk: 4 of 5 developed symptomatic retinopathy during MEK inhibitor therapy. Increased age was associated with a higher risk of any grade retinopathy {decade increase OR [95% confidence interval (CI)] = 1.03 (1.01–1.05); p = 0.009}, while increasing eGFR was significantly associated with a decreased risk of any grade retinopathy [0.98 (0.96–0.99); p = 0.004]; the associations were not statistically significant with symptomatic retinopathy. Other assessed CSCR risk factors were not significantly associated with MEKAR. Conclusion: Age, glomerular filtration rate and history of ocular disease (particularly inflammatory eye disease) were associated with a risk of MEK inhibitor induced retinopathy. Patients who are at increased risk of MEKAR may benefit from more regular ophthalmologic assessment during treatment.

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Choriocapillaris Assessment In Patients Under Mek-Inhibitor Therapy For Cutaneous Melanoma: An Optical Coherence Tomography Angiography Study

Seminars in Ophthalmology ◽

10.1080/08820538.2021.1903512 ◽

2021 ◽

pp. 1-7

Author(s):

Giuseppe Fasolino ◽

Gil Awada ◽

Jorgos Socrates Koulalis ◽

Bart Neyns ◽

Peter Van Elderen ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Cutaneous Melanoma ◽

Optical Coherence Tomography Angiography ◽

Mek Inhibitor ◽

Inhibitor Therapy ◽

Optical Coherence

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LGG-43. CLINICAL EXPERIENCE OF BRAF AND MEK INHIBITOR THERAPY IN PAEDIATRIC GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noy059.384 ◽

2018 ◽

Vol 20 (suppl_2) ◽

pp. i113-i114

Author(s):

Patricia O’Hare ◽

Thalia Loka ◽

Felice D’Arco ◽

Sarita Depani ◽

Anthony Michalski ◽

...

Keyword(s):

Clinical Experience ◽

Mek Inhibitor ◽

Inhibitor Therapy

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HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-3382 ◽

2019 ◽

Vol 25 (18) ◽

pp. 5686-5701 ◽

Cited By ~ 16

Author(s):

Fernanda Faião-Flores ◽

Michael F. Emmons ◽

Michael A. Durante ◽

Fumi Kinose ◽

Biswarup Saha ◽

...

Keyword(s):

Uveal Melanoma ◽

Mek Inhibitor ◽

Inhibitor Therapy ◽

Hdac Inhibition ◽

In Vivo Efficacy

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PALB2 mutation as a predictive biomarker for immunotherapy in patients with advanced melanoma: Results from (a pooled analysis of) five multicenter, randomized clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21537 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21537-e21537

Author(s):

Changxuan You ◽

Yating Zheng ◽

Mengli Huang

Keyword(s):

Randomized Clinical Trials ◽

Parp Inhibitor ◽

Objective Response ◽

Pooled Analysis ◽

Advanced Melanoma ◽

Inhibitor Therapy ◽

Study Cohort ◽

Platinum Based Chemotherapy ◽

Palb2 Mutation ◽

Inhibitor Treatment

e21537 Background: PALB2, a gene in the homologous recombination repair (HRR) pathway, has been shown to be associated with the efficacy of platinum based chemotherapy, and PARP inhibitor therapy in breast, prostate, ovarian, and pancreatic cancers. However, their predictive value of PALB2 remained unknown in patients with advanced melanoma. Methods: Five independent cohorts (Miao2018, Samstein2018, Allen 2015, Hugo2016, and Synder2014. study cohort) with data from 672 patients with advanced melanoma were used to analyze the correlation with immunogenic marker, and the prognostic effect of PALB2 on immunotherapy. Results: A pooled analysis of five independent cohorts of 672 advanced patients melanoma show that 31 (4.6%) harbored PALB2 mutation ( PALB2mut). PALB2mut (72.63Muts/Mb) was associated with higher tumor mutation burden (TMB) (P < 0.001) than PALB wild-type ( PALB2wt) (19.71Muts/Mb). The same phenomenon has also been observed in TNB, PALB2mut (1983 counts) was associated with higher tumor neoantigen burden (TNB) than PALB2wt (603.5 counts) (P = 0.0147). The objective response rate (ORR) of immunotherapy was 53.33% for the patients with PALB2mut and 24% for the PALB2wt subgroup (P = 0.027). The PALB2mut patients had significantly improved median overall survival (mOS) than the PALB2wt group (Not reach versus 29 months, hazard ratio (HR) = 0.38, 95%CI 0.19−0.73, P = 0.003). A subgroup analysis of CTLA4 inhibitor treatment found that PALB2mut was associated with better ORR (50% versus 18.3%, P = 0.016) on immunotherapy, and mOS in the PALB2mut group was significantly better than that in the PALB2wt group (Not reach versus 21 months, HR = 0.3, 95%CI 0.13−0.68, P = 0.002). However, in the subgroup receiving PD-L1 inhibitor treatment, no ORR benefit was found in the PALB2mut group (66.67% versus 56.76%, P = 1), and there was no difference on mOS between PALB2mut and PALB2wt (Not reach versus 31 months, HR = 0.45, 95%CI 0.11−1.8, P = 0.254). Conclusions: PALB2 mutations was associated with a higher TMB and TNB level. PALB2 may serve as a positive predictor of immunotherapy (CTLA4 inhibitor therapy) in patients with advanced melanoma and their clinical value warrants further investigation.

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Advanced melanoma, a pharmacological evaluation

European Journal of Public Health ◽

10.1093/eurpub/ckab120.091 ◽

2021 ◽

Vol 31 (Supplement_2) ◽

Author(s):

Anabela Andrade ◽

Jorge Balteiro

Keyword(s):

Overall Survival ◽

Targeted Therapy ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Advanced Melanoma ◽

New Drugs ◽

High Rate ◽

Free Survival ◽

Dismal Prognosis

Abstract Background Cutaneous melanoma is an aggressive cancer that occurs in melanocytes, located in the epidermis. Historically it has a high rate of morbidity and mortality, due to the resistance and toxicity of traditional therapies. Its incidence has increased annually by 4% to 8%. Until 2011 it was still considered a devastating and almost always fatal disease in a few months. Advances in therapies have significantly improved the results of most patients with advanced melanoma, especially those with a BRAFV600 mutation, which account for almost 50% of tumors. Before the recent evolution in treatment, the prognosis and overall survival were considered very bad. The introduction of new drugs has improved progression-free survival and overall survival, as well as producing faster clinical responses. Methods Comparison of endpoints such as progression-free survival and overall melanoma survival from the Summary of Product Characteristics (SPC) studies of each drug in the therapeutic groups under assessment used in the disease. The variables used were the Endpoints Global Survival at various times (12 months, 24 months, 36 months and the median) and Progression-Free Survival. Results Combined immunotherapy (Nivolumab and Ipilimumab) improves overall survival and progression-free survival, achieving better results than targeted therapy. In this, the combination of a BRAF inhibitor and a MEK inhibitor, presents better results with the combination of Encorafenib and Binimetinib. Conclusions Both targeted therapy and immunotherapy transform melanoma with a dismal prognosis into a life-threatening illness.

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