MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – An evaluation of the multicenter prospective skin cancer registry ADOREG

Kreft, Sophia; Glutsch, Valerie; Zaremba, Anne; Schummer, Patrick; Mohr, Peter; Grimmelmann, Imke; Gutzmer, Ralf; Meier, Friedegund; Pföhler, Claudia; Sachse, Michael Max; Meiß, Frank; Forschner, Andrea; Haferkamp, Sebastian; Welzel, Julia; Terheyden, Patrick; Herbst, Rudolf; Utikal, Jochen; Kaatz, Martin; Weishaupt, Carsten; Kreuter, Alexander; Debus, Dirk; Duecker, Pia; Sindrilaru, Anca; Löffler, Harald; Schley, Gaston; Weichenthal, Michael; Schadendorf, Dirk; Ugurel, Selma; Gesierich, Anja; Schilling, Bastian

doi:10.1016/j.ejca.2022.02.023

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…As for the treatment sequence, TT responded well both in first‐ and second‐line settings. In another study, BRAF/MEKi showed meaningful activity in patients who developed resistance to anti‐PD‐1‐based immunotherapy, 36 and it was efficacious across all lines of therapy 37 . On the other hand, responses to second‐line ICI therapy were not as good as those to first‐line ICI therapy.…”

Section: Discussionmentioning

confidence: 99%

Systemic therapy for Asian patients with advanced BRAF V600‐mutant melanoma in a real‐world setting: A multi‐center retrospective study in Japan (B‐CHECK‐RWD study)

Namikawa¹,

Ito

Yoshikawa

et al. 2023

Cancer Medicine

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BackgroundAnti‐PD‐1‐based immunotherapy is considered a preferred first‐line treatment for advanced BRAF V600‐mutant melanoma. However, a recent international multi‐center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non‐acral cutaneous subtype. We hypothesized that the optimal first‐line treatment for Asian patients may be different.MethodsWe retrospectively collected data of Asian patients with advanced BRAF V600‐mutant melanoma treated with first‐line BRAF/MEK inhibitors (BRAF/MEKi), anti‐PD‐1 monotherapy (Anti‐PD‐1), and nivolumab plus ipilimumab (PD‐1/CTLA‐4) between 2016 and 2021 from 28 institutions in Japan.ResultsWe identified 336 patients treated with BRAF/MEKi (n = 236), Anti‐PD‐1 (n = 64) and PD‐1/CTLA‐4 (n = 36). The median follow‐up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow‐up. For patients treated with BRAF/MEKi, anti‐PD‐1, PD‐1/CTLA‐4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression‐free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti‐PD‐1 and PD‐1/CTLA‐4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity‐score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD‐1/CTLA‐4 (HRs for PD‐1/CTLA‐4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second‐line treatment, BRAF/MEKi followed by PD‐1/CTLA‐4 showed poor survival outcomes.ConclusionsThe superiority of PD‐1/CTLA‐4 over BRAF/MEKi appears modest in Asian patients. First‐line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

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Section: Discussionmentioning

confidence: 99%

Systemic therapy for Asian patients with advanced BRAF V600‐mutant melanoma in a real‐world setting: A multi‐center retrospective study in Japan (B‐CHECK‐RWD study)

Namikawa¹,

Ito

Yoshikawa

et al. 2023

Cancer Medicine

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“…11 Thus, at this point, the data support the use of combined BRAF/MEK inhibition in second or later lines of therapy for advanced melanoma, but most patients progress within months if therapy is preceded by PD-1 or PD-L1 therapy, and BRAF targeted therapy appears to be more toxic if started within 6-12 weeks of last dose of immune checkpoint inhibition. [11][12][13][14] Therefore, the optimal role of BRAF targeted THE TAKEAWAY Part 2 of the COLUMBUS trial, reported in the article 10 that accompanies this editorial, confirmed that the combination of binimetinib to encorafenib 300 mg once daily, which is lower than the maximum tolerated combination dose (450 mg once daily), is associated with improved outcomes compared with single-agent encorafenib (dosed at 300 mg once daily) in patients with previously untreated, advanced BRAF-mutant melanoma. However, past and emerging data support the use of frontline immunotherapy instead of BRAF targeted therapy and thus a number of efforts now are underway to optimize BRAF targeted therapy in patients with advanced melanoma.…”

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confidence: 79%

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confidence: 99%

To Inhibit or Not to Inhibit MEK With BRAF Inhibitors: Is That the Question?

Sullivan

2023

JCO

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“…However, checkpoint modulation has been reported to be less therapeutically effective in cancers with an immunosuppressive microenvironment [ 247 , 248 ]. Although the advent of immunomodulatory agents has led to improved responses in tumor patients, as evidenced by achieving long-lasting tumor remission [ 249 , 250 ], many exhibit brief or no response to available immunomodulatory agents [ 251 , 252 ]. Thus, the development of alternate therapeutic strategies is of great interest.…”

Section: Tumor-promoting Chronic Inflammation As Therapeutic Target F...mentioning

confidence: 99%

Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment

Kharouf

Flanagan

Hassan

et al. 2023

Cancers

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The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma.

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MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma – An evaluation of the multicenter prospective skin cancer registry ADOREG

Cited by 10 publications

References 20 publications

Systemic therapy for Asian patients with advanced BRAF V600‐mutant melanoma in a real‐world setting: A multi‐center retrospective study in Japan (B‐CHECK‐RWD study)

Systemic therapy for Asian patients with advanced BRAF V600‐mutant melanoma in a real‐world setting: A multi‐center retrospective study in Japan (B‐CHECK‐RWD study)

To Inhibit or Not to Inhibit MEK With BRAF Inhibitors: Is That the Question?

Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment

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