Dataset Information

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF^V600-mutant advanced melanoma patients: a propensity-matched survival analysis.

ABSTRACT:

Background

Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF^V600-mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF^V600-mutant melanoma patients.

Methods

We selected patients diagnosed between 2014 and 2017 with advanced melanoma and a known BRAF^V600-mutation treated with first-line BRAF/MEK inhibitors or anti-PD-1 antibodies, registered in the Dutch Melanoma Treatment Registry. Patients were matched based on their propensity scores using the nearest neighbour and the optimal matching method.

Results

Between 2014 and 2017, a total of 330 and 254 advanced melanoma patients received BRAF/MEK inhibitors and anti-PD-1 monotherapy as first-line systemic therapy. In the matched cohort, patients receiving anti-PD-1 antibodies as a first-line treatment had a higher median and 2-year overall survival compared to patients treated with first-line BRAF/MEK inhibitors, 42.3 months (95% CI: 37.3-NE) vs. 19.8 months (95% CI: 16.7-24.3) and 65.4% (95% CI: 58.1-73.6) vs. 41.7% (95% CI: 34.2-51.0).

Conclusions

Our data suggest that in the matched BRAF^V600-mutant advanced melanoma patients, anti-PD-1 monotherapy is the preferred first-line treatment in patients with relatively favourable patient and tumour characteristics.

SUBMITTER: van Breeschoten J

PROVIDER: S-EPMC8007796 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF<sup>V600</sup>-mutant advanced melanoma patients: a propensity-matched survival analysis.

van Breeschoten Jesper J Wouters Michel W J M MWJM Hilarius Doranne L DL Haanen John B JB Blank Christian U CU Aarts Maureen J B MJB van den Berkmortel Franchette W P J FWPJ de Groot Jan-Willem B JB Hospers Geke A P GAP Kapiteijn Ellen E Piersma Djura D van Rijn Roos S RS Suijkerbuijk Karijn P M KPM Blokx Willeke A M WAM Tije Bert-Jan J Ten BJT Veldt Astrid A M van der AAMV Vreugdenhil Art A Boers-Sonderen Marye J MJ van den Eertwegh Alfonsus J M AJM

British journal of cancer 20210126 7

<h4>Background</h4>Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF<sup>V600</sup>-mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF<sup>V600</sup>-mutant melanoma patients.<h4>Methods</h4>We selected patients diagnosed between 2014 ...[more]

PMID: 33495600

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Project description:BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

Project description:Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

Dataset Information

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF^V600-mutant advanced melanoma patients: a propensity-matched survival analysis.

Background

Methods

Results

Conclusions

Publications

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF<sup>V600</sup>-mutant advanced melanoma patients: a propensity-matched survival analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAFV600-mutant advanced melanoma patients: a propensity-matched survival analysis.

Background

Methods

Results

Conclusions

Publications

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF<sup>V600</sup>-mutant advanced melanoma patients: a propensity-matched survival analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF^V600-mutant advanced melanoma patients: a propensity-matched survival analysis.