Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

Robert, Caroline; Grob, Jean Jacques; Stroyakovskiy, Daniil; Karaszewska, Bogusława; Hauschild, Axel; Levchenko, Evgeny; Chiarion-Sileni, Vanna; Schachter, Jacob; Garbe, Claus; Bondarenko, Igor; Gogas, Helen; Mandalà, Mario; Haanen, John B.A.G.; Lebbe, Célèste; Maćkiewicz, Andrzej; Rutkowski, Piotr; Nathan, Paul; Ribas, Antoni; Davies, Michael A.; Flaherty, Keith T.; Burgess, Paul; Tan, Monique; Gasal, Eduard; Voi, Maurizio; Schadendorf, Dirk; Long, Georgina V.

doi:10.1056/nejmoa1904059

Cited by 1,017 publications

(990 citation statements)

References 16 publications

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“…The median PFS reported in the global studies was 11.1 months, with 1‐, 2‐, 3‐ and 5‐year PFS rates of 48%, 31%, 24% and 19%, respectively. In our study, the median PFS was 12 months, with 1‐, 2‐ and 3‐year PFS rates of 48.8%, 37.8% and 29.7%, respectively, which were very similar to the global results . The median OS reported in the global studies was 25.9 months, with 1‐, 2‐, 3‐ and 5‐year OS rates of 74%, 52%, 44% and 34%, respectively.…”

Section: Discussionsupporting

confidence: 88%

“…In our study, we also found that the response rate differed depending on baseline LDH and the number of organs with metastasis: the response rate for patients with normal LDH at baseline and metastasis in less than three organs was 90.5%, higher than the 50% for those with elevated LDH and metastasis in three or more organs. With respect to PFS, in the global studies, for patients with normal LDH, 1‐, 2‐, 3‐ and 5‐year PFS rates were 61%, 39%, 31% and 25%, respectively, whereas for those with elevated LDH, 1‐, 2‐, 3‐ and 5‐year PFS rates were 24%, 14%, 9% and 8%, respectively . In our study, we also found that for patients with normal LDH, median PFS was 27 months, with 1‐, 2‐ and 3‐year PFS rates of 67.7%, 55.4% and 42.2%, respectively, whereas for those with elevated LDH, median PFS was 5 months, with 1‐, 2‐ and 3‐year PFS rates of 19%, 9.5% and 9.5%, respectively; all differences were significant.…”

Section: Discussionsupporting

confidence: 66%

“…In two global studies (the COMBI‐d and COMBI‐v trials), the reported response rate was 68% and the DCR was 91%; in our study, the response rate was 72.3% and the DCR was 91.5%, with an efficacy of 87.5% as a first‐line treatment. These results were as good as those seen in those global studies . No patient who had previously been treated with a BRAF inhibitor and developed PD responded to dabrafenib and trametinib combination therapy, indicating that in patients who have become resistant to BRAF inhibitors, disease control subsequently remains difficult, even with combination therapy.…”

Section: Discussionsupporting

confidence: 63%

“…The median OS reported in the global studies was 25.9 months, with 1‐, 2‐, 3‐ and 5‐year OS rates of 74%, 52%, 44% and 34%, respectively. In our study, the median OS was 23 months, with 1‐, 2‐ and 3‐year OS rates of 57.1%, 46.3% and 42.1%, respectively . Although 1‐year OS tended to be lower in our study, our real‐world patients included more cases of advanced disease than the subjects in clinical trials; therefore, more patients died within 1 year.…”

Section: Discussionmentioning

confidence: 58%

“…The global studies reported that LDH level at baseline and the number of organs with metastasis were important prognostic factors for response rate, PFS and OS . In those studies, the response rate for patients with normal LDH and metastasis in less than three organs was 78% (CR, 32%; PR, 46%), higher than the rates of 58% for those with LDH from 1 or more to less than 2 × upper limit of normal (ULN) (CR, 6%; PR, 52%) and 50% for those with LDH of 2 or more × ULN (CR, 0%; PR, 50%) .…”

Section: Discussionmentioning

confidence: 99%

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Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

Takahashi¹,

Namikawa²,

Nakano³

et al. 2019

The Journal of Dermatology

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We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma in real‐world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation‐positive advanced melanoma in our hospital (26 men and 24 women, aged 21–86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression‐free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long‐term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

Takahashi¹,

Namikawa²,

Nakano³

et al. 2019

The Journal of Dermatology

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FrontlineBRAFTesting–Guided Treatment for Advanced Melanoma in the Era of Immunotherapies

Shi

2020

JAMA Dermatol

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IMPORTANCEThe effectiveness of immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors has improved advanced melanoma recovery. However, it is unknown whether these novel therapies are cost-effective for newly diagnosed advanced melanoma with unknown BRAF status.OBJECTIVE To compare the cost-utility of these novel agents and their combinations with or without BRAF gene testing guidance for treating newly diagnosed advanced melanoma with unknown BRAF status.DESIGN AND SETTING A decision-analytic model was adopted to project the outcomes of 8 strategies containing different ICIs and BRAF and MEK inhibitors for newly diagnosed advanced melanoma with unknown BRAF pathogenic variant status. The key clinical data were derived from the CheckMate 067, KEYNOTE-006, COMBI-d, and COMBI-v trials, and the cost and health preference data were derived from the literature. Costs were estimated from the US payer perspective.MAIN OUTCOMES AND MEASURES Costs, quality-adjusted life-years (QALYs), incremental cost-utility ratio (ICUR), and incremental net health benefits were calculated. Subgroup, 1-way, and probabilistic sensitivity analyses were performed. RESULTSOf the 8 competing strategies, nivolumab plus ipilimumab without patient selection based on BRAF pathogenic variant testing yielded the most significant health outcome, and the nivolumab strategy was the cheapest option. The nivolumab, pembrolizumab, and nivolumab plus ipilimumab strategies formed the cost-effective frontier, which showed the ordered ICURs were $8593

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Melanoma Treatments and Mortality Rate Trends in the US, 1975 to 2019

et al. 2022

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ImportanceMelanoma accounts for most of the deaths due to skin cancer. In the past decade, effective US Food and Drug Administration (FDA)–approved therapies for melanoma have emerged.ObjectiveTo review changes in the long-term melanoma mortality rate (MMR) trends in the US and determine whether they have any temporal association with the FDA approval of new agents.Design, Setting, and ParticipantsThis cross-sectional study used population data from the Surveillance, Epidemiology, and End Results (SEER) database and retrospectively reviewed the age-adjusted MMR trends in adult patients (aged ≥18 years) from 1975 to 2019 in the US population. The timeline of the FDA approvals for melanoma treatment was also reviewed. Data were analyzed from March 15 to August 15, 2022.ExposuresOutcomes were assessed in association with FDA approval of drugs for the treatment of melanoma.Main Outcomes and MeasuresMortality rates are from the SEER database, reported per 100 000 population and age-adjusted to the 2000 US standard population. The annual percent change (APC) has been used to report long-term trends.ResultsAfter the introduction of newer treatments in 2011 (most after 2013), a significant reduction in MMR was seen from 2013 to 2017 in the US for the first time in the past 40 years. Rates increased from 1975 to 1988 (APC, 1.65% [95% CI, 1.30%-2.00%]; P &lt; .001). No statistically significant change in MMR was seen from 1988 to 2013 (APC, 0.01% [95% CI, −1.10% to 0.12%]; P = .85). The MMR decreased significantly from 2013 to 2017 (APC, −6.28% [95% CI, −8.52% to −3.97%]; P &lt; .001).Conclusions and RelevanceThese findings suggest a benefit associated with the availability of effective therapies in the past decade and further suggest that the use of new pharmacological therapies is associated with decreased MMR in the US population. These data are very encouraging and support the continued development of such therapies. Additionally, the accessibility of these treatments and the associated health care costs need to be addressed.

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Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

Cited by 1,017 publications

References 16 publications

Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

FrontlineBRAFTesting–Guided Treatment for Advanced Melanoma in the Era of Immunotherapies

Melanoma Treatments and Mortality Rate Trends in the US, 1975 to 2019

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