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In long-term follow-up of more than 500 patients with melanoma containing a BRAF V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in 19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.

In patients with surgically resected melanoma, those with BRAF mutations who received 1 year of oral adjuvant therapy with dabrafenib and trametinib had a 53% lower risk of 3-year recurrence than those who received placebo.

Patients with BRAF V600–mutated stage III melanoma received 1 year of adjuvant dabrafenib plus trametinib or placebo. After more than 8 years, the risk of death was 20% lower with treatment, but the benefit was not significant.

In patients with melanomas containing activating BRAF mutations, the combination of a BRAF inhibitor and a MEK inhibitor improved overall survival, as compared with a BRAF inhibitor alone, and was associated with many fewer second skin tumors. The treatment of metastatic melanoma is rapidly evolving. The potent and specific BRAF inhibitors vemurafenib and dabrafenib, as compared with chemotherapy, have significantly improved response rates, along with progression-free and overall survival, in patients with metastatic melanoma with BRAF V600E or V600K mutations. 1 , 2 However, acquired resistance to BRAF inhibitors frequently develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway, resulting in a median progression-free survival of 6 to 8 months. 2 – 5 In addition, the use of BRAF inhibitors may result in the development of secondary skin tumors, originating from a paradoxical activation of the MAPK pathway in cells . . .

The combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with metastatic melanoma produced a significantly higher response rate than dabrafenib alone. Median progression-free survival was 9.4 months, as compared with 5.8 months with dabrafenib alone. Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in the treatment of metastatic melanoma. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival, respectively, in randomized phase 3 trials involving patients with previously untreated melanoma. 1 – 6 Trametinib mediates blockade of MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival in BRAF V600 melanoma (comprising both V600E and V600K mutations). . . .

Luteinizing hormone–releasing hormone agonists that are used in androgen-deprivation therapy have a slow onset to suppress testosterone levels, and the level of suppression may be incomplete. This randomized trial assessed relugolix, an oral gonadotropin-releasing hormone antagonist with rapid onset, profound suppression of testosterone levels, and rapid recovery after cessation.

The addition of a MEK inhibitor to a BRAF inhibitor improved response rates by nearly 16 percentage points (from 51% to 67%) and improved progression-free survival by 0.5 months (from 8.8 to 9.3 months). Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with BRAF V600 mutations. 1 , 2 However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months. 3 , 4 Most reported resistance mechanisms reactivate the MAPK pathway. 5 – 7 In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway 8 – 10 can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors. 11 – 13 Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .

In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy—Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (–13·20, −8·05, −8·82, −12·69, −12·46, −11·41, and −10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population. GlaxoSmithKline.

In two international, randomized, double-blind, 24-week, phase 3 trials involving women with uterine fibroid–associated heavy menstrual bleeding, therapy with relugolix (an oral gonadotropin-releasing hormone receptor antagonist), combined with estradiol and norethindrone acetate, led to a significant reduction in menstrual bleeding while preserving bone mineral density.

Treatment with trametinib, a MEK inhibitor, resulted in significantly improved progression-free and overall survival, as compared with chemotherapy, in patients with advanced melanoma and activating BRAF mutations. About 160,000 new cases of melanoma are diagnosed and 48,000 melanoma-related deaths occur worldwide each year. 1 Among cancers in patients under 40 years of age, the incidence of melanoma is second only to that of breast cancer for women and leukemia for men. 2 Before 2010, no systemic therapy had been shown to improve overall survival among patients with metastatic melanoma, and only modest improvements were observed with interferon as an adjuvant drug. 3 Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and vemurafenib, a selective BRAF inhibitor, have both been shown to improve survival among patients with metastatic melanoma . . .