Explore the vast range of titles available.

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). . . .

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 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.

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 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 . . .

Background Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. Methods In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. Results 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1–11.4) and 7.0 months (0.2–11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2–44.1; control: 39.0%, 95% CI 28.0–50.8; difference: − 6.5, 95% CI − 21.5 to 8.7; 1-sided P  = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 ( P  < 0.01) in the control group and decreased from C1D1 to C2D1 ( P  < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. Conclusions Addition of epacadostat to pembrolizumab therapy for PD-L1–high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. Trial registration ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

Darapladib, an oral inhibitor of lipoprotein-associated phospholipase A2, was compared with placebo in 15,828 patients with stable coronary heart disease. Darapladib did not significantly reduce the risk of cardiovascular death, myocardial infarction, or stroke. Atherosclerotic lesions in humans — in particular, vulnerable 1 and ruptured plaques — are characterized by inflammatory activity and a high expression of lipoprotein-associated phospholipase A 2 . 2 , 3 In atherosclerotic plaques, lipoprotein-associated phospholipase A 2 increases the production of proinflammatory and proapoptotic mediators. 4 – 8 In a meta-analysis of individual records from 79,036 participants in 32 prospective studies, there was a continuous association between lipoprotein-associated phospholipase A 2 activity and the risk of coronary heart disease, with a relative increase in risk of 1.10 (95% confidence interval [CI], 1.05 to 1.16) for each 1-SD increase in lipoprotein-associated phospholipase A 2 activity, . . .

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF V600 in melanoma 1 , 2 . We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAF V600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P  = 0.064, pre-specified two-sided α  = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF -mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.