The New England Journal of Medicine

doi: 10.1056/NEJMoa1408868pmid: 25265494

BackgroundThe combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.MethodsWe randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.ResultsThe median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.ConclusionsThe addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann–La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)

doi: 10.1056/NEJMoa1406037pmid: 25265492

BackgroundCombined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.MethodsIn this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted.ResultsThe median progression-free survival was 9.3 months in the dabrafenib–trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib–trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib–trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib–trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib–trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib–trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib–trametinib group.ConclusionsA combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.)

doi: 10.1056/NEJMoa1401914pmid: 25386897

BackgroundIn South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease.MethodsWe conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups.ResultsSurveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (−89%; 95% confidence interval [CI], −92 to −86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, −63 to −50), from 3.7 to 1.6 cases per 100,000 person-years.ConclusionsRates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.)