Summary Background Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, ...including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS -mutated or Val600 BRAF -mutated advanced melanoma. Methods In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS -mutated or BRAF -mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS -mutated melanoma, twice-daily MEK162 45 mg for BRAF -mutated melanoma, and twice-daily MEK162 60 mg for BRAF -mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov , number NCT01320085 , and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). Findings Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6–8·7; IQR 2·2–5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS -mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF -mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 60% patients with NRAS -mutated melanoma and 15 37% patients with the BRAF -mutated melanoma), rash (six 20% and 16 39%), peripheral oedema (ten 33% and 14 34%), facial oedema (nine 30% and seven 17%), diarrhoea (eight 27% and 15 37%), and creatine phosphokinase increases (11 37% and nine 22%). Increased creatine phosphokinase was the most common grade 3–4 adverse event (seven 23% and seven 17%). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. Interpretation To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. Funding Novartis Pharmaceuticals.
Background Detection of IgE to recombinant Hymenoptera venom allergens has been suggested to improve the diagnostic precision in Hymenoptera venom allergy. However, the frequency of sensitization to ...the only available recombinant honeybee venom (HBV) allergen, rApi m 1, in patients with HBV allergy is limited, suggesting that additional HBV allergens might be of relevance. Objective We performed an analysis of sensitization profiles of patients with HBV allergy to a panel of HBV allergens. Methods Diagnosis of HBV allergy (n = 144) was based on history, skin test results, and allergen-specific IgE levels to HBV. IgE reactivity to 6 HBV allergens devoid of cross-reactive carbohydrate determinants (CCD) was analyzed by ImmunoCAP. Results IgE reactivity to rApi m 1, rApi m 2, rApi m 3, nApi m 4, rApi m 5, and rApi m 10 was detected in 72.2%, 47.9%, 50.0%, 22.9%, 58.3%, and 61.8% of the patients with HBV allergy, respectively. Positive results to at least 1 HBV allergen were detected in 94.4%. IgE reactivity to Api m 3, Api m 10, or both was detected in 68.0% and represented the only HBV allergen–specific IgE in 5% of the patients. Limited inhibition of IgE binding by therapeutic HBV and limited induction of Api m 3– and Api m 10–specific IgG4 in patients obtaining immunotherapy supports recent reports on the underrepresentation of these allergens in therapeutic HBV preparations. Conclusion Analysis of a panel of CCD-free HBV allergens improved diagnostic sensitivity compared with use of rApi m 1 alone, identified additional major allergens, and revealed sensitizations to allergens that have been reported to be absent or underrepresented in therapeutic HBV preparations.
...the low frequency of sensitization to recombinant (r) Api m 1 compared with the bee venom extract is a cause for concern. By contrast, IgE determination reveals double-positive results in up to ...59% of patients.2 Thus, a diagnostic tool is urgently needed to exclude cross-reactivity via cross-reactive carbohydrate determinants. Because wasp venom allergies are more frequent, and bee venom bears more cross-reactive carbohydrate determinants, typically nonspecific cross-reactions to bee venom must be excluded.
To the Editor: Epidemiologic studies indicate that 0.05% to 2% of the European and North American population develop systemic reactions after stings from honeybee or yellow jacket species.1 The ...diagnosis of Hymenoptera venom allergy is based on a combination of a clinical history of anaphylaxis to Hymenoptera sting, positive skin test response, and specific IgE (sIgE) antibodies. Because of the insufficient specificity and sensitivity of intradermal skin testing, ranging, respectively, between 54% and 100% and 26% and 89% depending on extracts and concentrations used, the measurement of sIgE against native extracts of Hymenoptera is an additional but not substitutive in vitro test.2 Thus, the group of patients with a clinical history of anaphylaxis but negative sIgE measurement against commercial venom extracts represents a major diagnostic challenge.
...our data suggest that IgE binding to nApi m 1 and rApi m 1 (i208) is comparable in CCD-negative patients with BV allergy and that only a minority of patients displaying low levels of IgE to ...nApi m 1 might not be detected by rApi m 1.
Patient 1 had twice undergone coronary artery bypass graft operations and presented with severe functional MR. Patient 2 also had previously undergone coronary artery bypass grafting and presented ...with significant renal impairment and severe degenerative MR. Patient 3 was a frail elderly man with severe degenerative MR. All had >1 hospital admission with overt heart failure in the 6 months before their implantation. Patient #1 Patient #2 Patient #3 Age, yrs 68 75 87 Sex Female Male Male Pre-TMVR NYHA functional class IV IV III Glomerular filtration rate, ml/min 47 18 44 Previous CABG Yes Yes No Heart failure hospital admission in previous 6 months 2 1 1 Etiology MR Secondary Primary Primary Pre-TMVR MR grade (EROA, cm2) 0.34 0.79 1.39 Post-TMVR MR grade None Trivial None Post-TMVR peak/mean mitral gradient, mm Hg 8/3 11/5 7/2 Length of hospital stay, days 20 7 5 Discharge destination Home Home Home Table 1 Patient Profiles CABG = coronary artery bypass grafting; EROA = effective regurgitant orifice area; MR = mitral regurgitation; NHYA = New York Heart Association; TMVR = transmitral valve replacement.
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