Summary Background Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF ...inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAFV 600 mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov , number NCT01721746. Findings Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5–40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5–23·1) of 47 patients in the ICC group. Grade 3–4 adverse events related to nivolumab included increased lipase (three 1% of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two 1% each); for ICC, these included neutropenia (14 14% of 102), thrombocytopenia (six 6%), and anaemia (five 5%). We noted grade 3–4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. Interpretation Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. Funding Bristol-Myers Squibb.
Summary Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAFV600 -mutated metastatic melanoma. ...We studied the efficacy of dabrafenib in patients with BRAFV600E -mutated metastatic melanoma. Methods We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAFV600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov , number NCT01227889. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18–0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3–4 adverse events were uncommon in both groups. Interpretation Dabrafenib significantly improved progression-free survival compared with dacarbazine. Funding GlaxoSmithKline.
Background The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC ...Outcomes with LDE225 Treatment study. Objective This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. Methods In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. Results Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). Limitations No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. Conclusion With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.
Background Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. ...Objective Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. Methods The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. Results We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. Conclusion H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.
Background The expression of the recently cloned histamine H4 receptor (H4 R) by leukocytes suggests a role in immunomodulation. Objective The expression and function of the H4 R on human monocytes ...obtained from peripheral blood was investigated. Methods H4 R expression was studied by using flow cytometry. Effects of H4 R stimulation on Ca2+ mobilization was determined fluorometrically, CCL2 production was determined by means of ELISA, intracellular CCL2 staining was measured with flow cytometry, and CCL2 mRNA was measured by using real-time quantitative LightCycler PCR. The relevance of CCL2 production was determined in chemotaxis transmigration assays. Results H4 R protein was expressed by monocytes and upregulated by IFN-γ. H4 R agonists (clobenpropit and 4-methylhistamine) induce a Ca2+ mobilization in monocytes, which could be blocked with the selective H4 R antagonist JNJ7777120. Furthermore, H4 R agonists downregulated CCL2 protein production. This effect could also be blocked by JNJ7777120. Supernatants of H4 R agonist–stimulated monocytes attracted less monocytes in transmigration assays. The downregulation of CCL2 production was regulated at different levels. First, the synthesis of CCL2 mRNA was significantly decreased. Second, intracellular staining suggested an inhibition of CCL2 secretion after stimulation with H4 R agonists. Conclusion Human monocytes express the H4 R, and its stimulation leads to a Ca2+ influx and an inhibition of CCL2 production, resulting in a reduction of monocyte recruitment. Clinical implications The H4 R could represent an important anti-inflammatory receptor on monocytes and could be an interesting target for drug development.
Background Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H4 R) is the most recently identified histamine receptor and is also expressed on human ...CD4+ T cells; however, its regulation and function are unclear. Objective To investigate expression, regulation, and function of the H4 R on human CD4+ T cells. Methods Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H4 R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) were determined by electrophoretic mobility shift assay and on cytokine production by RT-PCR and ELISA. Results Histamine receptor 4 mRNA and protein were expressed by CD4+ T cells and upregulated by IL-4. Its expression was higher on TH 2 cells than TH 1 cells and naive T-cells. H4 R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in TH 2 cells but not in TH 1 cells. This effect was blocked by the H4 R antagonist JNJ7777120. H4 R agonists upregulated IL-31 mRNA in PBMCs and TH 2 cells, a cytokine that has been associated with TH 2 cells and the induction of pruritus. IL-31 mRNA induction by H4 R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H4 R. Conclusion Human CD4+ T cells express a functional H4 R. The receptor is upregulated under TH 2 conditions, and its stimulation leads to induction of AP-1 and IL-31.
Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg ...in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 10% of 364 patients in the 10 mg/kg group vs 21 6% of 362 patients in the 3 mg/kg group), colitis (19 5% vs nine 2%), increased alanine aminotransferase (12 3% vs two 1%), and hypophysitis (ten 3% vs seven 2%). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.
Summary Background There are no established therapies specific for NRAS -mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor ...binimetinib versus that of dacarbazine in patients with advanced NRAS -mutant melanoma. Methods NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS -mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov , number NCT01763164 and with EudraCT, number 2012-003593-51. Findings Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4–4·1). Median progression-free survival was 2·8 months (95% CI 2·8–3·6) in the binimetinib group and 1·5 months (1·5–1·7) in the dacarbazine group (hazard ratio 0·62 95% CI 0·47–0·80; one-sided p<0·001). Grade 3–4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 19% of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 7% vs two 2%), anaemia (five 2% vs six 5%), and neutropenia (two 1% vs ten 9%). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. Interpretation Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS -mutant melanoma after failure of immunotherapy. Funding Array BioPharma and Novartis Pharmaceuticals Corporation.
Summary Background Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour ...activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. Methods BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov , number NCT01327053. Findings Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 32% of 79 patients vs 90 60% of 150) or treatment discontinuation (17 22% vs 54 36%) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five 6% in the 200 mg group vs 19 13% in the 800 mg group) and lipase concentration (four 5% vs eight 5%). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. Interpretation The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Funding Novartis Pharmaceuticals Corporation.
Summary Background Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients ...with BRAF -mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. Methods This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF -mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m2 on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov , NCT00936221. Findings Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2–15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6–14·7, in the placebo plus dacarbazine group; hazard ratio HR 0·93, 80% CI 0·67–1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47–0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9–5·9) versus 3·0 months (2·8–4·6), respectively. The most frequent adverse events included nausea (28 64% of 44 patients on selumetinib vs 25 56% of 45 on placebo), acneiform dermatitis (23 52% vs one 2%), diarrhoea (21 48% vs 13 29%), vomiting (21 48% vs 15 33%), and peripheral oedema (19 43% vs three 7%). The most common grade 3–4 adverse event was neutropenia (six 14% patients in the selumetinib plus dacarbazine group vs four 9% in the placebo plus dacarbazine group). Interpretation Selumetinib plus dacarbazine showed clinical activity in patients with BRAF -mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. Funding AstraZeneca.
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