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BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most

The Wnt pathway is integrally involved in regulating self-renewal, proliferation, and maintenance of cancer stem cells (CSCs). We explored the effect of the Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), in modulating epithelial to mesenchymal transition (EMT) in CSCs from human glioblastoma cells lines, U87 and U373. sFRP4 chemo-sensitized CSC-enriched cells to the most commonly used anti-glioblastoma drug, temozolomide (TMZ), by the reversal of EMT. Cell movement, colony formation, and invasion in vitro were suppressed by sFRP4+TMZ treatment, which correlated with the switch of expression of markers from mesenchymal (Twist, Snail, N-cadherin) to epithelial (E-cadherin). sFRP4 treatment elicited activation of the +2 pathway, which antagonizes the Wnt/ß-catenin pathway. Significantly, the chemo-sensitization effect of sFRP4 was correlated with the reduction in the expression of drug resistance markers ABCG2, ABCC2, and ABCC4. The efficacy of sFRP4+TMZ treatment was demonstrated in vivo using nude mice, which showed minimum tumor engraftment using CSCs pretreated with sFRP4+TMZ. These studies indicate that sFRP4 treatment would help to improve response to commonly used chemotherapeutics in gliomas by modulating EMT via the Wnt/ß-catenin pathway. These findings could be exploited for designing better targeted strategies to improve chemo-response and eventually eliminate glioblastoma CSCs.

Although much progress has been made for the treatment of prostate cancer, patients with advanced prostate cancer still have a poor 5 year survival rate. Current practices for hormone-refractory/castrate resistant, metastatic prostate cancer involve the use of taxanes. Docetaxel, in particular, is being incorporated in numerous current clinical trials either as a single or combination agent against androgen-independent prostate cancer. Combination therapies have the potential to increase the effectiveness of drug treatments while simultaneously increasing quality of life by reducing side effects, lowering effective dosage rates, or by increasing effectiveness of one compound once combined with another. Using three diverse human prostate cancer cell lines, LNCap, DU145, and PC3, we studied the effect of the novel prostate cancer drug phenoxodiol in combination with docetaxel by utilizing isobolograms, and found that docetaxelinduced cell death was attenuated by co-treatment or pre-treatment of cells with phenoxodiol. This attenuation is associated with the prevention of cells from entering the G2/M phase of the cell cycle where docetaxel is functional in damaging the spindle fibers, and potentially due to p21WAF1 mediated cell survival after docetaxel treatment.We also investigated the use of the Wnt signaling pathway antagonist secreted frizzled-related protein 4 (sFRP4) to increase the effectiveness of phenoxodiol treatment. We found that, through stabilization of the GSK3β molecule, sFRP4 induces degradation of active β-catenin, which causes an increased sensitivity to isoflavone cytotoxic induction by increasing p21WAF1 expression and decreasing expression of c-Myc, Cyclin-D1, and other potent oncogenes. Phenoxodiol induces significant cytotoxicity when combined with a Wnt/β-catenin receptor blocker such as sFRP4. This promotes the concept that combination therapy of a Wnt inhibitor with phenoxodiol might increase the effectiveness of phenoxodiol and give a subse

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Result(s): Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in >=10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 16

Background: Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth, decrease CSC frequency & cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect in human tumor xenograft models. Method(s): Pts received DEM (2.5, 5 or 7.5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 weeks followed by maintenance DEM or PEM (7.5 mg/kg cohort) every 3 weeks until progression. The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling. Result(s): Thirty-two pts were enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg & 6 received 7.5 mg/kg of DEM. Related AEs in > 20% of pts were: nausea (53%), fatigue (47%), hypertension (41%), vomiting (34%), edema (28%), neutropenia (25%), & increased B-type natriuretic peptide (BNP) (22%). Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two pts receiving 5 mg/kg developed reversible pulmonary hypertension & heart failure on days 167 and 183, respectively. As a result, DEM treatment was limited to 63 days in subsequent cohorts. One of 28 (4%) evaluable pts had a RECIST CR, 12 (43%) had a PR and 11 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5 and 7.5 mg/kg pts were 4.8, 5.3 and 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Day 223+, 243+, 457+, 497+, 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850. Conclusion(s): DEM, CARBO & PEM was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. The duration of DEM therapy is

In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient.

Background: Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness; however, the role of genetic loci has been little investigated to date. Objectives: To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. Methods: Participants were 800 individuals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA sample. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. Results: Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. Conclusions: Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding.

The optimal chemoradiation regimen for stage III non-small cell lung cancer (NSCLC) has not been determined. In this phase I/II study, the use of twice-weekly paclitaxel concomitant with weekly cisplatin and thoracic radiotherapy (RT) was evaluated. Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) were treated with thoracic RT (60 Gy in 30 fractions over 6 weeks) with concurrent weekly cisplatin 20 mg/m2 and escalating doses of twice-weekly paclitaxel (starting dose of paclitaxel of 20 mg/m2 increased in increments of 5 mg/m2) in successive cohorts of three to six patients until two or more patients experienced dose limiting toxicities (DLTs) at a particular dose level. All patients were planned to be given a further two cycles of consolidation chemotherapy consisting of paclitaxel 175 mg/m2 and carboplatin AUC 5 after completion of RT. Twenty-five patients were enrolled in this study from two institutions. At a dose of paclitaxel 35 mg/m2, two of four treated patients had DLTs (1 grade 3 oesophagitis and pulmonary toxicity; 1 grade 3 oesophagitis and infection). The recommended dose was therefore determined to be 30 mg/m2 and a total of 15 patients were enrolled in an expanded cohort at this level. The overall response rate for all patients was 64% (95% CI: 43-82%). The estimated median survival was 23.6 months with an estimated 1-year and 2-year survival of 72 and 49%, respectively. Paclitaxel can be safely given twice-weekly at a dose of 30 mg/m2 in combination with weekly cisplatin (20 mg/m2) and thoracic RT (60 Gy), and this regimen has significant activity in stage III NSCLC. © 2003 Elsevier Ireland Ltd. All rights reserved.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models, using an in vivo tumorigenicity limiting dilution assay. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received demcizumab (2.5 or 5 mg/kg) plus pemetrexed 500 mg/m2 and carboplatin (area under the concentrationtime curve, 6 mg/mL x min) once every 3 weeks for 6 cycles followed by maintenance demcizumab once every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were also administered as pemetrexed pre-medication. The primary study objective was to determine the safety profile and optimal dose of demcizumab when combined with pemetrexed and carboplatin. Other objectives included: preliminary efficacy, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles and tumor cells. Result(s): Twelve patients have been enrolled; 6 patients received 2.5 mg/kg and 6 patients received 5 mg/kg of demcizumab. The median age was 64 years and all 12 patients had stage IV disease. Adverse events reported as related to study drug in at least 10% of patients included: fatigue (50%), hypertension (42%), dyspnea on exertion (25%), ALT increased (25%), AST increased (25%), nausea (25%), vomiting (25%), neutropenia (17%), diarrhea (17%), palpitations (17%), decreased appetite (17%) and rash (17%). The hypertension was successfully managed with anti-hypertensives and no patients developed cardiac toxicity. The pharmacokinetic, immunogenicity and blood and hair biomarker specimens are being analyzed and these data will be presented. Six of the 10 (60%) evaluable patients h

The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any individual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment.