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Melanoma: HELP
Articles by Vanna Chiarion Sileni
Based on 65 articles published since 2008
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Between 2008 and 2019, V. Chiarion-Sileni wrote the following 65 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Systemic treatments for metastatic cutaneous melanoma. 2018

Pasquali, Sandro / Hadjinicolaou, Andreas V / Chiarion Sileni, Vanna / Rossi, Carlo Riccardo / Mocellin, Simone. ·Sarcoma Service, Fondazione IRCCS 'Istituto Nazionale Tumori', Via G. Venezian 1, Milano, Italy, 20133. ·Cochrane Database Syst Rev · Pubmed #29405038.

ABSTRACT: BACKGROUND: The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000. OBJECTIVES: To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma. SEARCH METHODS: We searched the following databases up to October 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers and the ASCO database in February 2017, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We considered RCTs of systemic therapies for people with unresectable lymph node metastasis and distant metastatic cutaneous melanoma compared to any other treatment. We checked the reference lists of selected articles to identify further references to relevant trials. DATA COLLECTION AND ANALYSIS: Two review authors extracted data, and a third review author independently verified extracted data. We implemented a network meta-analysis approach to make indirect comparisons and rank treatments according to their effectiveness (as measured by the impact on survival) and harm (as measured by occurrence of high-grade toxicity). The same two review authors independently assessed the risk of bias of eligible studies according to Cochrane standards and assessed evidence quality based on the GRADE criteria. MAIN RESULTS: We included 122 RCTs (28,561 participants). Of these, 83 RCTs, encompassing 21 different comparisons, were included in meta-analyses. Included participants were men and women with a mean age of 57.5 years who were recruited from hospital settings. Twenty-nine studies included people whose cancer had spread to their brains. Interventions were categorised into five groups: conventional chemotherapy (including single agent and polychemotherapy), biochemotherapy (combining chemotherapy with cytokines such as interleukin-2 and interferon-alpha), immune checkpoint inhibitors (such as anti-CTLA4 and anti-PD1 monoclonal antibodies), small-molecule targeted drugs used for melanomas with specific gene changes (such as BRAF inhibitors and MEK inhibitors), and other agents (such as anti-angiogenic drugs). Most interventions were compared with chemotherapy. In many cases, trials were sponsored by pharmaceutical companies producing the tested drug: this was especially true for new classes of drugs, such as immune checkpoint inhibitors and small-molecule targeted drugs.When compared to single agent chemotherapy, the combination of multiple chemotherapeutic agents (polychemotherapy) did not translate into significantly better survival (overall survival: HR 0.99, 95% CI 0.85 to 1.16, 6 studies, 594 participants; high-quality evidence; progression-free survival: HR 1.07, 95% CI 0.91 to 1.25, 5 studies, 398 participants; high-quality evidence. Those who received combined treatment are probably burdened by higher toxicity rates (RR 1.97, 95% CI 1.44 to 2.71, 3 studies, 390 participants; moderate-quality evidence). (We defined toxicity as the occurrence of grade 3 (G3) or higher adverse events according to the World Health Organization scale.)Compared to chemotherapy, biochemotherapy (chemotherapy combined with both interferon-alpha and interleukin-2) improved progression-free survival (HR 0.90, 95% CI 0.83 to 0.99, 6 studies, 964 participants; high-quality evidence), but did not significantly improve overall survival (HR 0.94, 95% CI 0.84 to 1.06, 7 studies, 1317 participants; high-quality evidence). Biochemotherapy had higher toxicity rates (RR 1.35, 95% CI 1.14 to 1.61, 2 studies, 631 participants; high-quality evidence).With regard to immune checkpoint inhibitors, anti-CTLA4 monoclonal antibodies plus chemotherapy probably increased the chance of progression-free survival compared to chemotherapy alone (HR 0.76, 95% CI 0.63 to 0.92, 1 study, 502 participants; moderate-quality evidence), but may not significantly improve overall survival (HR 0.81, 95% CI 0.65 to 1.01, 2 studies, 1157 participants; low-quality evidence). Compared to chemotherapy alone, anti-CTLA4 monoclonal antibodies is likely to be associated with higher toxicity rates (RR 1.69, 95% CI 1.19 to 2.42, 2 studies, 1142 participants; moderate-quality evidence).Compared to chemotherapy, anti-PD1 monoclonal antibodies (immune checkpoint inhibitors) improved overall survival (HR 0.42, 95% CI 0.37 to 0.48, 1 study, 418 participants; high-quality evidence) and probably improved progression-free survival (HR 0.49, 95% CI 0.39 to 0.61, 2 studies, 957 participants; moderate-quality evidence). Anti-PD1 monoclonal antibodies may also result in less toxicity than chemotherapy (RR 0.55, 95% CI 0.31 to 0.97, 3 studies, 1360 participants; low-quality evidence).Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival (HR 0.63, 95% CI 0.60 to 0.66, 1 study, 764 participants; high-quality evidence) and progression-free survival (HR 0.54, 95% CI 0.50 to 0.60, 2 studies, 1465 participants; high-quality evidence). Anti-PD1 monoclonal antibodies may result in better toxicity outcomes than anti-CTLA4 monoclonal antibodies (RR 0.70, 95% CI 0.54 to 0.91, 2 studies, 1465 participants; low-quality evidence).Compared to anti-CTLA4 monoclonal antibodies alone, the combination of anti-CTLA4 plus anti-PD1 monoclonal antibodies was associated with better progression-free survival (HR 0.40, 95% CI 0.35 to 0.46, 2 studies, 738 participants; high-quality evidence). There may be no significant difference in toxicity outcomes (RR 1.57, 95% CI 0.85 to 2.92, 2 studies, 764 participants; low-quality evidence) (no data for overall survival were available).The class of small-molecule targeted drugs, BRAF inhibitors (which are active exclusively against BRAF-mutated melanoma), performed better than chemotherapy in terms of overall survival (HR 0.40, 95% CI 0.28 to 0.57, 2 studies, 925 participants; high-quality evidence) and progression-free survival (HR 0.27, 95% CI 0.21 to 0.34, 2 studies, 925 participants; high-quality evidence), and there may be no significant difference in toxicity (RR 1.27, 95% CI 0.48 to 3.33, 2 studies, 408 participants; low-quality evidence).Compared to chemotherapy, MEK inhibitors (which are active exclusively against BRAF-mutated melanoma) may not significantly improve overall survival (HR 0.85, 95% CI 0.58 to 1.25, 3 studies, 496 participants; low-quality evidence), but they probably lead to better progression-free survival (HR 0.58, 95% CI 0.42 to 0.80, 3 studies, 496 participants; moderate-quality evidence). However, MEK inhibitors probably have higher toxicity rates (RR 1.61, 95% CI 1.08 to 2.41, 1 study, 91 participants; moderate-quality evidence).Compared to BRAF inhibitors, the combination of BRAF plus MEK inhibitors was associated with better overall survival (HR 0.70, 95% CI 0.59 to 0.82, 4 studies, 1784 participants; high-quality evidence). BRAF plus MEK inhibitors was also probably better in terms of progression-free survival (HR 0.56, 95% CI 0.44 to 0.71, 4 studies, 1784 participants; moderate-quality evidence), and there appears likely to be no significant difference in toxicity (RR 1.01, 95% CI 0.85 to 1.20, 4 studies, 1774 participants; moderate-quality evidence).Compared to chemotherapy, the combination of chemotherapy plus anti-angiogenic drugs was probably associated with better overall survival (HR 0.60, 95% CI 0.45 to 0.81; moderate-quality evidence) and progression-free survival (HR 0.69, 95% CI 0.52 to 0.92; moderate-quality evidence). There may be no difference in terms of toxicity (RR 0.68, 95% CI 0.09 to 5.32; low-quality evidence). All results for this comparison were based on 324 participants from 2 studies.Network meta-analysis focused on chemotherapy as the common comparator and currently approved treatments for which high- to moderate-quality evidence of efficacy (as represented by treatment effect on progression-free survival) was available (based on the above results) for: biochemotherapy (with both interferon-alpha and interleukin-2); anti-CTLA4 monoclonal antibodies; anti-PD1 monoclonal antibodies; anti-CTLA4 plus anti-PD1 monoclonal antibodies; BRAF inhibitors; MEK inhibitors, and BRAF plus MEK inhibitors. Analysis (which included 19 RCTs and 7632 participants) generated 21 indirect comparisons.The best evidence (moderate-quality evidence) for progression-free survival was found for the following indirect comparisons:• both combinations of immune checkpoint inhibitors (HR 0.30, 95% CI 0.17 to 0.51) and small-molecule targeted drugs (HR 0.17, 95% CI 0.11 to 0.26) probably improved progression-free survival compared to chemotherapy;• both BRAF inhibitors (HR 0.40, 95% CI 0.23 to 0.68) and combinations of small-molecule targeted drugs (HR 0.22, 95% CI 0.12 to 0.39) were probably associated with better progression-free survival compared to anti-CTLA4 monoclonal antibodies;• biochemotherapy (HR 2.81, 95% CI 1.76 to 4.51) probably lead to worse progression-free survival compared to BRAF inhibitors;• the combination of small-molecule targeted drugs probably improved progression-free survival (HR 0.38, 95% CI 0.21 to 0.68) compared to anti-PD1 monoclonal antibodies;• both biochemotherapy (HR 5.05, 95% CI 3.01 to 8.45) and MEK inhibitors (HR 3.16, 95% CI 1.77 to 5.65) were probably associated with worse progression-free survival compared to the combination of small-molecule targeted drugs; and• biochemotherapy was probably associated with worse progression-free survival (HR 2.81, 95% CI 1.54 to 5.11) compared to the combination of immune checkpoint inhibitors.The best evidence (moderate-quality evidence) for toxicity was found for the following indirect comparisons:• combination of immune checkpoint inhibitors (RR 3.49, 95% CI 2.12 to 5.77) probably increased toxicity compared to chemotherapy;• combination of immune checkpoint inhibitors probably increased toxicity (RR 2.50, 95% CI 1.20 to 5.20) compared to BRAF inhibitors;• the combination of immune checkpoint inhibitors probably increased toxicity (RR 3.83, 95% CI 2.59 to 5.68) compared to anti-PD1 monoclonal antibodies; and• biochemotherapy was probably associated with lower toxicity (RR 0.41, 95% CI 0.24 to 0.71) compared to the combination of immune checkpoint inhibitors.Network meta-analysis-based ranking suggested that the combination of BRAF plus MEK inhibitors is the most effective strategy in terms of progression-free survival, whereas anti-PD1 monoclonal antibodies are associated with the lowest toxicity.Overall, the risk of bias of the included trials can be considered as limited. When considering the 122 trials included in this review and the seven types of bias we assessed, we performed 854 evaluations only seven of which (< 1%) assigned high risk to six trials. AUTHORS' CONCLUSIONS: We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.Evidence quality was reduced due to imprecision, between-study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers.

2 Review [Pembrolizumab for the treatment of melanoma: updates and perspectives.] 2017

Chiarion Sileni, Vanna / Mandalà, Mario / Queirolo, Paola. ·Istituto Oncologico Veneto, Padova. · Ospedale Papa Giovanni XXIII, Bergamo. · Oncologia Medica 2, Ospedale San Martino, Genova. ·Recenti Prog Med · Pubmed #29297903.

ABSTRACT: Checkpoint inhibitors immunotherapy was a breakthrough in anti-tumor treatments. Anti-PD-1 monoclonal antibodies are now a standard of treatment for advanced melanoma patients, with a 3-year overall survival of over 50% and a low rate (<20%) of severe toxicities in the phase 3 studies. The aim of this review was to report the most important updates on anti-PD-1 drug pembrolizumab from ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) 2017 Annual Meetings.

3 Review Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis. 2017

Pasquali, Sandro / Chiarion-Sileni, Vanna / Rossi, Carlo Riccardo / Mocellin, Simone. ·Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Electronic address: pasqualisandro@hotmail.com. · Melanoma and Esophageal Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. · Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: carlor.rossi@unipd.it. · Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: simone.mocellin@unipd.it. ·Cancer Treat Rev · Pubmed #28189914.

ABSTRACT: BACKGROUND: Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. METHODS: A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). RESULTS: Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. CONCLUSIONS: The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.

4 Review Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. 2014

Ascierto, Paolo A / Chiarion-Sileni, Vanna / Muggiano, Antonio / Mandalà, Mario / Pimpinelli, Nicola / Del Vecchio, Michele / Rinaldi, Gaetana / Simeone, Ester / Queirolo, Paola. · ·J Chemother · Pubmed #24621162.

ABSTRACT: The degree to which interferon (IFN) alpha-2b offers real clinical benefits in the adjuvant therapy of melanoma at high risk of recurrence is a subject of debate. This, together with questions over optimal treatment scheme and concerns over toxicity, has limited its clinical use. On the basis of a review of the literature, an Italian Expert Panel has made practical recommendations for a consistent approach in the use of IFN. Although it is clear that more research into predictive factors to identify patients most likely to benefit from adjuvant IFN therapy is required, IFN remains the only currently available adjuvant option for melanoma. Based on meta-analyses of clinical trials, there is clear evidence that treatment with IFN is beneficial with regard to overall and recurrence-free survival (RFS). As such, IFN should be offered to patients who are at high risk of recurrence. Specific recommendations with regard to disease stage are provided.

5 Review Interferon alpha for the adjuvant treatment of cutaneous melanoma. 2013

Mocellin, Simone / Lens, Marko B / Pasquali, Sandro / Pilati, Pierluigi / Chiarion Sileni, Vanna. ·Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. simone.mocellin@unipd.it. ·Cochrane Database Syst Rev · Pubmed #23775773.

ABSTRACT: BACKGROUND: Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. OBJECTIVES: To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. SEARCH METHODS: We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). DATA COLLECTION AND ANALYSIS: Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates of treatment efficacy. MAIN RESULTS: Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38).Considering that the 5-year overall survival rate for TNM stage II-III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation. AUTHORS' CONCLUSIONS: The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.

6 Review Small molecules and targeted therapies in distant metastatic disease. 2009

Hersey, P / Bastholt, L / Chiarion-Sileni, V / Cinat, G / Dummer, R / Eggermont, A M M / Espinosa, E / Hauschild, A / Quirt, I / Robert, C / Schadendorf, D. ·Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia. Peter.Hersey@newcastle.edu.au ·Ann Oncol · Pubmed #19617296.

ABSTRACT: Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.

7 Review Surgery and radiotherapy in the treatment of cutaneous melanoma. 2009

Testori, A / Rutkowski, P / Marsden, J / Bastholt, L / Chiarion-Sileni, V / Hauschild, A / Eggermont, A M M. ·European Institute of Oncology, Division of Melanoma, Milan, Italy. alessandro.testori@ieo.it ·Ann Oncol · Pubmed #19617294.

ABSTRACT: Adequate surgical management of primary melanoma and regional lymph node metastasis, and rarely distant metastasis, is the only established curative treatment. Surgical management of primary melanomas consists of excisions with 1-2 cm margins and primary closure. The recommended method of biopsy is excisional biopsy with a 2 mm margin and a small amount of subcutaneous fat. In specific situations (very large lesions or certain anatomical areas), full-thickness incisional or punch biopsy may be acceptable. Sentinel lymph node biopsy provides accurate staging information for patients with clinically unaffected regional nodes and without distant metastases, although survival benefit has not been proved. In cases of positive sentinel node biopsy or clinically detected regional nodal metastases (palpable, positive cytology or histopathology), radical removal of lymph nodes of the involved basin is indicated. For resectable local/in-transit recurrences, excision with a clear margin is recommended. For numerous or unresectable in-transit metastases of the extremities, isolated limb perfusion or infusion with melphalan should be considered. Decisions about surgery of distant metastases should be based on individual circumstances. Radiotherapy is indicated as a treatment option in select patients with lentigo maligna melanoma and as an adjuvant in select patients with regional metastatic disease. Radiotherapy is also indicated for palliation, especially in bone and brain metastases.

8 Clinical Trial Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. 2018

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion-Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tüebingen, Tüebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague, Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine, Paris-Sud University, Gustave Roussy, Villejuif, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #29573941.

ABSTRACT: BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. FUNDING: Array BioPharma, Novartis.

9 Clinical Trial Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. 2017

Weber, Jeffrey / Mandala, Mario / Del Vecchio, Michele / Gogas, Helen J / Arance, Ana M / Cowey, C Lance / Dalle, Stéphane / Schenker, Michael / Chiarion-Sileni, Vanna / Marquez-Rodas, Ivan / Grob, Jean-Jacques / Butler, Marcus O / Middleton, Mark R / Maio, Michele / Atkinson, Victoria / Queirolo, Paola / Gonzalez, Rene / Kudchadkar, Ragini R / Smylie, Michael / Meyer, Nicolas / Mortier, Laurent / Atkins, Michael B / Long, Georgina V / Bhatia, Shailender / Lebbé, Celeste / Rutkowski, Piotr / Yokota, Kenji / Yamazaki, Naoya / Kim, Tae M / de Pril, Veerle / Sabater, Javier / Qureshi, Anila / Larkin, James / Ascierto, Paolo A / Anonymous7111184. ·From New York University Perlmutter Cancer Center, New York (J.W.) · Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · National and Kapodistrian University of Athens, Athens (H.J.G.) · Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France · Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker) · Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada · the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia · University of Colorado, Denver (R.G.) · Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.) · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · University of Washington, Seattle (S.B.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan · Seoul National University Hospital, Seoul, South Korea (T.M.K.) · and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.). ·N Engl J Med · Pubmed #28891423.

ABSTRACT: BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

10 Clinical Trial Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. 2017

Long, Georgina V / Hauschild, Axel / Santinami, Mario / Atkinson, Victoria / Mandalà, Mario / Chiarion-Sileni, Vanna / Larkin, James / Nyakas, Marta / Dutriaux, Caroline / Haydon, Andrew / Robert, Caroline / Mortier, Laurent / Schachter, Jacob / Schadendorf, Dirk / Lesimple, Thierry / Plummer, Ruth / Ji, Ran / Zhang, Pingkuan / Mookerjee, Bijoyesh / Legos, Jeff / Kefford, Richard / Dummer, Reinhard / Kirkwood, John M. ·From the Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals (G.V.L.), and Macquarie University, Melanoma Institute Australia, University of Sydney, and Westmead Hospital (R.K.), Sydney, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), and Alfred Hospital, Melbourne, VIC (A. Haydon) - all in Australia · University Hospital Schleswig-Holstein, Kiel (A. Hauschild), and University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg (D.S.) - all in Germany · Fondazione Istituto Nazionale Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute, Padua (V.C.-S.) - all in Italy · Rikshospitalet-Radiumhospitalet, Oslo (M.N.) · Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Institute Gustave Roussy, Paris (C.R.), Université de Lille, INSERM Unité 1189, Centre Hospitalier Régional Universitaire de Lille, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France · Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel (J.S.) · Royal Marsden NHS Foundation Trust, London (J. Larkin), and Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne (R.P.) - both in the United Kingdom · Novartis Pharmaceuticals, East Hanover, NJ (R.J., P.Z., B.M., J. Legos) · University Hospital Zürich Skin Cancer Center, Zurich, Switzerland (R.D.) · and the Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.). ·N Engl J Med · Pubmed #28891408.

ABSTRACT: BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

11 Clinical Trial Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2017

Wolchok, Jedd D / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher D / Wagstaff, John / Schadendorf, Dirk / Ferrucci, Pier F / Smylie, Michael / Dummer, Reinhard / Hill, Andrew / Hogg, David / Haanen, John / Carlino, Matteo S / Bechter, Oliver / Maio, Michele / Marquez-Rodas, Ivan / Guidoboni, Massimo / McArthur, Grant / Lebbé, Celeste / Ascierto, Paolo A / Long, Georgina V / Cebon, Jonathan / Sosman, Jeffrey / Postow, Michael A / Callahan, Margaret K / Walker, Dana / Rollin, Linda / Bhore, Rafia / Hodi, F Stephen / Larkin, James. ·From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.) · Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · University of Colorado, Denver (R.G.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · University of Michigan, Ann Arbor (C.D.L.) · the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Universitäts Spital, Zurich, Switzerland (R.D.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia · Netherlands Cancer Institute, Amsterdam (J.H.) · University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.) · General University Hospital Gregorio Marañón, Madrid (I.M.-R.) · Northwestern University, Chicago (J.S.) · Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.) · and the Dana-Farber Cancer Institute, Boston (F.S.H.). ·N Engl J Med · Pubmed #28889792.

ABSTRACT: BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

12 Clinical Trial Health-related quality of life results from the phase III CheckMate 067 study. 2017

Schadendorf, Dirk / Larkin, James / Wolchok, Jedd / Hodi, F Stephen / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher / Wagstaff, John / Callahan, Margaret K / Postow, Michael A / Smylie, Michael / Ferrucci, Pier Francesco / Dummer, Reinhard / Hill, Andrew / Taylor, Fiona / Sabater, Javier / Walker, Dana / Kotapati, Srividya / Abernethy, Amy / Long, Georgina V. ·Department of Dermatology, University of Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Royal Marsden Hospital, London, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Istituto Oncologico Veneto, Veneto, Italy. · University of Colorado, Denver, CO, USA. · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Hospital de la Timone, Marseille, France. · Texas Oncology-Baylor Cancer Center, Dallas, TX, USA. · University of Michigan, Ann Arbor, MI, USA. · The College of Medicine, Swansea University, Swansea, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. · Cross Cancer Institute, Edmonton, Alberta, Canada. · Istituto Europeo di Oncologia, Milan, Italy. · University of Zurich, Zurich, Switzerland. · Tasman Oncology Research, Brisbane, QLD, Australia. · Adelphi Values, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Duke University Medical Center, Durham, NC, USA. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. ·Eur J Cancer · Pubmed #28651159.

ABSTRACT: BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067. PATIENTS AND METHODS: HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated. RESULTS: Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause. CONCLUSION: These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting. STUDY NUMBER: NCT01844505.

13 Clinical Trial Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. 2017

Schadendorf, Dirk / Long, Georgina V / Stroiakovski, Daniil / Karaszewska, Boguslawa / Hauschild, Axel / Levchenko, Evgeny / Chiarion-Sileni, Vanna / Schachter, Jacob / Garbe, Claus / Dutriaux, Caroline / Gogas, Helen / Mandalà, Mario / Haanen, John B A G / Lebbé, Céleste / Mackiewicz, Andrzej / Rutkowski, Piotr / Grob, Jean-Jacques / Nathan, Paul / Ribas, Antoni / Davies, Michael A / Zhang, Ying / Kaper, Mathilde / Mookerjee, Bijoyesh / Legos, Jeffrey J / Flaherty, Keith T / Robert, Caroline. ·Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia. · Moscow City Oncology Hospital No 62, Moscow 143423, Russia. · Przychodnia Lekarska KOMED, Wojska Polskiego 6, 62-500 Konin, Poland. · Department of Dermatology, University Medical Center Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Via Gattamelata 64, 35128 Padova, Italy. · Oncology Division, Sheba Medical Center, Tel HaShomer, Emek HaEla St 1, Ramat Gan, Israel. · Department of Dermatology, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany. · Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Saint-André, 1 Rue Jean Burguet, 33000 Bordeaux, France. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens 157 72, Greece. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznań, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wawelska 15B, 02-034 Warsaw, Poland. · Department of Dermatology, University Hospital Center, Timone Hospital, Aix Marseille University, 264 Rue St Pierre, 13885 Marseille Cedex 05, France. · Mount Vernon Cancer Centre, Rickmansworth Road, HA6 2RN Northwood, UK. · Department of Medicine, Hematology/Oncology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA. · Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston 02114, MA, USA. · Department of Medical Oncology, Dermatology Service, Gustave Roussy Comprehensive Cancer Center and Faculty of Medicine, University Paris-South, F-94805, Villejuif, France. ·Eur J Cancer · Pubmed #28648698.

ABSTRACT: AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months. CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

14 Clinical Trial Dabrafenib plus trametinib in patients with BRAF 2017

Davies, Michael A / Saiag, Philippe / Robert, Caroline / Grob, Jean-Jacques / Flaherty, Keith T / Arance, Ana / Chiarion-Sileni, Vanna / Thomas, Luc / Lesimple, Thierry / Mortier, Laurent / Moschos, Stergios J / Hogg, David / Márquez-Rodas, Iván / Del Vecchio, Michele / Lebbé, Céleste / Meyer, Nicolas / Zhang, Ying / Huang, Yingjie / Mookerjee, Bijoyesh / Long, Georgina V. ·Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mdavies@mdanderson.org. · Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Medical Oncology, Hospital Clinic of Barcelona, Carrer de Villarroel, Barcelona, Spain. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · Service de Dermatologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Oncologie Dermatologique, Centre Eugène Marquis, Rennes, France. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Le Centre Hospitalier Régional Universitaire de Lille, University Lille 2, Lille, France. · Melanoma Program, Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Clinical Cancer Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada. · Servicio de Oncología Médica; Hospital General Universitario Gregorio Marañon, Madrid, Spain. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Hôpital Saint Louis Paris, Paris, France. · Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #28592387.

ABSTRACT: BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF FUNDING: Novartis.

15 Clinical Trial Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAF 2017

Blank, Christian U / Larkin, James / Arance, Ana M / Hauschild, Axel / Queirolo, Paola / Del Vecchio, Michele / Ascierto, Paolo A / Krajsova, Ivana / Schachter, Jacob / Neyns, Bart / Garbe, Claus / Chiarion Sileni, Vanna / Mandalà, Mario / Gogas, Helen / Espinosa, Enrique / Hospers, Geke A P / Miller, Wilson H / Robson, Susan / Makrutzki, Martina / Antic, Vladan / Brown, Michael P. ·The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. Electronic address: c.blank@nki.nl. · The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: James.Larkin@rmh.nhs.uk. · Department of Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. Electronic address: AMARANCE@clinic.ub.es. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · IRCCS San Martino-IST, Genova, Italy. Electronic address: paola.queirolo@hsanmartino.it. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michele.delvecchio@istitutotumori.mi.it. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · General University Hospital, Dermatooncology U, Prague, Czech Republic. Electronic address: Ivana.Krajsova@vfn.cz. · Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. Electronic address: Jacob.schachter@sheba.health.gov.il. · Afdelingshoofd, Medische Oncologie, Brussels, Belgium. Electronic address: bart.neyns@uzbrussel.be. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · Oncology Institute of Veneto-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. · Papa Giovanni XIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. · University of Athens, Athens, Greece. Electronic address: hgogas@hol.gr. · Hospital La Paz, Madrid, Spain. Electronic address: eespinosa00@hotmail.com. · University Medical Centre Groningen, Groningen, The Netherlands. Electronic address: g.a.p.hospers@umcg.nl. · McGill University, Segal Cancer Centre, Montreal, Quebec, Canada. Electronic address: wilsonmiller@gmail.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: susan.robson@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: martina.makrutzki@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: vladan.antic@roche.com. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Discipline of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: MichaelP.brown@sa.gov.au. ·Eur J Cancer · Pubmed #28501764.

ABSTRACT: BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAF METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAF

16 Clinical Trial Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017

Long, G V / Flaherty, K T / Stroyakovskiy, D / Gogas, H / Levchenko, E / de Braud, F / Larkin, J / Garbe, C / Jouary, T / Hauschild, A / Chiarion-Sileni, V / Lebbe, C / Mandalà, M / Millward, M / Arance, A / Bondarenko, I / Haanen, J B A G / Hansson, J / Utikal, J / Ferraresi, V / Mohr, P / Probachai, V / Schadendorf, D / Nathan, P / Robert, C / Ribas, A / Davies, M A / Lane, S R / Legos, J J / Mookerjee, B / Grob, J-J. ·Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA. · Moscow City Oncology Hospital #62, Moscow, Russia. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University of Tübingen, Tübingen, Germany. · Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany. · Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. · Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Novartis Pharmaceuticals Corporation, East Hanover, USA. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France. ·Ann Oncol · Pubmed #28475671.

ABSTRACT: Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

17 Clinical Trial Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. 2017

Ascierto, Paolo A / Del Vecchio, Michele / Robert, Caroline / Mackiewicz, Andrzej / Chiarion-Sileni, Vanna / Arance, Ana / Lebbé, Céleste / Bastholt, Lars / Hamid, Omid / Rutkowski, Piotr / McNeil, Catriona / Garbe, Claus / Loquai, Carmen / Dreno, Brigitte / Thomas, Luc / Grob, Jean-Jacques / Liszkay, Gabriella / Nyakas, Marta / Gutzmer, Ralf / Pikiel, Joanna / Grange, Florent / Hoeller, Christoph / Ferraresi, Virginia / Smylie, Michael / Schadendorf, Dirk / Mortier, Laurent / Svane, Inge Marie / Hennicken, Delphine / Qureshi, Anila / Maio, Michele. ·Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Medical Oncology, National Cancer Institute, Milan, Italy. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. · AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France. · Odense University Hospital, Odense, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. · Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Eberhard Karls University, Tübingen, Germany. · University Medical Center, Mainz, Germany. · Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Hospital de la Timone, Marseille, France. · National Institute of Oncology, Budapest, Hungary. · Oslo University Hospital, Oslo, Norway. · Medizinische Hochschule Hannover, Hannover, Germany. · Wojewodzkie Centrum Oncologii, Gdańsk, Poland. · Department of Dermatology, Reims University Hospital, Reims, France. · Medical University of Vienna, Vienna, Austria. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · University Hospital Essen, Essen, Germany. · Hôspital Claude Huriez, Lille, France. · Herlev Hospital, University of Copenhagen, Herlev, Denmark. · Bristol-Myers Squibb, Princeton, NJ, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. ·Lancet Oncol · Pubmed #28359784.

ABSTRACT: 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.

18 Clinical Trial Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. 2017

Coens, Corneel / Suciu, Stefan / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Celeste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bottomley, Andrew / Kotapati, Srividya / de Pril, Veerle / Testori, Alessandro / Eggermont, Alexander M M. ·EORTC Headquarters, Brussels, Belgium. Electronic address: corneel.coens@eortc.be. · EORTC Headquarters, Brussels, Belgium. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hôpital de la Timone, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Oncology Specialists S C, Park Ridge, IL, USA. · Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #28162999.

ABSTRACT: BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. FUNDING: Bristol-Myers Squibb.

19 Clinical Trial Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. 2017

Segal, Neil H / Logan, Theodore F / Hodi, F Stephen / McDermott, David / Melero, Ignacio / Hamid, Omid / Schmidt, Henrik / Robert, Caroline / Chiarion-Sileni, Vanna / Ascierto, Paolo A / Maio, Michele / Urba, Walter J / Gangadhar, Tara C / Suryawanshi, Satyendra / Neely, Jaclyn / Jure-Kunkel, Maria / Krishnan, Suba / Kohrt, Holbrook / Sznol, Mario / Levy, Ronald. ·Memorial Sloan Kettering Cancer Center, New York, New York. · Indiana University Simon Cancer Center, Indianapolis, Indiana. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Clinica Universidad de Navarra, Pamplona, Spain. · The Angeles Clinic and Research Institute, Los Angeles, California. · Aarhus University Hospital, Aarhus, Denmark. · Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France. · Istituto Oncologico Veneto, Padua, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy. · University Hospital of Siena, Siena, Italy. · Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. · Bristol-Myers Squibb, Princeton, New Jersey. · Stanford University School of Medicine, Stanford, California. · Yale Comprehensive Cancer Center, New Haven, Connecticut. · Stanford University School of Medicine, Stanford, California. levy@stanford.edu. ·Clin Cancer Res · Pubmed #27756788.

ABSTRACT:

20 Clinical Trial Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. 2016

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bastholt, Lars / Mortier, Laurent / Thomas, Luc / Tahir, Saad / Hauschild, Axel / Hassel, Jessica C / Hodi, F Stephen / Taitt, Corina / de Pril, Veerle / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France · the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy · University of Zurich Hospital, Zurich, Switzerland (R.D.) · Memorial Sloan Kettering Cancer Center, New York (J.D.W.) · Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark · the Angeles Clinic and Research Institute, Los Angeles (O.H.) · Oncology Specialists, Park Ridge, IL (J.M.R.) · Cross Cancer Institute, Edmonton, AB, Canada (M.S.) · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.) · Broomfield Hospital, Chelmsford, United Kingdom (S.T.) · Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany · Dana-Farber Cancer Institute, Boston (F.S.H.) · Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.) · and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.). ·N Engl J Med · Pubmed #27717298.

ABSTRACT: BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

21 Clinical Trial Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. 2015

Grob, Jean Jacques / Amonkar, Mayur M / Karaszewska, Boguslawa / Schachter, Jacob / Dummer, Reinhard / Mackiewicz, Andrzej / Stroyakovskiy, Daniil / Drucis, Kamil / Grange, Florent / Chiarion-Sileni, Vanna / Rutkowski, Piotr / Lichinitser, Mikhail / Levchenko, Evgeny / Wolter, Pascal / Hauschild, Axel / Long, Georgina V / Nathan, Paul / Ribas, Antoni / Flaherty, Keith / Sun, Peng / Legos, Jeffrey J / McDowell, Diane Opatt / Mookerjee, Bijoyesh / Schadendorf, Dirk / Robert, Caroline. ·Service de Dermatologie, Aix Marseille University, and Assistance Publique Hôpitaux de Marseille (APHM), University Hospital Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. · GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA. · Przychodnia Lekarska Komed, Konin, Poland. · Sheba Medical Center, Ramat Gan, Ramat, Israel. · Department of Dermatology, Universität Zürich, Zurich, Switzerland. · Oncology Division, Poznan University of Medical Sciences, Med-Polonia, Poznan, Poland. · Moscow City Oncology Hospital #62, Stepanovskoye, Moscow, Russia. · Swissmed Centrum Zdrowia and Gdansk Medical University, Gdansk, Poland. · Centre Hospitalier Universitairede Reims-Hôpital Robert Debré, Reims, France. · Istituto Oncologico Veneto Istituto Di Ricovero e Cura a Carattere Scientifico, Padua, Italy. · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · N N Blokhin Russian Cancer Research Center, Moscow, Russia. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. · Universitätsklinikum Schleswig-Holstein (UKSH), Department of Dermatology, Kiel, Germany. · Melanoma Institute Australia, The University of Sydney and The Mater Hospital, Sydney, Australia. · Mount Vernon Cancer Centre, Northwood, UK. · University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany. · Gustave Roussy, Département de Médecine oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. ·Lancet Oncol · Pubmed #26433819.

ABSTRACT: BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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.

22 Clinical Trial Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 2015

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean-Jacques / Chiarion-Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Swann, Suzanne / Legos, Jeffrey J / Jin, Fan / Mookerjee, Bijoyesh / Flaherty, Keith. ·Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Moscow City Oncology Hospital, Moscow, Russia. · Department of Medicine, University of Athens, Medical School, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Royal Marsden Hospital, London, UK. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France. · University Hospital Schleswig-Holstein, Kiel, Germany. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France. · Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia. · Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain. · Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. · University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany. · Istituto Nazionale Tumori Regina Elena, Rome, Italy. · Volograd Regional Oncology Dispensary #3, Volzhsky, Russia. · Elbe Klinikum Stade, Stade, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · University Hospital Essen, Essen, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Merck & Co, Kenilworth, NJ, USA. · Massachusetts General Hospital Cancer Center, Boston MA, USA. ·Lancet · Pubmed #26037941.

ABSTRACT: 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 common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. INTERPRETATION: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. FUNDING: GlaxoSmithKline.

23 Clinical Trial Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. 2015

Larkin, James / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean Jacques / Cowey, C Lance / Lao, Christopher D / Schadendorf, Dirk / Dummer, Reinhard / Smylie, Michael / Rutkowski, Piotr / Ferrucci, Pier F / Hill, Andrew / Wagstaff, John / Carlino, Matteo S / Haanen, John B / Maio, Michele / Marquez-Rodas, Ivan / McArthur, Grant A / Ascierto, Paolo A / Long, Georgina V / Callahan, Margaret K / Postow, Michael A / Grossmann, Kenneth / Sznol, Mario / Dreno, Brigitte / Bastholt, Lars / Yang, Arvin / Rollin, Linda M / Horak, Christine / Hodi, F Stephen / Wolchok, Jedd D. ·From the Department of Medical Oncology, Royal Marsden Hospital, London (J.L.), and South West Wales Cancer Institute, Singleton Hospital, Swansea (J.W.) - both in the United Kingdom · Melanoma Oncology Unit, Veneto Region Oncology Research Institute, Padua (V.C.-S.), Oncology of Melanoma Unit, European Institute of Oncology, Milan (P.F.F.), University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · Division of Medical Oncology, University of Colorado, Denver, Denver (R.G.) · Aix-Marseille University, Hôpital de La Timone, Assitance Publique-Hôpitaux de Marseille, Marseille (J.J.G.), and Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.) - both in France · Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.) · Departments of Internal Medicine and Dermatology, University of Michigan, Ann Arbor (C.D.L.) · Department of Dermatology, University of Essen, Essen, Germany (D.S.) · University of Zürich Hospital, Zurich, Switzerland (R.D.) · Cross Cancer Institute, Edmonton, AB, Canada (M. Smylie) · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (P.R.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), and Westmead and Blacktown Hospitals (M.S.C.) and Melanoma Institute Australia (M.S.C., G.V.L.), University of Sydney, and the Mater Hospital (G.V.L.), Sydney, and Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (G.A.M.) - all in Australia · Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam (J.B.H.) · Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid (I.M.-R.) · Ludwig Center, Memorial Sloan Kettering Cancer Center (M.K.C., M.A.P., J.D.W.) and Weill Cornell Medical College (M.K.C., M.A.P., J.D.W.) - both in New York · Huntsman Cancer Institute, University of Utah, Salt Lake City (K.G.) · Yale Cancer Center, Smilow Cancer Hospital of the Yale-New Haven Hospital, Yale University Sc ·N Engl J Med · Pubmed #26027431.

ABSTRACT: BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

24 Clinical Trial Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. 2015

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Konto, Cyril / Hoos, Axel / de Pril, Veerle / Gurunath, Ravichandra Karra / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Aix-Marseille University, Hôpital de La Timone APHM, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Oncology Specialists SC, Park Ridge, IL, USA. · Assistance Publique Hôpitaux de Paris, Dermatology and CIC Departments, Hôpital Saint Louis, University Paris 7, INSERM U976, France. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, Alberta, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · EORTC Headquarters, Brussels, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #25840693.

ABSTRACT: BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.

25 Clinical Trial Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. 2015

Schadendorf, Dirk / Amonkar, Mayur M / Stroyakovskiy, Daniil / Levchenko, Evgeny / Gogas, Helen / de Braud, Filippo / Grob, Jean-Jacques / Bondarenko, Igor / Garbe, Claus / Lebbe, Celeste / Larkin, James / Chiarion-Sileni, Vanna / Millward, Michael / Arance, Ana / Mandalà, Mario / Flaherty, Keith T / Nathan, Paul / Ribas, Antoni / Robert, Caroline / Casey, Michelle / DeMarini, Douglas J / Irani, Jhangir G / Aktan, Gursel / Long, Georgina V. ·Universitätsklinikum Essen, Hufelandstr. 55, Essen 45147, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: mayur.m.amonkar@gsk.com. · Moscow City Oncology Hospital #62, Moscow 143423, Russia. Electronic address: sdaniel@mail.ru. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. Electronic address: levchenko@newmail.ru. · University of Athens, Aghiou Thoma 17, Athens 11527, Greece. Electronic address: hgogas@hol.gr. · Fondazione IRCCS Istituto Nazionale Tumori, via Giacomo Venezian, 1, Milan, Italy. Electronic address: filippo.debraud@istitutotumori.mi.it. · Service de Dermatologie, Centre Hospitalo-Universitaire Sainte-Marguerite, 270 Boulevard de Sainte-Marguerite, Marseille 13009, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Dnepropetrovsk State Medical Academy, Dzerzhyns'koho Street 9, Dnepropetrovsk 49044, Ukraine. Electronic address: oncology@dsma.dp.ua. · Department of Dermatology, University Hospital Tuebingen, Liebermeisterstraße 25, Tuebingen 72076, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. Electronic address: james.larkin@rmh.nhs.uk. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, via Gattamelata, 64, Padua 35128, Italy. Electronic address: mgaliz@tiscali.it. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA 6009, Australia. Electronic address: michael.millward@uwa.edu.au. · Hospital Clinic, Carrer Villarroel 170, Barcelona 08036, Spain. Electronic address: amarance@clinic.ub.es. · Papa Giovanni XIII Hospital, Piazza OMS 1, Bergamo 24127, Italy. Electronic address: mmandala@hpg23.it. · Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston 02114, MA, United States. Electronic address: kflaherty@partners.org. · Mount Vernon Cancer Centre, Rickmansworth Road, Northwood HA6 2RN, United Kingdom. Electronic address: p.nathan@nhs.net. · David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles 90095, CA, United States. Electronic address: aribas@mednet.ucla.edu. · Gustave Roussy and Paris 11 University, 114 Rue Edouard Vaillant, Villejuif-Paris-Sud 94805, France. Electronic address: Caroline.Robert@igr.fr. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: meshellcasey@yahoo.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: douglas.j.demarini@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: jhangir.g.irani@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: gursel.aktan@gmail.com. · Melanoma Institute Australia & The University of Sydney, 40 Rocklands Road, Sydney 2060, Australia. Electronic address: georgina.long@sydney.edu.au. ·Eur J Cancer · Pubmed #25794603.

ABSTRACT: AIM: To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. METHODS: HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. RESULTS: Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. CONCLUSION: This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

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