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Melanoma: HELP
Articles by Victoria G. Atkinson
Based on 25 articles published since 2008
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Between 2008 and 2019, V. Atkinson wrote the following 25 articles about Melanoma.
 
+ Citations + Abstracts
1 Review Recent advances in malignant melanoma. 2017

Atkinson, Victoria. ·University of Queensland, Brisbane, Queensland, Australia. · Cancer Care Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Greenslopes Private Hospital, Brisbane, Queensland, Australia. ·Intern Med J · Pubmed #28994264.

ABSTRACT: In Australia, there is a high incidence of melanoma, and until recently, the treatment and median overall survival for advanced metastatic melanoma had not changed in decades. The recognition of BRAF as an important tumour oncogene in melanoma has led to the development of targeted therapies, and in the last few years, we have seen the impact of these therapies, with significant improvement in response rate, duration of disease control and overall survival for patients with BRAF mutation-positive metastatic melanoma. Concurrently, the science of immunotherapy has evolved beyond the knowledge of the importance of the immune system in cancer, leading to the development of checkpoint inhibitors. The development of checkpoint inhibitors as a tolerable and effective therapy for metastatic melanoma, which has demonstrated improved response rates, duration of control and overall survival for patients, has implications beyond the care of patients with metastatic melanoma as these therapies are being trialled in other malignancies. This article will review the current standard of care and available therapies for metastatic malignant melanoma.

2 Review Response rate to vemurafenib in patients with B-RAF-positive melanoma brain metastases: a retrospective review. 2014

Dzienis, Marcin R / Atkinson, Victoria G. ·Division of Cancer Services, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. ·Melanoma Res · Pubmed #24709889.

ABSTRACT: The intracerebral response rate (RR) to vemurafenib in patients with B-RAF mutated melanoma brain metastasis was assessed. Patients with B-RAF-positive metastatic melanoma and asymptomatic brain metastases at initiation of vemurafenib were eligible. Records were analysed retrospectively to calculate the RR, duration of responses, time to central nervous system (CNS) progression and overall survival. Twenty-two patients with CNS metastasis received vemurafenib (male : female=13 : 9; median age 49); 12 had received no previous local therapy to the brain (group A), six had undergone previous surgery and/or radiotherapy with residual disease (group B; n=6) and four patients had received previous local therapy to the brain but with evidence of progression in the CNS before the start of vemurafenib and were included in group A (n=12+4=16). A 50% RR was observed in group A. Duration of responses was between 8 and 32 weeks. Similarly, a 50% RR was observed in group B; however, the contribution of vemurafenib to CNS control in this group was more difficult to assess. The duration of responses in group B was 4-33 weeks. All except two patients progressed in CNS before, or at the time of, systemic progression. The median time to CNS progression for the entire cohort was 23 weeks (range 12-60) in responding patients and 14 weeks (3-22) in those without a response. The median overall survival was 46 weeks for the patients with an objective response and 21 weeks among the nonresponding patients. Vemurafenib resulted in a 50% CNS RR. A prospective assessment of the medication in patients with B-RAF mutated melanoma cerebral metastases is warranted.

3 Clinical Trial Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. 2018

Eggermont, Alexander M M / Blank, Christian U / Mandala, Mario / Long, Georgina V / Atkinson, Victoria / Dalle, Stéphane / Haydon, Andrew / Lichinitser, Mikhail / Khattak, Adnan / Carlino, Matteo S / Sandhu, Shahneen / Larkin, James / Puig, Susana / Ascierto, Paolo A / Rutkowski, Piotr / Schadendorf, Dirk / Koornstra, Rutger / Hernandez-Aya, Leonel / Maio, Michele / van den Eertwegh, Alfonsus J M / Grob, Jean-Jacques / Gutzmer, Ralf / Jamal, Rahima / Lorigan, Paul / Ibrahim, Nageatte / Marreaud, Sandrine / van Akkooi, Alexander C J / Suciu, Stefan / Robert, Caroline. ·From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France · Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands · Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy · Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia · Cancer Research Center, Moscow (M.L.) · Royal Marsden Hospital, London (J.L.) · Hospital Clinic Universitari de Barcelona, Barcelona (S.P.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany · Washington University School of Medicine, St. Louis (L.H.-A.) · Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.) · Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.) · Merck, Kenilworth, NJ (N.I.) · and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu). ·N Engl J Med · Pubmed #29658430.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

4 Clinical Trial Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. 2018

Long, Georgina V / Atkinson, Victoria / Lo, Serigne / Sandhu, Shahneen / Guminski, Alexander D / Brown, Michael P / Wilmott, James S / Edwards, Jarem / Gonzalez, Maria / Scolyer, Richard A / Menzies, Alexander M / McArthur, Grant A. ·Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia. · Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia. · Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. · Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. · Royal Adelaide Hospital, Centre for Cancer Biology (SA Pathology and University of South Australia) and University of Adelaide, Adelaide, SA, Australia. · Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia. · Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; Medical, Dental and Health Sciences, University of Melbourne, Parkville, VIC, Australia. ·Lancet Oncol · Pubmed #29602646.

ABSTRACT: BACKGROUND: Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases. METHODS: This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis. FINDINGS: Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred. INTERPRETATION: Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. FUNDING: Melanoma Institute Australia and Bristol-Myers Squibb.

5 Clinical Trial Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAF 2018

Dréno, Brigitte / Ascierto, Paolo A / Atkinson, Victoria / Liszkay, Gabriella / Maio, Michele / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Bartley, Karen / Karagiannis, Thomas / Chang, Ilsung / Rooney, Isabelle / Koralek, Daniel O / Larkin, James / McArthur, Grant A / Ribas, Antoni. ·Department of Dermato Cancerology, Nantes University, Nantes 44093, France. · Istituto Nazionale Tumori Fondazione G. Pascale, Naples 80131, Italy. · Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. · National Institute of Oncology, Budapest 1122, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy. · Department of Oncology and Haematology, Papa Giovanni XXIII Hospital, Bergamo 24127, Italy. · N. N. Blokhin Russian Cancer Research Center, Moscow 115478, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk 14301, Russia. · Service de Dermatologie, Centre Hospitalier Lyon Sud, Pierre-Bénite 69495, France. · Hospital Universitario Virgen Macarena, Seville 41009, Spain. · Hôpital Saint André, Bordeaux 33075, France. · Department of Dermatology, University of Tübingen, Tübingen 72074, Germany. · Genentech, Inc., South San Francisco, CA 94080, USA. · The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia. · University of Melbourne, Parkville, VIC 3052, Australia. · Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA. ·Br J Cancer · Pubmed #29438370.

ABSTRACT: BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAF

6 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 .).

7 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 .).

8 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

9 Clinical Trial Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. 2016

Ascierto, Paolo A / McArthur, Grant A / Dréno, Brigitte / Atkinson, Victoria / Liszkay, Gabrielle / Di Giacomo, Anna Maria / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Yan, Yibing / Wongchenko, Matthew / Chang, Ilsung / Hsu, Jessie J / Koralek, Daniel O / Rooney, Isabelle / Ribas, Antoni / Larkin, James. ·Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Nantes University, Nantes, France. · Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · National Institute of Oncology, Budapest, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena, Italy. · Papa Giovanni XXIII Hospital, Bergamo, Italy. · N N Blokhin Russian Cancer Research Center, Moscow, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk, Russia. · Centre Hospitalier Lyon Sud, Lyon 1 University, Lyon, France; Lyons Cancer Research Center, Lyon, France. · Hospital Universitario Virgen Macarena, Seville, Spain. · Hôpital Saint André, Bordeaux, France. · University of Tübingen, Tübingen, Germany. · Genentech Inc, South San Francisco, CA, USA. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, CA, USA. · Royal Marsden NHS Foundation Trust, London, UK. ·Lancet Oncol · Pubmed #27480103.

ABSTRACT: BACKGROUND: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING: F Hoffmann-La Roche-Genentech.

10 Clinical Trial Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. 2016

Long, G V / Atkinson, V / Ascierto, P A / Robert, C / Hassel, J C / Rutkowski, P / Savage, K J / Taylor, F / Coon, C / Gilloteau, I / Dastani, H B / Waxman, I M / Abernethy, A P. ·Melanoma Institute Australia, The University of Sydney, and Mater Hospital, Sydney, Australia georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Greenslopes, Australia. · Istituto Nazionale Tumori Fondazione Pascale, Napoli, Italy. · Gustave-Roussy, Paris, France. · University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany. · Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · BC Cancer Agency, University of British Columbia, Vancouver, Canada. · Adelphi Values, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Duke Clinical Research Institute, Durham, NC, USA. ·Ann Oncol · Pubmed #27405322.

ABSTRACT: BACKGROUND: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.

11 Clinical Trial Nivolumab in previously untreated melanoma without BRAF mutation. 2015

Robert, Caroline / Long, Georgina V / Brady, Benjamin / Dutriaux, Caroline / Maio, Michele / Mortier, Laurent / Hassel, Jessica C / Rutkowski, Piotr / McNeil, Catriona / Kalinka-Warzocha, Ewa / Savage, Kerry J / Hernberg, Micaela M / Lebbé, Celeste / Charles, Julie / Mihalcioiu, Catalin / Chiarion-Sileni, Vanna / Mauch, Cornelia / Cognetti, Francesco / Arance, Ana / Schmidt, Henrik / Schadendorf, Dirk / Gogas, Helen / Lundgren-Eriksson, Lotta / Horak, Christine / Sharkey, Brian / Waxman, Ian M / Atkinson, Victoria / Ascierto, Paolo A. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25399552.

ABSTRACT: BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

12 Clinical Trial Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. 2014

Larkin, James / Ascierto, Paolo A / Dréno, Brigitte / Atkinson, Victoria / Liszkay, Gabriella / Maio, Michele / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Sovak, Mika A / Chang, Ilsung / Choong, Nicholas / Hack, Stephen P / McArthur, Grant A / Ribas, Antoni. ·From Royal Marsden Hospital, London (J.L.) · Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Azienda Ospedaliera Universitaria Senese, Siena (M. Maio), and Papa Giovanni XXIII Hospital, Bergamo (M. Mandalà) - all in Italy · Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.), Centre Hospitalier Lyon Sud, Pierre-Bénite (L.T.), and Hôpital Saint André, Bordeaux (C.D.) - all in France · Princess Alexandra Hospital, Woolloongabba, QLD (V.A.), and Peter MacCallum Cancer Centre, Melbourne, VIC (G.A.M.) - both in Australia · National Institute of Oncology, Budapest, Hungary (G.L.) · N.N. Blokhin Russian Cancer Research Center, Moscow (L.D.), and Moscow City Oncology Hospital 62, Krasnogorsk (D.S.) - both in Russia · Hospital Universitario Virgen Macarena, Seville, Spain (L.C.-M.) · University of Tübingen, Tübingen, Germany (C.G.) · Genentech, South San Francisco, CA (M.A.S., I.C., N.C., S.P.H.) · and Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles (A.R.). ·N Engl J Med · Pubmed #25265494.

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

13 Article The changing paradigm of management in melanoma brain metastases. 2018

Ladwa, Rahul / Atkinson, Victoria. ·Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · School of Medicine, The University of Queensland, Brisbane, Queensland, Australia. · Department of Medical Oncology, Greenslopes Private Hospital, Brisbane, Queensland, Australia. ·Asia Pac J Clin Oncol · Pubmed #29932306.

ABSTRACT: AIM: Improved systemic treatment has improved the prognosis of metastatic melanoma (MM). However, brain metastases (BMs) are a frequent complication. We aimed to explore the outcome of these patients with modern therapeutic options. METHOD: We retrospectively analyzed 142 patients diagnosed with BM from MM at two institutions in Brisbane, Queensland, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. RESULTS: With a median follow-up of 8 months, 115 patients had died, 112 from MM and 99 from neurologic death. Management included ablative therapy (n = 8), ablative therapy with targeted/immunotherapy (n = 54), targeted/immunotherapy (n = 55) and whole-brain radiotherapy/best supportive care (n = 25). The median overall survival (OS) was 8 (6.9-9.1) months. Statistically improved OS was found with the use of ablative techniques and BRAF/MEK tyrosine kinase inhibitor (TKI) post diagnosis of BM. In BRAF mutant patients (n = 117) who were TKI naïve at diagnosis of BM (n = 60), the median OS was 9 (6.2-11.8) months versus 5 (1.1-8.9) months in patients who developed BM on TKI treatment (P = 0.001). A complete intracranial response rate occurred in 12% of patients who had immunotherapy (n = 65) with all but two patients receiving stereotactic radiosurgery and no deaths have occurred in this group. CONCLUSIONS: The outcomes of those with BM remain poor, particularly of those with BRAF mutant MM who fail TKI therapy with new BM. Most patients present with multiple BM and death is frequently due to neurological progressive disease. The use of ablative techniques and TKI use confers a longer OS in selected patients.

14 Article Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. 2017

Sznol, Mario / Ferrucci, Pier Francesco / Hogg, David / Atkins, Michael B / Wolter, Pascal / Guidoboni, Massimo / Lebbé, Celeste / Kirkwood, John M / Schachter, Jacob / Daniels, Gregory A / Hassel, Jessica / Cebon, Jonathan / Gerritsen, Winald / Atkinson, Victoria / Thomas, Luc / McCaffrey, John / Power, Derek / Walker, Dana / Bhore, Rafia / Jiang, Joel / Hodi, F Stephen / Wolchok, Jedd D. ·Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Pier Francesco Ferrucci, Istituto Europeo di Oncologia, Milan · Massimo Guidoboni, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy · David Hogg, Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Celeste Lebbé, Université Paris Diderot, Paris · Luc Thomas, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France · John M. Kirkwood, Hillman Cancer Center, Pittsburgh, PA · Jacob Schachter, Sheba Medical Center, Ramat Gan, Israel · Gregory A. Daniels, University of California San Diego, Moores Cancer Center, La Jolla, CA · Jessica Hassel, University Hospital, Heidelberg, Germany · Jonathan Cebon, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria · Winald Gerritsen, University of Queensland, St Lucia · Victoria Atkinson, Gallipoli Medical Research Foundation, Greenslopes · Victoria Atkinson, Princess Alexandra Hospital, Brisbane, Queensland, Australia · Winald Gerritsen, Radboud University Medical Center, Nijmegen, the Netherlands · John McCaffrey, Irish Clinical Oncology Research Group, Dublin · Derek Power, Irish Clinical Oncology Research Group, Cork, Ireland · Dana Walker, Rafia Bhore, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · and Jedd D. Wolchok, Parker Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #28915085.

ABSTRACT: Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

15 Article Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. 2017

Long, Georgina V / Weber, Jeffrey S / Larkin, James / Atkinson, Victoria / Grob, Jean-Jacques / Schadendorf, Dirk / Dummer, Reinhard / Robert, Caroline / Márquez-Rodas, Ivan / McNeil, Catriona / Schmidt, Henrik / Briscoe, Karen / Baurain, Jean-François / Hodi, F Stephen / Wolchok, Jedd D. ·Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia. · Mater Hospital, North Sydney, New South Wales, Australia. · Department of Medical Oncology, Moffitt Cancer Center, Tampa, Florida. · now with Department of Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York. · Department of Oncology, Royal Marsden Hospital, London, United Kingdom. · Gallipoli Medical Research Foundation and Princess Alexandra Hospital, and University of Queensland, Queensland, Australia. · Department of Dermatology and Skin Cancer, Hospital Timone APHM, Aix-Marseille University, Marseille, France. · Department of Skin, University Hospital Essen, Essen, Germany. · Department of Urology, University Hospital Essen, Essen, Germany. · Department of Dermatology, UniversitaetsSpital, Zurich, Switzerland. · Department of Medicine Institute Gustave Roussy, Gustave Roussy and Paris-Sud University, Villejuif Paris-Sud, France. · Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Chris O'Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales, Australia. · Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. · Department of Medical Oncology, Coffs Harbour Health Campus, New South Wales, Australia. · Melanoma Clinic at King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium. · Melanoma Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York. ·JAMA Oncol · Pubmed #28662232.

ABSTRACT: Importance: Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression. Objective: To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression. Design, Setting, and Participants: Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017. Interventions: Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion. Main Outcomes and Measures: Tumor response and safety in TBP and non-TBP patients. Results: Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively). Conclusions and Relevance: A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression. Trial Registration: clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067).

16 Article The cessation of anti-PD-1 antibodies of complete responders in metastatic melanoma. 2017

Ladwa, Rahul / Atkinson, Victoria. ·aDepartment of Medical Oncology, Princess Alexandra Hospital bDepartment of Medical Oncology, Greenslopes Private Hospital cSchool of Medicine, University of Queensland, Brisbane, Queensland, Australia. ·Melanoma Res · Pubmed #28099369.

ABSTRACT: The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In previous trials, there has been the potential to cease therapy if the patient achieves a complete response (CR). We aimed to assess the outcomes of patients who had ceased anti-PD-1 antibodies in this setting. A retrospective review was carried out of CR to PD-1-based therapy across two institutions. Patients were from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy (NIVO), and reimbursed Pembrolizumab (r PEM). Patients had to have experienced a CR to PD-1-based therapy and ceased therapy because of this. Disease recurrence was the primary outcome measured. Twenty-nine patients (PEM NPP, N=20; Nivo, N=3; r PEM, N=6) ceased anti-PD-1 therapy after CR for observation. The median age was 64 (27-83) years. All patients had treatment discontinued for observation. The median time to CR was 10.5 months in the PEM NPP, 7.5 months on r PEM groups, and 17 months in the NIVO group. The median time off therapy in PEM NPP was 10 months, NIVO was 9 months, and r PEM was 4.5 months. To date, three patients have shown a relapse at a median follow-up off treatment of 8 months. This is the first report of patients who have intentionally ceased PD-1-based therapy because of CR. With a follow-up of 8 months off treatment, the risk of relapse was low. Data such as these are clinically relevant as we need to be able to discuss cessation of therapy and relevant from a pharmacoeconomic perspective, given the cost of PD-1 antibodies to society.

17 Article Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. 2017

Menzies, A M / Johnson, D B / Ramanujam, S / Atkinson, V G / Wong, A N M / Park, J J / McQuade, J L / Shoushtari, A N / Tsai, K K / Eroglu, Z / Klein, O / Hassel, J C / Sosman, J A / Guminski, A / Sullivan, R J / Ribas, A / Carlino, M S / Davies, M A / Sandhu, S K / Long, G V. ·Melanoma Institute Australia and The University of Sydney, Sydney, Australia. · Royal North Shore and Mater Hospitals, Sydney, Australia. · Vanderbilt University Medical Center, Nashville, USA. · Princess Alexandra Hospital, Greenslopes Hospital and University of Queensland, Brisbane, Australia. · Peter MacCallum Cancer Centre, Melbourne, Australia. · Crown Princess Mary Cancer Centre Westmead, Sydney, Australia. · The University of Texas MD Anderson Cancer Center, Houston, USA. · Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Medical Oncology, University of California San Francisco, San Francisco, USA. · Department of Medical Oncology, Moffitt Cancer Centre, Tampa, USA. · Department of Medical Oncology, Olivia Newton-John Cancer Centre & Cancer Research Institute, Austin Health, Melbourne, Australia. · Department of Dermatology, Heidelberg University, Heidelberg, Germany. · Massachusetts General Hospital Cancer Center, Boston, USA. · Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, USA. ·Ann Oncol · Pubmed #27687304.

ABSTRACT: Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

18 Article Radiotherapy utilization in BRAF mutation-tested metastatic melanoma in the targeted therapy era. 2017

Gorayski, Peter / Dzienis, Marcin / Foote, Matthew / Atkinson, Victoria / Burmeister, Elizabeth / Burmeister, Bryan. ·Department of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. · Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. · Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. · Nursing Practice Development Unit, Princess Alexandra Hospital & Centre for Health Practice Innovation, Griffith University, Brisbane, Queensland, Australia. ·Asia Pac J Clin Oncol · Pubmed #25865802.

ABSTRACT: AIM: Tumor BRAF mutation testing is routine for all patients with metastatic melanoma (MM) owing to the availability of agents targeting this intracellular pathway. To test whether there is a difference in radiotherapy (RT) utilization according to BRAF mutation status, we performed a retrospective review of RT utilization in a contemporary cohort undergoing BRAF mutation testing. METHODS: Clinical records of MM patients undergoing BRAF mutation testing between April 2010 and August 2012 were reviewed. Overall survival (OS) was calculated using Kaplan-Meier methods. Differences between BRAF status were calculated using chi-square tests for categorical variables, median tests for continuous variables and Cox proportional hazards models to compare OS. RESULTS: Up to 158 patients were identified but 17 were excluded due to inadequate clinical data. Of the remaining 141 patients, 69 (49%) tested BRAF mutant (BRAF-m), median age 47 years (range 21-79) with median follow-up of 16.8 months (IQR11.3-25.2). Seventy-two (51%) tested BRAF wild type (BRAF-w), median age 62 years (range 25-84) with median follow-up of 27.1 months (IQR12.5-57.4). Overall, RT utilization was similar: 68% in BRAF-m and 69% in BRAF-w. Mean number of treatment courses was 1.70 for BRAF-m and 2.36 for BRAF-w (Pearson chi-square 3.92, P = 0.05). Up to 51% of BRAF-m and 56% of BRAF-w required ≧2 RT courses. Forty-six percent BRAF-m compared with 29% BRAF-w received brain RT (P = 0.04). Median OS was 17.7 months (IQR7.6-35.5) in BRAF-m and 19 months (IQR7.8-35.1) in BRAF-w (P = 0.99). CONCLUSION: High RT utilization rates were observed irrespective of BRAF mutation status. Significantly more BRAF-w patients received RT but more BRAF-m patients received brain RT.

19 Article Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists. 2016

Atkinson, Victoria / Long, Georgina V / Menzies, Alexander M / McArthur, Grant / Carlino, Matteo S / Millward, Michael / Roberts-Thomson, Rachel / Brady, Benjamin / Kefford, Richard / Haydon, Andrew / Cebon, Jonathan. ·Princess Alexandra Hospital, Greenslopes Private Hospital and University of Queensland, Brisbane, Queensland, Australia. · Melanoma Institute Australia, Royal North Shore and Mater Hospitals, The University of Sydney, Sydney, New South Wales, Australia. · Peter MacCallum Cancer Centre and Cabrini Health, Melbourne, Victoria, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · School of Medicine and Pharmacology, University of Western Australia and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. · Queen Elizabeth Hospital, Adelaide, South Australia, Australia. · Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia. · The Alfred Hospital, Melbourne, Victoria, Australia. · Olivia Newton John Cancer Wellness & Research Centre, Austin Health Melbourne, Victoria, Australia. ·Asia Pac J Clin Oncol · Pubmed #27905182.

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

20 Article A case of acute paraneoplastic neurological syndrome in BRAF mutant metastatic melanoma. 2016

Lee, Shu F / Atkinson, Victoria. ·aDepartment of Medical Oncology, Princess Alexandra Hospital bDepartment of Medical Oncology, Greenslopes Private Hospital, Brisbane, Queensland, Australia. ·Melanoma Res · Pubmed #27138260.

ABSTRACT: A 58-year-old man with indolent metastatic BRAF mutant melanoma presented with several days' history of progressive ataxia and dysdiadochokinesia. His PET/computed tomography restaging scan indicated two new fluorine-18-fluorodeoxyglucose-avid mesenteric lymph nodes. Meanwhile, his MRI brain and whole spine were within normal limits. A lumbar puncture indicated an elevated protein level with a normal cell count and negative paraneoplastic antibodies. Because of the lack of an alternative differential, the diagnosis of paraneoplastic syndrome was made. He was started on high-dose corticosteroids as well as dabrafenib and trametinib. Despite this, his neurological symptoms continued to progress. Consequently, he was trialed on a course of intravenous immunoglobulin, which stabilized his symptoms. He continued to improve over several weeks, with near-complete resolution of all his neurological symptoms, and showed a complete radiological response of his disease. To our knowledge, this is the first reported case of paraneoplastic neurological syndrome with mixed neurology associated with BRAF mutant cutaneous melanoma that responded to BRAF targeted therapy.

21 Article Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. 2016

Bowyer, S / Prithviraj, P / Lorigan, P / Larkin, J / McArthur, G / Atkinson, V / Millward, M / Khou, M / Diem, S / Ramanujam, S / Kong, B / Liniker, E / Guminski, A / Parente, P / Andrews, M C / Parakh, S / Cebon, J / Long, G V / Carlino, M S / Klein, O. ·Rockingham General Hospital, Cooloongup, Western Australia, Australia. · School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia. · Olivia Newton- John Cancer Centre, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia. · Olivia Newton-John Cancer Research Institute, Heidelberg, Melbourne, Victoria, Australia. · The Christie NHS Foundation Trust and University of Manchester, Manchester, UK. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. · Princess Alexandra Hospital, Greenslopes Private Hospital, Brisbane, Queensland, Australia. · Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Box Hill Hospital, Box Hill, Victoria, Australia. · University of Sydney, Sydney, New South Wales, Australia. ·Br J Cancer · Pubmed #27124339.

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

22 Article BRAFV600E mutation status of involuting and stable nevi in dabrafenib therapy with or without trametinib. 2014

McClenahan, Phil / Lin, Lynlee L / Tan, Jean-Marie / Flewell-Smith, Ross / Schaider, Helmut / Jagirdar, Kasturee / Atkinson, Victoria / Lambie, Duncan / Prow, Tarl W / Sturm, Richard A / Soyer, H Peter. ·Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia. · Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia2The University of Queensland, Institute for Molecular Biosciences, Brisbane, Queensland, Australia. · Medical Oncology, Princess Alexandra Hospital, Wooloongabba, Queensland, Australia. · The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia5IQ Pathology, Brisbane, Queensland, Australia. ·JAMA Dermatol · Pubmed #24695877.

ABSTRACT: IMPORTANCE: Recent advances in targeting BRAFV600E mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes. OBSERVATIONS: A man in his 30s had been monitored with whole-body dermoscopy at roughly 7-month intervals as part of a nevus surveillance study. Fourteen months after his initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with or without trametinib therapy. Continued dermoscopic monitoring for the next 12 months revealed that approximately 50% of the existing acquired melanocytic nevi involuted, while the remaining nevi did not change. Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAFV600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one. CONCLUSIONS AND RELEVANCE: Our observations indicate that a previously suggested hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E mutation, while others that grow or remain unchanged are wild type. However larger-scale trials are required to gather conclusive data and create a more complete clinical picture.

23 Minor Omitting radiosurgery in melanoma brain metastases: a drastic and dangerous de-escalation - Authors' reply. 2018

Long, Georgina V / Atkinson, Victoria / Hong, Angela / McArthur, Grant A / Menzies, Alexander M. ·Disciplines of Medical Oncology, Melanoma Institute Australia, University of Sydney, Sydney, NSW 2065, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia. · Radiation Oncology, Melanoma Institute Australia, University of Sydney, Sydney, NSW 2065, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. · Peter MacCallum Cancer Centre and Medical, Dental and Health Sciences, University of Melbourne, Parkville, VIC, Australia. · Disciplines of Medical Oncology, Melanoma Institute Australia, University of Sydney, Sydney, NSW 2065, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #30102217.

ABSTRACT: -- No abstract --

24 Minor Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''. 2017

Bowyer, Samantha / Prithviraj, Prashanth / Lorigan, Paul / Larkin, James / McArthur, Grant / Atkinson, Victoria / Millward, Michael / Khou, Muoi / Diem, Stefan / Ramanujam, Sangeetha / Kong, Ben / Liniker, Elizabeth / Guminski, Alexander / Parente, Phillip / Andrews, Miles C / Parakh, Sagun / Cebon, Jonathan / Long, Georgina V / Carlino, Matteo S / Klein, Oliver. ·Rockingham General Hospital, Perth, Western Australia, Australia. · School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia. · Department of Medical Oncology, Olivia Newton-John Cancer Centre, Austin Hospital, Melbourne, Victoria, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. · The Christie NHS Foundation Trust and University of Manchester, Manchester, UK. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. · Princess Alexandra Hospital, Greenslopes Private Hospital, Brisbane, Queensland, Australia. · Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Box Hill Hospital, Melbourne, Victoria, Australia. · University of Sydney, Sydney, New South Wales, Australia. ·Br J Cancer · Pubmed #28324885.

ABSTRACT: -- No abstract --

25 Minor Sentinel node biopsy for melanoma: The medical oncology perspective. 2015

Menzies, Alexander M / Atkinson, Victoria G / Brown, Michael P / Carlino, Matteo S / Cebon, Jonathan / Guminski, Alexander / Kefford, Richard F / Long, Georgina V / McArthur, Grant / McNeil, Catriona M / Millward, Michael / Sandhu, Shahneen. · ·Aust Fam Physician · Pubmed #27505912.

ABSTRACT: -- No abstract --