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Melanoma: HELP
Articles by Victoria G. Atkinson
Based on 37 articles published since 2010
(Why 37 articles?)
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Between 2010 and 2020, V. Atkinson wrote the following 37 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Pregnancy with successful foetal and maternal outcome in a melanoma patient treated with nivolumab in the first trimester: case report and review of the literature. 2019

Xu, Wen / Moor, Rebecca J / Walpole, Euan T / Atkinson, Victoria G. ·Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba. · The University of Queensland, Brisbane. · Greenslopes Private Hospital, Cyril Gilbert Cancer Centre, Greenslopes, Queensland, Australia. ·Melanoma Res · Pubmed #30730328.

ABSTRACT: Although T-cell checkpoint blockade has revolutionized melanoma therapy, metastatic melanoma in pregnancy remains a challenging area of unmet need. Treatment with anti-PD1 therapy decreases foetal-maternal tolerance and increases the risk of pregnancy loss in animal studies and is considered category D by the Food and Drug Administration. We describe a unique case of conception and pregnancy, with successful maternal and foetal outcomes, in a patient with metastatic melanoma who had received combination anti-CTLA-4 and anti-PD1 therapy. A 32-year-old G0P0 lady, with a 10-year history of infertility of unclear cause, was found to be 7 weeks pregnant after 14 months of nivolumab maintenance therapy, having previously received combination ipilimumab and nivolumab. Nivolumab was ceased upon discovery of pregnancy in the first trimester. The patient had an uneventful pregnancy, followed by spontaneously premature labour, and delivered by caesarean section at 33 weeks' gestation. The foetus had moderate intrauterine growth restriction, as well as congenital hypothyroidism, which possibly constitutes the first documented case of foetal immune-related adverse event from maternal anti-PD1 exposure. No adverse events were noted in the mother. At 6 months of follow-up postpartum, the mother had a sustained complete response to treatment, and the baby had appropriate weight gain with normal developmental milestones. We summarize and discuss the available literature of immune checkpoint inhibitor exposure in pregnancy, which consists of a total of three case reports.

2 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.

3 Review Medical management of malignant melanoma. 2015

Atkinson, Victoria. ·Greenslopes Private Hospital, Brisbane. ·Aust Prescr · Pubmed #26648623.

ABSTRACT: The treatment and outcomes for people with metastatic melanoma have changed considerably in the past few years with the introduction of targeted anticancer drugs. About half of the patients with metastatic melanoma will have activating mutations in the BRAF gene. These people may benefit from a BRAF inhibitor (vemurafenib or dabrafenib) or a MEK inhibitor (trametinib). Addition of a MEK inhibitor to a BRAF inhibitor improves progression-free survival and alters the adverse effect profile. Ipilimumab is another drug indicated for metastatic melanoma. It works by altering the patient's own immune response to the tumour. Toxicities are common with these drugs and include arthralgias, fatigue, photosensitivity, squamous cell carcinomas, fever, diarrhoea, pruritus and immune-related adverse effects.

4 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.

5 Clinical Trial Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. 2019

Ribas, Antoni / Lawrence, Donald / Atkinson, Victoria / Agarwal, Sachin / Miller, Wilson H / Carlino, Matteo S / Fisher, Rosalie / Long, Georgina V / Hodi, F Stephen / Tsoi, Jennifer / Grasso, Catherine S / Mookerjee, Bijoyesh / Zhao, Qing / Ghori, Razi / Moreno, Blanca Homet / Ibrahim, Nageatte / Hamid, Omid. ·University of California, Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu. · Massachusetts General Hospital, Boston, MA, USA. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia. · Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA. · Segal Cancer Centre, Montreal, Quebec, Canada. · Jewish General Hospital, Montreal, Quebec, Canada. · McGill University, Montreal, Quebec, Canada. · Westmead Hospital, Sydney, New South Wales, Australia. · Blacktown Hospital, Sydney, New South Wales, Australia. · The University of Sydney, Sydney, New South Wales, Australia. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Auckland District Health Board, Auckland, New Zealand. · Royal North Shore Hospital, Sydney, New South Wales, Australia. · Mater Hospital, Sydney, New South Wales, Australia. · Dana-Farber Cancer Institute, Boston, MA, USA. · University of California, Los Angeles, Los Angeles, CA, USA. · Novartis, East Hanover, NJ, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. ·Nat Med · Pubmed #31171879.

ABSTRACT: Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAF

6 Clinical Trial Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. 2019

Ascierto, Paolo Antonio / Ferrucci, Pier Francesco / Fisher, Rosalie / Del Vecchio, Michele / Atkinson, Victoria / Schmidt, Henrik / Schachter, Jacob / Queirolo, Paola / Long, Georgina V / Di Giacomo, Anna Maria / Svane, Inge Marie / Lotem, Michal / Bar-Sela, Gil / Couture, Felix / Mookerjee, Bijoyesh / Ghori, Razi / Ibrahim, Nageatte / Moreno, Blanca Homet / Ribas, Antoni. ·Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy. paolo.ascierto@gmail.com. · European Institute of Oncology IRCCS, Milan, Italy. pier.ferrucci@ieo.it. · Auckland City Hospital, Auckland, New Zealand. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Brisbane, Queensland, Australia. · Aarhus University Hospital, Aarhus, Denmark. · Ella Lemelbaum Institute for Melanoma, Sheba Medical Center at Tel HaShomer, Cancer Center (Oncology Institute), Ramat Gan, Israel. · IRCCS San Martino-IST, Genova, Italy. · Melanoma Institute Australia and the University of Sydney, Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia. · Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. · Herlev Hospital, University of Copenhagen, Herlev, Denmark. · Sharett Institute of Oncology, Hadassah Hebrew Medical Center, Jerusalem, Israel. · Rambam Health Care Campus, Haifa, Israel. · Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec, Québec, Canada. · Novartis, East Hanover, NJ, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · University of California Los Angeles and the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. aribas@mednet.ucla.edu. ·Nat Med · Pubmed #31171878.

ABSTRACT: Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK

7 Clinical Trial Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. 2019

Ascierto, Paolo A / Long, Georgina V / Robert, Caroline / Brady, Benjamin / Dutriaux, Caroline / Di Giacomo, Anna Maria / 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 / Ny, Lars / Arance, Ana / Svane, Inge Marie / Schadendorf, Dirk / Gogas, Helen / Saci, Abdel / Jiang, Joel / Rizzo, Jasmine / Atkinson, Victoria. ·Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Department of Medicine, Institute Gustave Roussy, Villejuif, France. · Medical Oncology and Haematology, Cabrini Health, Melbourne, Victoria, Australia. · Dermatology Service, University Hospital of Bordeaux, Bordeaux, France. · UOC Oncological Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Institut National de la Santé et de la Recherche Médicale (INSERM) U1189, Centre Hospitalier Régional Universitaire de Lille, Lille, France. · Department of Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Chris O'Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales. · Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Polish Mother's Memorial Hospital Research Institute, Lodz, Poland. · Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. · Assistance Publique-Hôpitaux de Paris Dermatology and Centre d'Investigation Clinique, University Paris Diderot INSERM U976, Saint Louis Hospital, Paris, France. · Institute for Advanced Biosciences, Université Grenoble Alpes/INSERM U1209/CNRS UMR 5309 Joint Research Center, Grenoble, France. · Dermatology Department, Grenoble Alpes University Hospital, Grenoble, France. · Department of Oncology, McGill University, Montreal, Quebec, Canada. · Melanoma Cancer Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy. · Department of Dermatology, University Hospital Cologne, Cologne, Germany. · Division of Oncology, Regina Elena Institute, Rome, Italy. · Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. · Center for Cancer Immune Therapy, Herlev Hospital, Herlev, Denmark. · Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. · Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey. · Oncology Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey. · Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, Australia. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia. ·JAMA Oncol · Pubmed #30422243.

ABSTRACT: Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Conclusions and Relevance: Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT01721772.

8 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 .).

9 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.

10 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

11 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 / Anonymous5750918. ·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 .).

12 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 .).

13 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.

14 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.

15 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.

16 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.).

17 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.).

18 Article Combined ipilimumab and nivolumab first-line and after BRAF-targeted therapy in advanced melanoma. 2019

Mason, Robert / Dearden, Helen C / Nguyen, Bella / Soon, Jennifer A / Smith, Jessica Louise / Randhawa, Manreet / Mant, Andrew / Warburton, Lydai / Lo, Serigne / Meniawy, Tarek / Guminski, Alexander / Parente, Phillip / Ali, Sayed / Haydon, Andrew / Long, Georgina V / Carlino, Matteo S / Millward, Michael / Atkinson, Victoria G / Menzies, Alexander M. ·Princess Alexandra Hospital, Brisbane, Qld, Australia. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Sir Charles Gairdner Hospital, Nedlands, WA, Australia. · Alfred Hospital, Monash University, Melbourne, Vic., Australia. · Westmead Hospital, University of Sydney, Sydney, NSW, Australia. · The Canberra Hospital, Canberra, ACT, Australia. · Eastern Health, Box Hill, Vic., Australia. · Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. · St John of God Hospital, Subiaco, WA, Australia. · University of Western Australia, Nedlands, WA, Australia. · Royal North Shore Hospital and Mater Hospitals, Sydney, NSW, Australia. · Monash University, Melbourne, Vic., Australia. · Greenslopes Private Hospital, Brisbane, Qld, Australia. · University of Queensland, Brisbane, Qld, Australia. ·Pigment Cell Melanoma Res · Pubmed #31587511.

ABSTRACT: The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine-protein kinase B-Raf (BRAF)-targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment-naïve and 22% failed first-line BRAF/MEK inhibitors. Treatment-related adverse events occurred in 67% of patients, grade 3-5 in 38%. The overall objective response rate was 41%, 57% in treatment-naïve and 21% in BRAF/MEK failure patients. Median progression-free survival was 4.0 months (95% CI, 3.0-6.0) in the whole cohort, 11.0 months (95% CI, 6.0-NR) in treatment-naïve and 2.0 months (95% CI, 1.4-4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real-world population. While first-line efficacy appears comparable to trial populations, BRAF-mutant patients failing prior BRAF/MEK inhibitors show less response.

19 Article Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma. 2019

Eggermont, Alexander M M / Blank, Christian U / Mandala, Mario / Long, Georgina V / Atkinson, Victoria G / 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 / Di Giacomo, Anna Maria / van den Eertwegh, Alfonsus Jm / Grob, Jean-Jacques / Gutzmer, Ralf / Jamal, Rahima / Lorigan, Paul C / Lupinacci, Robert / Krepler, Clemens / Ibrahim, Nageatte / Kicinski, Michal / Marreaud, Sandrine / van Akkooi, Alexander C / Suciu, Stefan / Robert, Caroline. ·Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands. · Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. · Melanoma Institute Australia, The University of Sydney, and Mater and Royal North Shore Hospitals, Sydney, NSW, Australia. · Princess Alexandra Hospital, Brisbane, QLD, Australia. · Hospices Civils de Lyon Cancer Institute, Lyon, France. · Alfred Hospital, Melbourne, VIC, Australia. · Russian Oncology Scientific Centre, Moscow, Russia. · Fiona Stanley Hospital/University of Western Australia, Perth, WA, Australia. · Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia. · Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. · Royal Marsden Hospital, London, United Kingdom. · Hospital Clinic Universitari de Barcelona, Barcelona, Spain. · Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy. · Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. · Universitaetsklinikum - University Essen, Essen, Germany. · Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands. · Washington University School of Medicine, St. Louis, MO, USA. · Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. · Amsterdam University Medical Center, Location VUMC, Amsterdam, the Netherlands. · Aix Marseille University, Hôpital de la Timone, Marseille, France. · Skin Cancer Center, Hannover Medical School, Hannover, Germany. · Centre Hospitalier de l'Université de Montréal (CHUM), Centre de recherche du CHUM, Montreal, QC, Canada. · Christie NHS Foundation Trust, Manchester, United Kingdom. · Merck & Co., Inc., Kenilworth, NJ, United States. · EORTC Headquarters, Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. ·Eur J Cancer · Pubmed #31200321.

ABSTRACT: BACKGROUND: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy. PATIENTS, METHODS AND RESULTS: Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00]). CONCLUSIONS: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients.

20 Article Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. 2019

Jansen, Y J L / Rozeman, E A / Mason, R / Goldinger, S M / Geukes Foppen, M H / Hoejberg, L / Schmidt, H / van Thienen, J V / Haanen, J B A G / Tiainen, L / Svane, I M / Mäkelä, S / Seremet, T / Arance, A / Dummer, R / Bastholt, L / Nyakas, M / Straume, O / Menzies, A M / Long, G V / Atkinson, V / Blank, C U / Neyns, B. ·Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussel, Belgium. · Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Medical Oncology, Princess Alexandra Hospital, Brisbane. · Greenslope Oncology, Greenslope Private Hospital, Brisbrane. · Melanoma Institute Australia and The University of Syndey, Sydney, Australia. · Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. · Department of Oncology, Odense University Hospital, Odense. · Department of Oncology, Aarhus Universitet, Aarhus, Denmark. · Department of Oncology, Tampere University Hospital, Tampere, Finland. · Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. · Department of Oncology, University of Helsinki, Helsinki, Finland. · Department of Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. · Department of Clinical Cancer Research, Oslo University Hospital, Oslo. · Department of Oncology, Universitetet Bergen, Bergen, Norway. · Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney. · Department of Medical Oncology, Mater Hospital, Sydney, Australia. ·Ann Oncol · Pubmed #30923820.

ABSTRACT: BACKGROUND: Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. PATIENTS AND METHODS: This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N = 167) or nivolumab (N = 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. RESULTS: Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. CONCLUSIONS: In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. CLINICAL TRIAL REGISTRATION: NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3).

21 Article Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies. 2019

Pires da Silva, Ines / Glitza, Isabella C / Haydu, Lauren E / Johnpulle, Romany / Banks, Patricia D / Grass, George D / Goldinger, Simone M A / Smith, Jessica L / Everett, Ashlyn S / Koelblinger, Peter / Roberts-Thomson, Rachel / Millward, Michael / Atkinson, Victoria G / Guminski, Alexander / Kapoor, Rony / Conry, Robert M / Carlino, Matteo S / Wang, Wei / Shackleton, Mark J / Eroglu, Zeynep / Lo, Serigne / Hong, Angela M / Long, Georgina V / Johnson, Douglas B / Menzies, Alexander M. ·Melanoma Institute Australia and The University of Sydney, Sydney, New South Wales, Australia. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Vanderbilt University Medical Center, Nashville, Tennessee. · Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. · University Hospital Zurich, Zurich, Switzerland. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. · University of Alabama at Birmingham, Birmingham, Alabama. · Paracelsus Medical University, Salzburg, Austria. · The Queen Elizabeth Hospital, Woodville South, South Australia, Australia. · School of Medicine, University of Western Australia, Perth, Western Australia, Australia. · Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. · Princess Alexandra Hospital and Greenslopes Private Hospital, University of Queensland, Brisbane, Queensland, Australia. · Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. · Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia. · Department of Oncology, Alfred Health, Melbourne, Victoria, Australia. ·Pigment Cell Melanoma Res · Pubmed #30767428.

ABSTRACT: BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination. METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148). RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

22 Article Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection. 2018

Tio, Martin / Rai, Rajat / Ezeoke, Ogochukwu M / McQuade, Jennifer L / Zimmer, Lisa / Khoo, Chloe / Park, John J / Spain, Lavinia / Turajlic, Samra / Ardolino, Luke / Yip, Desmond / Goldinger, Simone M / Cohen, Justine V / Millward, Michael / Atkinson, Victoria / Kane, Alisa Y / Ascierto, Paolo A / Garbe, Claus / Gutzmer, Ralf / Johnson, Douglas B / Rizvi, Hira A / Joshua, Anthony M / Hellmann, Matthew D / Long, Georgina V / Menzies, Alexander M. ·Melanoma Institute Australia, Sydney, Australia. Electronic address: mtio0565@uni.sydney.edu.au. · Melanoma Institute Australia, Sydney, Australia. · Memorial Sloan Kettering Cancer Center, New York, USA. · MD Anderson Cancer Center, Houston, USA. · University of Duisburg-Essen Hospital, Heidelberg, Germany. · Peter MacCallum Cancer Centre, Melbourne, Australia. · Crown Princess Mary Cancer Centre, Sydney, Australia; Westmead Hospital, Sydney, Australia. · Skin and Renal Unit, The Royal Marsden NHS Foundation Trust, London, UK. · Skin and Renal Unit, The Royal Marsden NHS Foundation Trust, London, UK; Francis Crick Institute, London, UK. · St Vincents Hospital, Sydney, Australia. · The Canberra Hospital, Canberra, Australia; ANU Medical School, Australian National University, Canberra, Australia. · University Hospital Zurich, Zurich, Switzerland. · Massachusetts General Hospital, Boston, USA. · Sir Charles Gairdner Hospital, Perth, Australia. · Princess Alexandra Hospital, Brisbane, Australia. · Liverpool Hospital, Sydney, Australia; Garvan Institute, Sydney, Australia. · Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. · University of Tubingen, Tubingen, Germany. · Hannover Medical School, Hannover, Germany. · Vanderbilt Ingram Cancer Center, Nashville, USA. · Melanoma Institute Australia, Sydney, Australia; St Vincents Hospital, Sydney, Australia; University of New South Wales, Sydney, Australia. · Melanoma Institute Australia, Sydney, Australia; The University of Sydney, Sydney, Australia; Royal North Shore Hospital, Sydney, Australia. ·Eur J Cancer · Pubmed #30347289.

ABSTRACT: BACKGROUND: Anti-programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immunotherapy is now routinely used to treat several cancers. Clinical trials have excluded several populations, including patients with solid organ transplant, HIV infection and hepatitis B/C infection. We examined the safety outcomes of these populations treated with anti-PD-1/PD-L1 treatment in a multicentre retrospective study. METHODS: Patients from 16 centres with advanced cancer and solid organ transplant, HIV infection or hepatitis B/C infection were included. Demographic, tumour, treatment, toxicity and outcome data were recorded. RESULTS: Forty-six patients were included for analysis, with a median age of 60 years, and the majority of patients diagnosed with melanoma (72%). Among six patients with solid organ transplants, two graft rejections occurred, with one resulting in death, whereas two patients achieved partial responses. There were four responses in 12 patients with HIV infection. In 14 patients with hepatitis B, there were three responses, and similarly, there were three responses in 14 patients with hepatitis C. There was no unexpected toxicity in any viral infection group or an increase in viral load. CONCLUSION: Patients with HIV or hepatitis B/C infections treated with anti-PD-1/PD-L1 immunotherapy may respond to treatment without increased toxicity. Given the risk of graft rejection in solid organ transplant patients and also the potential for response, the role of anti-PD-1/PD-L1 immunotherapy needs to be carefully considered.

23 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.

24 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.

25 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).

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