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Melanoma: HELP
Articles by Naoya Yamazaki
Based on 45 articles published since 2008
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Between 2008 and 2019, N. Yamazaki wrote the following 45 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Clinical Trial Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. 2019

Yamazaki, Naoya / Kiyohara, Yoshio / Uhara, Hisashi / Uehara, Jiro / Fujisawa, Yasuhiro / Takenouchi, Tatsuya / Otsuka, Masaki / Uchi, Hiroshi / Ihn, Hironobu / Hatsumichi, Masahiro / Minami, Hironobu. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan. · Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan. · Department of Dermatology, University of Tsukuba Hospital, Ibaraki, Japan. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Ono Pharmaceutical Co., Ltd., Osaka, Japan. · Department of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Hyogo, Japan. ·Cancer Sci · Pubmed #30959557.

ABSTRACT: The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long-term follow up of a single-arm, open-label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post-hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment-related adverse events (TRAE), including select immune-related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3-year OS rate was 43.5%, and the 3-year PFS rate was 17.2%. A long-term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long-term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.

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

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague and Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux Cédex, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif Cedex, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #30219628.

ABSTRACT: BACKGROUND: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF METHODS: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment. INTERPRETATION: The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF FUNDING: Array BioPharma, Novartis.

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

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

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

4 Clinical Trial Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. 2018

Yamazaki, Naoya / Tsutsumida, Arata / Takahashi, Akira / Namikawa, Kenjiro / Yoshikawa, Shusuke / Fujiwara, Yutaka / Kondo, Shunsuke / Mukaiyama, Akihira / Zhang, Fanghong / Kiyohara, Yoshio. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. · Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Development Department, Novartis Pharma K.K., Tokyo, Japan. ·J Dermatol · Pubmed #29399853.

ABSTRACT: The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

5 Clinical Trial Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON). 2017

Namikawa, Kenjiro / Tsutsumida, Arata / Mizutani, Tomonori / Shibata, Taro / Takenouchi, Tatsuya / Yoshikawa, Shusuke / Kiyohara, Yoshio / Uchi, Hiroshi / Furue, Masutaka / Ogata, Dai / Tsuchida, Tetsuya / Yamazaki, Naoya. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo. · JCOG Data Center/Operations Office, National Cancer Center, Tokyo. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata. · Department of Dermatology, Shizuoka Cancer Center, Shizuoka. · Department of Dermatology, Kyushu University Hospital, Fukuoka. · Department of Dermatology, Saitama Medical University Hospital, Saitama, Japan. ·Jpn J Clin Oncol · Pubmed #29136453.

ABSTRACT: The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].

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 Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study. 2017

Yamazaki, Naoya / Kiyohara, Yoshio / Uhara, Hisashi / Uehara, Jiro / Fujimoto, Manabu / Takenouchi, Tatsuya / Otsuka, Masaki / Uchi, Hiroshi / Ihn, Hironobu / Minami, Hironobu. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan. · Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan. · Department of Dermatology, University of Tsukuba Hospital, Ibaraki, Japan. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Department Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Hyogo, Japan. ·Cancer Sci · Pubmed #28342215.

ABSTRACT: Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI-142533.).

8 Clinical Trial Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). 2017

Yamazaki, Naoya / Takenouchi, Tatsuya / Fujimoto, Manabu / Ihn, Hironobu / Uchi, Hiroshi / Inozume, Takashi / Kiyohara, Yoshio / Uhara, Hisashi / Nakagawa, Kazuhiko / Furukawa, Hiroshi / Wada, Hidefumi / Noguchi, Kazuo / Shimamoto, Takashi / Yokota, Kenji. ·Department of Dermatologic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. nyamazaki@ncc.go.jp. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Department of Dermatology, Kyushu University School of Medicine, Fukuoka, Japan. · Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. · Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan. · Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan. · Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan. · Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. · Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan. · MSD K.K., Tokyo, Japan. · Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. ·Cancer Chemother Pharmacol · Pubmed #28283736.

ABSTRACT: PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

9 Clinical Trial Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. 2017

Yamazaki, Naoya / Kiyohara, Yoshio / Uhara, Hisashi / Iizuka, Hajime / Uehara, Jiro / Otsuka, Fujio / Fujisawa, Yasuhiro / Takenouchi, Tatsuya / Isei, Taiki / Iwatsuki, Keiji / Uchi, Hiroshi / Ihn, Hironobu / Minami, Hironobu / Tahara, Hideaki. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan. · Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan. · Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Dermatology, Kansai Medical University, Osaka, Japan. · Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Department Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Hyogo, Japan. · Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ·Cancer Sci · Pubmed #28266140.

ABSTRACT: Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.

10 Clinical Trial Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma. 2016

Yamazaki, Naoya / Uhara, Hisashi / Wada, Hidefumi / Matsuda, Kenji / Yamamoto, Keiko / Shimamoto, Takashi / Kiyohara, Yoshio. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. nyamazak@ncc.go.jp. · Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. · Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. · Japan Development, MSD K.K., Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center, Sunto-Gun, Japan. ·J Dermatol · Pubmed #27087489.

ABSTRACT: In the adjuvant setting for malignant melanoma, interferon (IFN)-α-2b and pegylated (PEG) IFN-α-2b were approved in several countries including the USA before these were approved in Japan. To resolve the "drug-lag" issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN-α-2b. As with a previously reported phase III study, patients were to receive PEG IFN-α-2b 6 μg/kg per week s.c. during an 8-week induction phase, followed by a maintenance phase at a dose of 3 μg/kg per week up to 5 years. Dose-limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose-limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug-related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration-time curve and maximum observed serum concentration were observed between Japanese and historical non-Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN-α-2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

11 Clinical Trial Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. 2015

Yamazaki, N / Kiyohara, Y / Uhara, H / Fukushima, S / Uchi, H / Shibagaki, N / Tsutsumida, A / Yoshikawa, S / Okuyama, R / Ito, Y / Tokudome, T. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. · Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Dermatology, University of Yamanashi Hospital, Yamanashi, Japan. · Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. · Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. takuto0806@gmail.com. ·Cancer Chemother Pharmacol · Pubmed #26410424.

ABSTRACT: PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01990859.

12 Clinical Trial Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma. 2015

Yamazaki, N / Uhara, H / Fukushima, S / Uchi, H / Shibagaki, N / Kiyohara, Y / Tsutsumida, A / Namikawa, K / Okuyama, R / Otsuka, Y / Tokudome, T. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Dermatology, Yamanashi University Hospital, Yamanashi, Japan. · Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. · Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. · Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. takuto0806@gmail.com. ·Cancer Chemother Pharmacol · Pubmed #26407818.

ABSTRACT: PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

13 Clinical Trial Phase I/II study of vemurafenib in patients with unresectable or recurrent melanoma with BRAF(V) (600) mutations. 2015

Yamazaki, Naoya / Kiyohara, Yoshio / Sugaya, Naofumi / Uhara, Hisashi. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan. · Chugai Pharmaceutical, Tokyo, Japan. · Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan. ·J Dermatol · Pubmed #25884515.

ABSTRACT: We investigated the efficacy and safety of vemurafenib in Japanese patients with unresectable or recurrent melanoma with BRAF(V) (600) mutations. This was a two-step open-label multicenter phase I/II study. Step 1 evaluated the initial safety of vemurafenib 960 mg administrated p.o. twice daily in three patients. In step 2, eight patients received vemurafenib 960 mg administrated p.o. twice daily for 28-day treatment cycles; the primary outcome measure was response rate, as determined by independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events (AE) experienced by five or more patients were arthralgia (n = 10), myalgia (n = 8), alopecia (n = 7), and rash, maculopapular rash and decreased appetite (n = 5 each). Three patients had grade 3 AE. One serious AE occurred in one patient (abnormal hepatic function). Six patients required dose reduction because of AE. One patient died within 28 days after the last dose, but death was caused by disease progression and not associated with the study drug. In the eight patients in step 2, overall response rate was 75.0%, none had a complete response and six had a partial response (75.0%). Median response duration was 240.0 days, disease control rate 87.5%, median progression-free survival 416.0 days and median overall survival 443.0 days. In conclusion, vemurafenib treatment resulted in an overall response rate of 75% in Japanese patients with metastatic melanoma with BRAF(V) (600) mutations. All toxicities were manageable.

14 Clinical Trial Dendritic cell-based vaccination in metastatic melanoma patients: phase II clinical trial. 2012

Oshita, Chie / Takikawa, Masako / Kume, Akiko / Miyata, Haruo / Ashizawa, Tadashi / Iizuka, Akira / Kiyohara, Yoshio / Yoshikawa, Shusuke / Tanosaki, Ryuji / Yamazaki, Naoya / Yamamoto, Akifumi / Takesako, Kazutoh / Yamaguchi, Ken / Akiyama, Yasuto. ·Division of Immunotherapy, Shizuoka Cancer Center Research Institute, Shizuoka 411-8777, Japan. ·Oncol Rep · Pubmed #22895835.

ABSTRACT: Metastatic and chemoresistant melanoma can be a good target of immunotherapy because it is an intractable cancer with a very poor prognosis. Previously, we tested a dendritic cell (DC)-based phase I vaccine, and confirmed that it was safe. In the present study, we performed a phase II trial of a DC vaccine for metastatic melanoma patients with mainly the HLA-A24 genotype, and investigated the efficacy of the vaccine. Twenty-four patients with metastatic melanoma were enrolled into a phase II study of DC-based immunotherapy. The group included 19 HLA-A24-positive (A*2402) patients and 3 HLA-A2-positive (A*0201) patients. The protocol for DC production was similar to that in the phase I trial. Briefly, a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-A2, MAGE-A3 and MART-1 or MAGE‑A1) restricted to HLA-A2 or A24 and KLH were used for DC pulsing. Finally, DCs were injected subcutaneously (s.c.) into the inguinal region in the dose range of 1-5x107 per shot. The DC ratio (lin-HLA-DR+) of the vaccine was 38.1±13.3% and the frequency of CD83+ DCs was 25.7±20.8%. Other parameters regarding DC processing were not different from phase I. Immune response-related parameters including the ELISPOT assay, DTH reaction to peptide or KLH, DC injection numbers were shown to be related to a good prognosis. The ELISPOT reaction was positive in 75% of the patients vaccinated. The increase of anti-melanoma antigen antibody titer before vaccination was also shown to be a prognosis factor, but that post-vaccination was not. Based on immunohistochemical analysis, CD8 and IL-17 were not involved in the prognosis. Adverse effects of more than grade III were not seen. Overall survival analysis revealed a significant survival prolongation effect in DC-given melanoma patients. These results suggest that peptide cocktail-treated DC vaccines may be a safe and effective therapy against metastatic melanoma in terms of prolongation of overall survival time.

15 Clinical Trial Applicability of radiocolloids, blue dyes and fluorescent indocyanine green to sentinel node biopsy in melanoma. 2012

Uhara, Hisashi / Yamazaki, Naoya / Takata, Minoru / Inoue, Yuji / Sakakibara, Akihiro / Nakamura, Yasuhiro / Suehiro, Keisuke / Yamamoto, Akifumi / Kamo, Riei / Mochida, Kosuke / Takenaka, Hideya / Yamashita, Toshiharu / Takenouchi, Tatsuya / Yoshikawa, Shusuke / Takahashi, Akira / Uehara, Jiro / Kawai, Mikio / Iwata, Hiroaki / Kadono, Takafumi / Kai, Yoshitaka / Watanabe, Shoichi / Murata, Satoru / Ikeda, Tetsuya / Fukamizu, Hidekazu / Tanaka, Toshihiro / Hatta, Naohito / Saida, Toshiaki. ·Department of Dermatology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan. uhara@shinshu-u.ac.jp ·J Dermatol · Pubmed #21933261.

ABSTRACT: Patients with primary cutaneous melanoma underwent sentinel node (SN) mapping and biopsy at 25 facilities in Japan by the combination of radiocolloid with gamma probe and dye. Technetium-99m ((99m)Tc)-tin colloid, (99m)Tc-phytate, 2% patent blue violet (PBV) and 0.4% indigo carmine were used as tracers. In some hospitals, 0.5% fluorescent indocyanine green, which allows visualization of the SN with an infrared camera, was concomitantly used and examined. A total of 673 patients were enrolled, and 562 cases were eligible. The detection rates of SN were 95.5% (147/154) with the combination of tin colloid and PBV, 98.9% (368/372) with the combination of phytate and PBV, and 97.2% (35/36) with the combination of tin colloid or phytate and indigo carmine. SN was not detected in 12 cases by the combination method, and the primary tumor was in the head and neck in six of those 12 cases. In eight of 526 cases (1.5%), SN was detected by PBV but not by radiocolloid. There were 13 cases (2.5%) in which SN was detected by radiocolloid but not by PBV. In 18 of 36 cases (50%), SN was detected by radiocolloid but not by indigo carmine. Concomitantly used fluorescent indocyanine green detected SN in all of 67 cases. Interference with transcutaneous oximetry by PVB was observed in some cases, although it caused no clinical trouble. Allergic reactions were not reported with any of the tracers. (99m)Tc-tin colloid, (99m)Tc-phytate, PBV and indocyanine green are useful tracers for SN mapping.

16 Article Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance. 2018

Kiyohara, Yoshio / Uhara, Hisashi / Ito, Yoshihiko / Matsumoto, Noritake / Tsuchida, Tetsuya / Yamazaki, Naoya. ·Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan. · Pharmacovigilance Division, Ono Pharmaceutical, Osaka, Japan. · Department of Dermatology, Saitama Medical University, Saitama, Japan. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. ·J Dermatol · Pubmed #29464755.

ABSTRACT: A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ-glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval [CI], 290-not reached [NR]) in the overall population, NR (95% CI, 305-NR) for cutaneous melanoma and 340 days (95% CI, 275-NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.

17 Article Success of rechallenging dabrafenib and trametinib combination therapy after trametinib-induced rhabdomyolysis: a case report. 2018

Muto, Yusuke / Ng, William / Namikawa, Kenjiro / Takahashi, Akira / Tsutsumida, Arata / Nishida, Makiko / Yamazaki, Naoya. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. ·Melanoma Res · Pubmed #29356791.

ABSTRACT: The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

18 Article Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan. 2018

Uhara, H / Kiyohara, Y / Tsuda, A / Takata, M / Yamazaki, N. ·Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan. uharah@sapmed.ac.jp. · Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan. uharah@sapmed.ac.jp. · Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan. · Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. ·Clin Transl Oncol · Pubmed #28674996.

ABSTRACT: BACKGROUND: Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. RESULTS: Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. CONCLUSIONS: EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.

19 Article Nail apparatus melanoma in a Japanese population: a comparative study of surgical procedures and prognoses in a large series of 151 cases. 2017

Ogata, Dai / Uhara, Hisashi / Tsutsumida, Arata / Yamazaki, Naoya / Mochida, Kosuke / Amano, Masahiro / Yoshikawa, Shusuke / Kiyohara, Yoshio / Tsuchida, Tetsuya. ·Saitama Medical University, Department of Dermatology, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan, Shizuoka Cancer Center Hospital, Division of Dermatology, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. · Shinsyu University, Department of Dermatology, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan. · National Cancer Center Hospital, Department of Dermatologic Oncology, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Miyazaki University, Department of Dermatology, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan. · Shizuoka Cancer Center Hospital, Division of Dermatology, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. · Saitama Medical University, Department of Dermatology, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan. ·Eur J Dermatol · Pubmed #29165298.

ABSTRACT: Nail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown. The purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour. We performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared. We identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for ≤1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for ≥4.01-mm tumours. Surgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAM is comparable to that of other types of melanoma.

20 Article Efficacy and toxicity of transarterial chemoembolization therapy using cisplatin and gelatin sponge in patients with liver metastases from uveal melanoma in an Asian population. 2017

Shibayama, Yoshitsugu / Namikawa, Kenjiro / Sone, Miyuki / Takahashi, Akira / Tsutsumida, Arata / Sugawara, Shunsuke / Arai, Yasuaki / Aihara, Yukiko / Suzuki, Shigenobu / Nakayama, Juichiro / Imafuku, Shinichi / Yamazaki, Naoya. ·Department of Dermatologic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Dermatology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0133, Japan. · Department of Dermatologic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. knamikaw@ncc.go.jp. · Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Ophthalmic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. ·Int J Clin Oncol · Pubmed #28144882.

ABSTRACT: BACKGROUND: Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. METHODS: We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m RESULTS: We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, <25% of the tumor volume within the liver at baseline, and normal serum lactate dehydrogenase (LDH) and normal alkaline phosphatase at baseline. Among them, normal LDH at baseline was the only independent prognostic factor in multivariate analysis. The common adverse events (AEs) were liver enzyme elevation (100%), nausea (72.4%), abdominal pain (65.5%), vomiting (55.2%), post-embolization syndrome (34.5% of patients, 9.6% of TACE procedures), and pyrexia (24.1%). Grade ≥3 AEs consisted of aspartate aminotransferase elevation (34.5%), alanine aminotransferase elevation (51.7%), and serum creatinine elevation (3.4%). CONCLUSION: TACE therapy has a certain degree of clinical efficacy with a tolerable toxicity and, therefore, can still be one of the treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.

21 Article Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. 2016

Nakamura, Yoshio / Kitano, Shigehisa / Takahashi, Akira / Tsutsumida, Arata / Namikawa, Kenjiro / Tanese, Keiji / Abe, Takayuki / Funakoshi, Takeru / Yamamoto, Noboru / Amagai, Masayuki / Yamazaki, Naoya. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, Keio University School of Medicine, Tokyo, Japan. · Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. · Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical Translational Research Center, Keio University School of Medicine, Tokyo, Japan. ·Oncotarget · Pubmed #27764805.

ABSTRACT: BACKGROUND: An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice. METHODS: We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks. RESULTS: As for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS. CONCLUSION: ALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.

22 Article Frequency of level II and III axillary nodes metastases in patients with positive sentinel lymph nodes in melanoma: a multi-institutional study in Japan. 2016

Tsutsumida, Arata / Takahashi, Akira / Namikawa, Kenjiro / Yamazaki, Naoya / Uhara, Hisashi / Teramoto, Yukiko / Takenouchi, Tatsuya / Fukushima, Satoshi / Yokota, Kenji / Uehara, Jiro / Matsushita, Shigeto / Shibayama, Yoshitsugu / Hatta, Naohito / Masui, Yuri / Uchi, Hiroshi / Fujisawa, Yasuhiro / Ogata, Dai. ·Department of Dermatologic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. atsutsum@ncc.go.jp. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Dermatology, Shinshu University, Matsumoto, Japan. · Department of Skin Oncology and Dermatology, Saitama Medical University, International Medical Center, Hidaka, Japan. · Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan. · Department of Dermatology, Nagoya University, Nagoya, Japan. · Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan. · Department of Dermato-Oncology/Dermatology, Kagoshima Medical Center and Department of Dermatology, Kagoshima University, Kagoshima, Japan. · Department of Dermatology, Fukuoka University, Fukuoka, Japan. · Department of Dermatology, Toyama Prefectural Central Hospital, Toyama, Japan. · Department of Dermatology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Dermatology, Kyushu University, Fukuoka, Japan. · Department of Dermatology, University of Tsukuba, Tsukuba, Japan. · Department of Dermatology, Saitama Medical University, Moroyama, Japan. ·Int J Clin Oncol · Pubmed #26759315.

ABSTRACT: BACKGROUND: Axillary lymph node dissection (ALND) has been recommended to include levels I-III for melanoma patients who have evidence of metastasis in the axillary sentinel lymph node (SLN). The extent of the subsequent axillary dissection is in debate. The objective of this study was to determine the frequency of metastasis of level III nodes in addition to that of level II nodes in this setting. METHODS: A multi-institutional retrospective study was undertaken in 14 melanoma treatment centers in Japan. RESULTS: Between 2007 and 2012, 69 patients with involved axillary SLNs underwent a subsequent ALND and 55 underwent level I and II dissections. Level III metastatic nodes, which is our primary endpoint, were seen in only 1 patient (1.5 %). The level II metastatic rate was 4.4 %. CONCLUSIONS: Our study sample size was small, but melanoma patients with positive SLN rarely had level III disease, suggesting that level III dissection may be unnecessary. We also found that level II metastasis was not so frequent. More evidence is needed to standardize the extent of ALND and to identify the patients who would have the most benefit with undergoing level II dissection for positive axillary SLNs.

23 Article Low Probability of Lymphatic Drainage to Cloquet's Node Is of Limited Value as Indicator for Pelvic Lymph Node Dissection in Patients with Lower Limb Melanoma. 2016

Teramoto, Yukiko / Nakamura, Yasuhiro / Sato, Sayuri / Yamazaki, Naoya / Yamamoto, Akifumi. ·1 Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center , Saitama, Japan . · 2 Department of Dermatologic Oncology, National Cancer Center Hospital , Tokyo, Japan . ·Lymphat Res Biol · Pubmed #26495774.

ABSTRACT: BACKGROUND AND OBJECTIVES: For patients with melanoma, the choice between an inguinal lymph node dissection (ILND) alone and both an ILND and a pelvic lymph node dissection (PLND) is controversial. Although Cloquet's node (CN) is considered the sentinel pelvic node, evaluation of this factor to predict pelvic node status has produced varied results. We investigated inguinal and pelvic lymphatic drainage patterns and focused on CN to clarify whether CN status could be an indicator of PLND. METHODS: Patients with primary cutaneous lower limb melanoma who underwent lymphatic mapping and sentinel lymph node biopsy (SLNB) using dynamic lymphoscintigraphy and SPECT/CT were retrospectively reviewed. RESULTS: Thirty-two patients underwent lymphatic mapping and SLNB. Each patient's CN was identified by SPECT/CT. A radioactive CN was detected in only 37.5% (12/32) of patients, and no lymphatic drainage to CN occurred in 62.5% (20/32). In 37.5% (12/32) of patients, the lymph drained directly from the inguinal to the pelvic nodes bypassing CN. CONCLUSION: In melanoma patients, lymphatic drainage from the lower extremity does not always pass from the inguinal node to the pelvic nodes via CN. Tumor-negative status of CN alone is of limited value as an indicator for avoiding PLND.

24 Article Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. 2015

Sakaizawa, Kaori / Ashida, Atsuko / Uchiyama, Aya / Ito, Takamichi / Fujisawa, Yasuhiro / Ogata, Dai / Matsushita, Shigeto / Fujii, Kazuyasu / Fukushima, Satoshi / Shibayama, Yoshitsugu / Hatta, Naohito / Takenouchi, Tatsuya / Uehara, Jiro / Okuyama, Ryuhei / Yamazaki, Naoya / Uhara, Hisashi. ·Department of Dermatology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. · Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. · Department of Dermatology, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan. · Department of Dermatology, Saitama Medical University, 38, Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. · Department of Dermato-Oncology/Dermatology, Kagoshima Medical Center, 8-1, Shiroyama-cho, Kagoshima 892-0853, Japan. · Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan. · Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-0811, Japan. · Department of Dermatology, Faculty of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. · Department of Dermatology, Toyama Prefectural Central Hospital, 2-2-78, Nishinagae, Toyama 930-8550, Japan. · Department of Dermatology, Niigata Cancer Center Hospital, 2-15-3, Kawagishi-cho, Chuo-ku, Niigata 951-8566, Japan. · Department of Dermatology, Asahikawa Medical University, 1-1-1, Higashinijo, Midorigaoka, Asahikawa 078-8510, Japan. · Department of Dermatologic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. · Department of Dermatology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. Electronic address: uhara@shinshu-u.ac.jp. ·J Dermatol Sci · Pubmed #26282084.

ABSTRACT: BACKGROUND: The importance of the genetic background of melanoma cells to the individual susceptibility to treatment has become apparent. In Caucasians, BRAF mutations are frequently detected in lesions on the skin of younger patients compared to NRAS and KIT mutations. However, clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations have not been fully evaluated in East Asians. OBJECTIVE: To clarify clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. METHODS: Clinical data were retrospectively collected from 11 hospitals in Japan. BRAF, NRAS and KIT mutations were evaluated with polymerase chain reaction and Sanger sequencing. The relationships between these gene mutations and pathological and clinical findings were analyzed. RESULTS: The number of cases examined was 171 (primary: 135, metastases: 11, paired: 25), and all were Japanese patients. The detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively. Compared with the wild type, the presence of BRAF mutations was significantly associated with younger age (median, 50.0 years vs. 70.0 years, p<0.001). BRAF mutation was frequently detected in the lesions of the scalp (80%; 4/5), trunk (72.0%; 18/25), extremities (56.7%; 17/30) and neck (44.4%; 4/9), and the least prevalent were the face (22.2%; 2/9), nail (12.5%; 3/24), palm or sole (8.9%; 4/45) and mucosa (0%). NRAS mutations were prevalent in the face (33.3%) and palm or sole (20.0%), and the median age of these patients was 70.5 years. A KIT mutation was observed in the nail apparatus (25%), palm or sole (15.6%) and mucosa (18.2%). The median age of the patients with a KIT mutation was 63.0 years. Heterogeneity of mutations between primary and metastatic lesions was detected in six of 25 cases (24%). Solar elastosis was identified in 12 of 71 cases (15.3%), among which four cases harbored BRAF(V600E) (2 cases), BRAF(V600K), NRAS(Q61K) or NRAS(Q61L), respectively. CONCLUSION: Some clinical characteristics associated with BRAF, NRAS and KIT mutations were observed in Japanese patients, and we observed both similarities to and differences from those of Caucasians. Our findings could provide useful information in efforts to clarify the tumor genesis of malignant melanomas.

25 Article [Nivolumab for metastatic melanoma-basic knowledge and clinical data]. 2015

Yamazaki, Naoya / Maeda, Yuka. ·Dept. of dermatologic oncology, national cancer center hospital, Tokyo, Japan ·Gan To Kagaku Ryoho · Pubmed #26020984.

ABSTRACT: -- No abstract --

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