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Weichenthal M, Mangana J, Gavrilova I, Lugowska I, Shalamanova GK, Kandolf L, Chiarion-Sileni V, Mohr P, Karanikolova TS, Teterycz P, Espinosa E, Schnecko P, Cheng P, Bender M, Jiang S, Burke T, Ascierto PA, Gogas H, Rodas IM, Rutkowski P, Schadendorf D, Dummer R. Adjuvant Use of Pembrolizumab for Stage III Melanoma in a Real-World Setting in Europe. Cancers (Basel) 2024; 16:3558. [PMID: 39517999 PMCID: PMC11545249 DOI: 10.3390/cancers16213558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/04/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Although data on patients treated with pembrolizumab are available from clinical trials and single-country real-world reports, to our knowledge no multi-country real-world studies have investigated the use of pembrolizumab as an adjuvant treatment for stage III melanoma. METHODS We used the European Melanoma Registry (EUMelaReg), a disease entity-based registry specific for melanoma, to examine treatment and outcomes for adult patients with stage III melanoma with lymph node involvement who had complete resection and received adjuvant treatment with pembrolizumab. The primary objectives were to describe the demographic and clinical characteristics of the included patients as well as time on adjuvant pembrolizumab treatment (TOT), real-world recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) from adjuvant pembrolizumab initiation. Secondary objectives were time to next treatment (TTNT) after adjuvant use of pembrolizumab, next-line therapy for stage III and unresectable stage IV melanoma and overall survival (OS) from initiation of pembrolizumab. RESULTS Patients were stratified according to age, sex, BRAF status, number of positive lymph nodes and disease substage. Median TOT was 11.1 (9.2-11.5) months, median RFS was 29.6 [18.7-not reached (NR)] months and median DMFS was 32.4 (22.7-NR) months. TTNT was 29.9 (22.2-NR) months, while median OS was not reached. CONCLUSIONS The results of this study offer insights into the real-world use of pembrolizumab as an adjuvant therapy for melanoma in Europe.
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Affiliation(s)
- Michael Weichenthal
- Skin Cancer Center Kiel, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Joanna Mangana
- University Hospital of Zurich, 8091 Zurich, Switzerland; (J.M.); (P.C.); (R.D.)
| | - Iva Gavrilova
- National Oncology Hospital Sofia, g.k. Darvenitsa, 1756 Sofia, Bulgaria;
| | - Iwona Lugowska
- Instytut im. Marii Skłodowskiej-Curie, 02-781 Warsaw, Poland; (I.L.); (P.T.); (P.R.)
| | | | - Lidija Kandolf
- Military Medical Academy (CSEEMEG), 11000 Belgrade, Serbia;
| | | | - Peter Mohr
- Elbe Kliniken Buxtehude-Stade, 21614 Buxtehude, Germany;
| | | | - Pawel Teterycz
- Instytut im. Marii Skłodowskiej-Curie, 02-781 Warsaw, Poland; (I.L.); (P.T.); (P.R.)
| | | | | | - Phil Cheng
- University Hospital of Zurich, 8091 Zurich, Switzerland; (J.M.); (P.C.); (R.D.)
| | - Marc Bender
- Skin Cancer Center, Division of Molecular Cell Biology, Elbe Kliniken Stade-Buxtehude, 21614 Buxtehude, Germany;
| | - Shan Jiang
- Merck & Co., Inc., Rahway, NJ 07065, USA; (S.J.); (T.B.)
| | - Thomas Burke
- Merck & Co., Inc., Rahway, NJ 07065, USA; (S.J.); (T.B.)
| | - Paolo Antonio Ascierto
- Melanoma and Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, 80131 Naples, Italy;
| | - Helen Gogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, University of Athens, 15772 Athens, Greece;
| | | | - Piotr Rutkowski
- Instytut im. Marii Skłodowskiej-Curie, 02-781 Warsaw, Poland; (I.L.); (P.T.); (P.R.)
| | | | - Reinhard Dummer
- University Hospital of Zurich, 8091 Zurich, Switzerland; (J.M.); (P.C.); (R.D.)
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Gogas H, Ravimohan S, Datta A, Chhibber A, Couselo EM, Diab A, Pereira C, Quéreux G, Sandhu S, Curti B, Khushalani NI, Taylor MH, Daniels GA, Spreafico A, Meniawy T, Van Den Eertwegh AJM, Sun Y, Arriaga Y, Zhou M, Long GV, Lebbé C. Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab. NPJ Precis Oncol 2024; 8:150. [PMID: 39025948 PMCID: PMC11258232 DOI: 10.1038/s41698-024-00641-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/09/2024] [Indexed: 07/20/2024] Open
Abstract
In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.
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Affiliation(s)
- Helen Gogas
- National and Kapodistrian University of Athens, Athens, Greece.
| | | | | | | | - Eva Muñoz Couselo
- Vall d'Hebron Barcelona Hospital and Vall d'Hebron Instituto de Oncología (VHIO), Barcelona, Spain
| | - Adi Diab
- MD Anderson Cancer Center, Houston, TX, USA
| | - Caio Pereira
- Fundação Pio XII - Hospital de Câncer de Barretos, São Paulo, Brazil
| | | | | | - Brendan Curti
- Eerle A. Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA
| | | | - Matthew H Taylor
- Eerle A. Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA
| | | | - Anna Spreafico
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Tarek Meniawy
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia
| | - Alfons J M Van Den Eertwegh
- Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | | | | | - Ming Zhou
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Georgina V Long
- The Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
| | - Céleste Lebbé
- Université Paris Cité, Dermato-Oncology and CIC AP-HP Hôpital Saint Louis, Cancer Institute APHP, Nord-Université Paris Cité, Paris, France
- INSERM U976 HIPI, Paris, France
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3
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Gupta M, Stukalin I, Meyers DE, Heng DYC, Monzon J, Cheng T, Navani V. Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: a retrospective observational cohort study. Front Oncol 2024; 14:1385425. [PMID: 38884085 PMCID: PMC11176500 DOI: 10.3389/fonc.2024.1385425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/13/2024] [Indexed: 06/18/2024] Open
Abstract
Background The association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice. Methods We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving anti-programmed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumab-nivolumab. Secondary outcomes were identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT). Results 198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2-10.1) months for progressive disease (log-rank p<0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85-4.63, p=0.121). Elevated LDH level (OR 0.46; 95%CI 0.21-0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03-0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13-0.72, p=0.007) were associated with decreased likelihood of response. Conclusion No significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings.
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Affiliation(s)
- Mehul Gupta
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Igor Stukalin
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel E Meyers
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel Y C Heng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Jose Monzon
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Tina Cheng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Vishal Navani
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
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Topham B, de Vries M, Nonis M, van Berkel R, Pullar JM, Magon NJ, Vissers MCM, Currie MJ, Robinson BA, Gibbs D, Ang A, Dachs GU. Blood Vitamin C Levels of Patients Receiving Immunotherapy and Relationship to Monocyte Subtype and Epigenetic Modification. EPIGENOMES 2024; 8:17. [PMID: 38804366 PMCID: PMC11130941 DOI: 10.3390/epigenomes8020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
The treatment of metastatic melanoma has been revolutionised by immunotherapy, yet a significant number of patients do not respond, and many experience autoimmune adverse events. Associations have been reported between patient outcome and monocyte subsets, whereas vitamin C (ascorbate) has been shown to mediate changes in cancer-stimulated monocytes in vitro. We therefore investigated the relationship of ascorbate with monocyte subsets and epigenetic modifications in patients with metastatic melanoma receiving immunotherapy. Patients receiving immunotherapy were compared to other cancer cohorts and age-matched healthy controls. Ascorbate levels in plasma and peripheral blood-derived mononuclear cells (PBMCs), monocyte subtype and epigenetic markers were measured, and adverse events, tumour response and survival were recorded. A quarter of the immunotherapy cohort had hypovitaminosis C, with plasma and PBMC ascorbate levels significantly lower than those from other cancer patients or healthy controls. PBMCs from the immunotherapy cohort contained similar frequencies of non-classical and classical monocytes. DNA methylation markers and intracellular ascorbate concentration were correlated with monocyte subset frequency in healthy controls, but correlation was lost in immunotherapy patients. No associations between ascorbate status and immune-related adverse events or tumour response or overall survival were apparent.
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Affiliation(s)
- Ben Topham
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
| | - Millie de Vries
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
| | - Maria Nonis
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
| | - Rebecca van Berkel
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
| | - Juliet M. Pullar
- Mātai Hāora—Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (J.M.P.); (M.C.M.V.)
| | - Nicholas J. Magon
- Mātai Hāora—Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (J.M.P.); (M.C.M.V.)
| | - Margreet C. M. Vissers
- Mātai Hāora—Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (J.M.P.); (M.C.M.V.)
| | - Margaret J. Currie
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
| | - Bridget A. Robinson
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
- Canterbury Regional Cancer and Haematology Service, Te Whatu Ora Waitaha, Canterbury, Christchurch 8011, New Zealand
| | - David Gibbs
- Canterbury Regional Cancer and Haematology Service, Te Whatu Ora Waitaha, Canterbury, Christchurch 8011, New Zealand
| | - Abel Ang
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
- Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK
| | - Gabi U. Dachs
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8011, New Zealand; (B.T.); (M.J.C.); (B.A.R.); (A.A.)
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Reyes-Gibby CC, Caterino JM, Coyne CJ, Kyriacou DN, Qdaisat A, McQuade J, Owen DH, Bischof JJ, Shete S, Yeung SCJ. Immune-related adverse event in the emergency department: methodology of the immune-related emergency disposition index (IrEDi). EMERGENCY CANCER CARE 2024; 3:1. [PMID: 38725994 PMCID: PMC11081141 DOI: 10.1186/s44201-023-00023-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 12/13/2023] [Indexed: 05/12/2024]
Abstract
For many cancer patients, immune checkpoint inhibitors (ICIs) can be life-saving. However, the immune-related adverse events (irAEs) from ICIs can be debilitating and can quickly become severe or even be fatal. Often, irAEs will precipitate visits to the emergency department (ED). Therefore, early recognition and the decision to admit, observe, or discharge these patients from the ED can be key to a cancer patient's morbidity and mortality. ED clinicians typically make their decision for disposition (admit, observe, or discharge) within 2-6 h from their patient's ED presentation. However, irAEs are particularly challenging in the ED because of atypical presentations, the absence of classic symptoms, the delayed availability of diagnostic tests during the ED encounter, and the fast pace in the ED setting. At present, there is no single sufficiently large ED data source with clinical, biological, laboratory, and imaging data that will allow for the development of a tool that will guide early recognition and appropriate ED disposition of patients with potential irAEs. We describe an ongoing federally funded project that aims to develop an immune-related emergency disposition index (IrEDi). The project capitalizes on a multi-site collaboration among 4 members of the Comprehensive Oncologic Emergency Research Network (CONCERN): MD Anderson Cancer Center, Ohio State University, Northwestern University, and University of California San Diego. If the aims are achieved, the IrEDi will be the first risk stratification tool derived from a large racial/ethnically and geographically diverse population of cancer patients. The future goal is to validate irEDi in general EDs to improve emergency care of cancer patients on ICIs.
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Affiliation(s)
- Cielito C. Reyes-Gibby
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey M. Caterino
- Departments of Emergency Medicine and Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Christopher J. Coyne
- Department of Emergency Medicine, University of California San Diego, San Diego, CA, USA
| | - Demetrios N. Kyriacou
- Department of Emergency Medicine and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Aiham Qdaisat
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dwight H. Owen
- Departments of Emergency Medicine and Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jason J. Bischof
- Departments of Emergency Medicine and Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sanjay Shete
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sai-Ching Jim Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Seňavová J, Rajmonová A, Heřman V, Jura F, Veľasová A, Hamová I, Tkachenko A, Kupcová K, Havránek O. Immune Checkpoints and Their Inhibition in T-Cell Lymphomas. Folia Biol (Praha) 2024; 70:123-151. [PMID: 39644109 DOI: 10.14712/fb2024070030123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyperprogression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associa-ted with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies.
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Affiliation(s)
- Jana Seňavová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Anežka Rajmonová
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Václav Heřman
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Filip Jura
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Adriana Veľasová
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Iva Hamová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Anton Tkachenko
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kristýna Kupcová
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Ondřej Havránek
- 1st Department of Medicine - Department of Haematology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
- BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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7
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Schina A, Pedersen S, Spenning AL, Laursen OK, Pedersen C, Haslund CA, Schmidt H, Bastholt L, Svane IM, Ellebaek E, Donia M. Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies. Eur J Cancer 2023; 195:113392. [PMID: 37924648 DOI: 10.1016/j.ejca.2023.113392] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 11/06/2023]
Abstract
BACKGROUND The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. METHODS In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria. RESULTS We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. CONCLUSIONS The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.
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Affiliation(s)
- Aimilia Schina
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Sidsel Pedersen
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | | | | | - Cecilia Pedersen
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Henrik Schmidt
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Eva Ellebaek
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
| | - Marco Donia
- National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
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8
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Stukalin I, Navani V, Gupta M, Ruan Y, Boyne DJ, O’Sullivan DE, Meyers DE, Goutam S, Sander M, Ewanchuk BW, Brenner DR, Suo A, Cheung WY, Heng DYC, Monzon JG, Cheng T. Development and Validation of a Prognostic Risk Model for Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors. Oncologist 2023; 28:812-822. [PMID: 37011230 PMCID: PMC10485285 DOI: 10.1093/oncolo/oyad073] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 02/08/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Risk stratification tools for patients with advanced melanoma (AM) treated with immune checkpoint inhibitors (ICI) are lacking. We identified a new prognostic model associated with overall survival (OS). PATIENTS AND METHODS A total of 318 treatment naïve patients with AM receiving ICI were collected from a multi-centre retrospective cohort study. LASSO Cox regression identified independent prognostic factors associated with OS. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel's C-index was calculated and internally validated to outline the model's discriminatory performance. External validation was carried out in 142 advanced melanoma patients receiving ICI in later lines. RESULTS High white blood cell count (WBC), high lactate dehydrogenase (LDH), low albumin, Eastern Cooperative Oncology Group (ECOG) performance status ≥1, and the presence of liver metastases were included in the model. Patients were parsed into 3 risk groups: favorable (0-1 factors) OS of 52.9 months, intermediate (2-3 factors) OS 13.0 months, and poor (≥4 factors) OS 2.7 months. The C-index of the model from the discovery cohort was 0.69. External validation in later-lines (N = 142) of therapy demonstrated a c-index of 0.65. CONCLUSIONS Liver metastases, low albumin, high LDH, high WBC, and ECOG≥1 can be combined into a prognostic model for AM patients treated with ICI.
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Affiliation(s)
- Igor Stukalin
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Vishal Navani
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Mehul Gupta
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Yibing Ruan
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Devon J Boyne
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Dylan E O’Sullivan
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Daniel E Meyers
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Siddhartha Goutam
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Michael Sander
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Benjamin W Ewanchuk
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Darren R Brenner
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Aleksi Suo
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Winson Y Cheung
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel Y C Heng
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Jose G Monzon
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Tina Cheng
- Department of Oncology, Division of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
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9
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Gupta M, Stukalin I, Meyers D, Goutam S, Heng DYC, Cheng T, Monzon J, Navani V. Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma. JAMA Netw Open 2023; 6:e2319607. [PMID: 37351883 PMCID: PMC10290253 DOI: 10.1001/jamanetworkopen.2023.19607] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/07/2023] [Indexed: 06/24/2023] Open
Abstract
Importance Treatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting. Objective To evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting. Design, Setting, and Participants This multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022. Exposures Patients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab. Main Outcomes and Measures Treatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up. Results A total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively. Conclusions and Relevance This cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.
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Affiliation(s)
- Mehul Gupta
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Igor Stukalin
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Daniel Meyers
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Sid Goutam
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Daniel Y. C. Heng
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Tina Cheng
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Jose Monzon
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Vishal Navani
- Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
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10
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Wang QQ, Li YM, Qin G, Liu F, Xu YY. Primary malignant melanoma of the esophagus: A case report. World J Clin Cases 2023; 11:1426-1433. [PMID: 36926119 PMCID: PMC10013115 DOI: 10.12998/wjcc.v11.i6.1426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/07/2023] [Accepted: 02/07/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Primary malignant melanoma of the esophagus (PMME) is a rare malignant disease whose clinical and molecular pathological features, origin and pathogenesis, diagnosis and treatment have not been elucidated.
CASE SUMMARY In this paper, we report a case of a 73-year-old male with PMME. The patient complained of progressive dysphagia accompanied by substantial weight loss. Gastroscopy revealed a purple black bulging-type mass in the lower esophagus with easy bleeding on contact and scattered satellite lesions in the stomach. Histopathological biopsy revealed melanocytes in the esophageal mucosa. Physical examination and multidisciplinary consultation led to diagnostic exclusion of melanoma originating in other organs, such as the skin. Through this case report and literature review, we aimed to describe the clinical and molecular pathological features of PMME and summarize possible pathways of pathogenesis as well as cutting-edge therapeutic advances.
CONCLUSION PMME is a rare malignancy of the esophagus with a poor prognosis. Clinicians should raise their awareness and be able to identify early lesions.
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Affiliation(s)
- Qian-Qian Wang
- Department of Gastroenterology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Yan-Mei Li
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Fang Liu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Ying-Ying Xu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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11
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Real Check RIO: A Real-World Analysis of Nivolumab in First Line Metastatic Melanoma Assessing Efficacy, Safety and Predictive Factors. Cancers (Basel) 2023; 15:cancers15041265. [PMID: 36831607 PMCID: PMC9953812 DOI: 10.3390/cancers15041265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/08/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
We performed a retrospective study on 51 metastatic melanoma patients treated with Nivolumab in first line, at the Regional Institute of Oncology (RIO) Iasi, Romania between April 2017 and December 2019. We studied the efficacy and safety of anti-PD-1 immune checkpoint inhibitor therapy on a treatment-naive population. After a median follow-up of 36 months, the median progression free survival (PFS) was 26 months (95% CI, 15-36) and the median overall survival (OS) was 31 months (95% CI, 20.1-41.8). At 12 months after the initiation of immunotherapy, the percentage of patients alive was 70%, and at 24 months 62.5%. The most common adverse events observed were dermatological (23.5%) and grade ≥3 was identified in 4 (6.8%) patients. Multivariate analysis indicated that the presence of liver metastases (HR 4.42; 95% CI: 1.88-10.4, p = 0.001) and a neutrophils/lymphocytes ratio (NLR) were associated with poor survival (HR 3.21; 95% CI: 1.04-9.87, p = 0.04). Although retrospective data on a small group of patients were analyzed, we can conclude that our results in RIO are similar to those described in clinical trials and other real-world studies. Our study highlights the potential usefulness of liver metastases and NLR as novel predictive factors in clinical decision-making.
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12
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Ab Rahman AS, Strother RM, Paddison J. New Zealand national retrospective cohort study of survival outcomes of patients with metastatic melanoma receiving immune-checkpoint inhibitors. Asia Pac J Clin Oncol 2023; 19:179-186. [PMID: 35686690 DOI: 10.1111/ajco.13801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/27/2022] [Accepted: 05/08/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have increased overall survival (OS) in metastatic melanoma in all clinical trials to date. However, pivotal trial populations were not representative of the real-world population in New Zealand. Real-world treatment effectiveness studies help evaluate the value of public pharmaceutical expenditure. AIM To determine the survival outcomes of New Zealand patients with unresectable or metastatic melanoma treated with pembrolizumab or nivolumab. METHODS This is a national retrospective cohort study. Patients with advanced unresectable or metastatic melanoma who received publicly funded immune-checkpoint inhibitors (ICIs) from 2017 to 2019 were included. Individual patient data were extracted from national administrative databases. The primary endpoint was OS, and secondary endpoints included OS by age, duration of treatment, posttreatment survival, and 30-day mortality from last pharmaceutical claim. RESULTS Five hundred ninety-seven patients were included, with a median follow-up of 25 months. One-year OS was 72%, the 2-year OS estimate was 60%, and median OS not reached. Survival did not differ by dichotomized age (≥70 vs. <70 year old), hazard ratio (HR) .94 (95% confidence interval (CI): .72-1.22; p = .62). Median duration of treatment was 9.0 months (95% CI: 7.9-10.1). Median post-treatment survival for the subgroup who had ceased treatment was 12.0 months (95% CI: 9.0-14.0). For the sample as a whole, the estimated 30-day mortality from last pharmaceutical claim was 15.7%. CONCLUSION OS in our New Zealand real-world population is comparable to pivotal clinical trials and real-world data (RWD) from other countries. These findings support the achievement of health gains from use of ICI in advanced unresectable and metastatic melanoma.
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Affiliation(s)
- Ahmad Sufian Ab Rahman
- Christchurch Medical Oncology Department, Christchurch, New Zealand.,Cancer CRI Centre, Kuala Lumpur, Malaysia
| | - Robert Matthew Strother
- Christchurch Medical Oncology Department, Christchurch, New Zealand.,Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Johanna Paddison
- Christchurch Medical Oncology Department, Christchurch, New Zealand.,Timaru Hospital, South Canterbury District Health Board, Timaru, New Zealand
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13
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van Laar SA, Kapiteijn E, Gombert-Handoko KB, Guchelaar HJ, Zwaveling J. Application of Electronic Health Record Text Mining: Real-World Tolerability, Safety, and Efficacy of Adjuvant Melanoma Treatments. Cancers (Basel) 2022; 14:5426. [PMID: 36358844 PMCID: PMC9657798 DOI: 10.3390/cancers14215426] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 08/13/2023] Open
Abstract
Introduction: Nivolumab (N), pembrolizumab (P), and dabrafenib plus trametinib (D + T) have been registered as adjuvant treatments for resected stage III and IV melanoma since 2018. Electronic health records (EHRs) are a real-world data source that can be used to review treatments in clinical practice. In this study, we applied EHR text-mining software to evaluate the real-world tolerability, safety, and efficacy of adjuvant melanoma treatments. Methods: Adult melanoma patients receiving adjuvant treatment between January 2019 and October 2021 at the Leiden University Medical Center, the Netherlands, were included. CTcue text-mining software (v3.1.0, CTcue B.V., Amsterdam, The Netherlands) was used to construct rule-based queries and perform context analysis for patient inclusion and data collection from structured and unstructured EHR data. Results: In total, 122 patients were included: 54 patients treated with nivolumab, 48 with pembrolizumab, and 20 with D + T. Significantly more patients discontinued treatment due to toxicity on D + T (N: 16%, P: 6%, D + T: 40%), and X2 (6, n = 122) = 14.6 and p = 0.024. Immune checkpoint inhibitors (ICIs) mainly showed immune-related treatment-limiting adverse events (AEs), and chronic thyroid-related AE occurred frequently (hyperthyroidism: N: 15%, P: 13%, hypothyroidism: N: 20%, P: 19%). Treatment-limiting toxicity from D + T was primarily a combination of reversible AEs, including pyrexia and fatigue. The 1-year recurrence-free survival was 70.3% after nivolumab, 72.4% after pembrolizumab, and 83.0% after D + T. Conclusions: Text-mining EHR is a valuable method to collect real-world data to evaluate adjuvant melanoma treatments. ICIs were better tolerated than D + T, in line with RCT results. For BRAF+ patients, physicians must weigh the higher risk of reversible treatment-limiting AEs of D + T against the risk of long-term immune-related AEs.
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Affiliation(s)
- Sylvia A. van Laar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Ellen Kapiteijn
- Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Kim B. Gombert-Handoko
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Juliette Zwaveling
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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14
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Serra-Bellver P, Versluis JM, Oberoi HK, Zhou C, Slattery TD, Khan Y, Patrinely JR, Pires da Silva I, Martínez-Vila C, Cook N, Graham DM, Carlino MS, Menzies AM, Arance AM, Johnson DB, Long GV, Pickering L, Larkin JMG, Blank CU, Lorigan P. Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study. Eur J Cancer 2022; 176:121-132. [PMID: 36215945 DOI: 10.1016/j.ejca.2022.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma. PATIENTS AND METHODS This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated. RESULTS A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded. CONCLUSION The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.
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Affiliation(s)
- Patricio Serra-Bellver
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom.
| | - Judith M Versluis
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Honey K Oberoi
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom; Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Cong Zhou
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, United Kingdom
| | - Timothy D Slattery
- Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - James R Patrinely
- Department of Medical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Inês Pires da Silva
- Melanoma Institute Australia, The University of Sydney and the Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Westmead and Blacktown Hospital, Sydney, Australia
| | - C Martínez-Vila
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Natalie Cook
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, University of Manchester, United Kingdom
| | - Donna M Graham
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, University of Manchester, United Kingdom
| | - Matteo S Carlino
- Melanoma Institute Australia, The University of Sydney and the Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Westmead and Blacktown Hospital, Sydney, Australia
| | - Alexander M Menzies
- Melanoma Institute Australia, The University of Sydney and the Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia
| | - Ana M Arance
- Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Douglas B Johnson
- Department of Medical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney and the Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, Australia
| | - Lisa Pickering
- Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - James M G Larkin
- Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Christian U Blank
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Paul Lorigan
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom; Division of Cancer Sciences, University of Manchester, United Kingdom
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15
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Cazzato G, Cascardi E, Colagrande A, Lettini T, Resta L, Bizzoca C, Arezzo F, Loizzi V, Dellino M, Cormio G, Casatta N, Lupo C, Scillimati A, Scacco S, Parente P, Lospalluti L, Ingravallo G. The Thousand Faces of Malignant Melanoma: A Systematic Review of the Primary Malignant Melanoma of the Esophagus. Cancers (Basel) 2022; 14:3725. [PMID: 35954389 PMCID: PMC9367585 DOI: 10.3390/cancers14153725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
Primary Malignant Melanoma of the Esophagus (PMME) is an extremely rare cancer of the esophagus, accounting for 0.1−0.8% of all oro-esophageal cancers and <0.05% of all melanoma subtypes, with an estimated incidence of 0.0036 cases per million/year. We conduct a careful analysis of the literature starting from 1906 to the beginning of 2022, searching the PubMed, Science.gov, Scopus and Web of Science (WoS) databases. A total of 457 records were initially identified in the literature search, of which 17 were duplicates. After screening for eligibility and inclusion criteria, 303 publications were ultimately included, related to 347 patients with PMME. PMME represents a very rare entity whose very existence has been the subject of debate for a long time. Over time, an increasing number of cases have been reported in the literature, leading to an increase in knowledge and laying the foundations for a discussion on the treatment of this pathology, which still remains largely represented by surgery. In recent times, the possibility of discovering greater mutations in gene hotspots has made it possible to develop new therapeutic strategies of which nivolumab is an example. Future studies with large case series, with clinicopathological and molecular data, will be necessary to improve the outcome of patients with PMME.
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Affiliation(s)
- Gerardo Cazzato
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.C.); (T.L.); (L.R.); (G.I.)
| | - Eliano Cascardi
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy;
- Pathology Unit, FPO-IRCCS Candiolo Cancer Institute, Str. Provinciale 142 lm 3.95, 10060 Candiolo, Italy
| | - Anna Colagrande
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.C.); (T.L.); (L.R.); (G.I.)
| | - Teresa Lettini
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.C.); (T.L.); (L.R.); (G.I.)
| | - Leonardo Resta
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.C.); (T.L.); (L.R.); (G.I.)
| | - Cinzia Bizzoca
- Section of General Surgery, Azienda Ospedaliero-Universitaria Policlinico di Bari, 70124 Bari, Italy;
| | - Francesca Arezzo
- Section of Gynecology and Obstetrics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.A.); (V.L.); (M.D.)
| | - Vera Loizzi
- Section of Gynecology and Obstetrics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.A.); (V.L.); (M.D.)
| | - Miriam Dellino
- Section of Gynecology and Obstetrics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.A.); (V.L.); (M.D.)
| | - Gennaro Cormio
- Oncology Unit IRCSS Istituto Tumori “Giovanni Paolo II”, Department of Interdisciplinary Medicine (DIM), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Nadia Casatta
- Innovation Department, Diapath S.p.A., Via Savoldini n.71, 24057 Martinengo, Italy; (N.C.); (C.L.)
| | - Carmelo Lupo
- Innovation Department, Diapath S.p.A., Via Savoldini n.71, 24057 Martinengo, Italy; (N.C.); (C.L.)
| | - Antonio Scillimati
- Department of Pharmacy-Pharmaceutical Sciences, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Salvatore Scacco
- Department of Basic Medical Sciences and Neurosciences, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Lucia Lospalluti
- Section of Dermatology and Venereology, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giuseppe Ingravallo
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.C.); (T.L.); (L.R.); (G.I.)
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16
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Okamoto T, Nakano E, Yamauchi T. Complete remission in metastatic primary malignant melanoma of the esophagus with nivolumab: a case report. J Med Case Rep 2021; 15:345. [PMID: 34256852 PMCID: PMC8278729 DOI: 10.1186/s13256-021-02928-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 05/24/2021] [Indexed: 12/19/2022] Open
Abstract
Background Primary malignant melanoma of the esophagus is a rare form of mucosal melanoma with a poor prognosis. While immune checkpoint inhibitors have recently extended overall survival in metastatic melanoma, data on their effects on primary malignant melanoma of the esophagus are limited because of its rarity. Here, we report the first case of long-term complete remission of metastatic primary malignant melanoma of the esophagus after nivolumab monotherapy. Case presentation A 79-year-old Asian man with a history of prostate cancer, gallbladder cancer, deep vein thrombosis, hypertension, and diabetes mellitus presented with gross hematuria. Cystoscopy revealed a solitary tumor on the right posterior wall of the bladder, and transurethral resection of bladder tumor was performed. Pathology was consistent with metastatic melanoma. A pigmented submucosal tumor-like growth in the esophagus was discovered on esophagogastroduodenoscopy. Computed tomography showed widespread metastases. The patient was diagnosed as having primary malignant melanoma of the esophagus with metastases to the stomach, subcutaneous tissue, lung, bladder, pleura, and peritoneum. Complete remission was achieved after seven cycles of triweekly nivolumab monotherapy. While nivolumab was discontinued because of kidney injury, the patient has remained tumor-free for over 4 years without further treatment. Conclusion Immune checkpoint inhibitors may have astonishing curative effects in selected populations. More research is warranted to identify factors that increase the likelihood of achieving complete remission in primary malignant melanoma of the esophagus as well as in other melanomas.
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Affiliation(s)
- Takeshi Okamoto
- Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan.
| | - Eriko Nakano
- Department of Oncology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Teruo Yamauchi
- Department of Oncology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan
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17
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Ellebaek E, Svane IM, Schmidt H, Haslund CA, Donia M, Hoejberg L, Ruhlmann C, Guldbrandt LM, Køhler UH, Bastholt L. The Danish metastatic melanoma database (DAMMED): A nation-wide platform for quality assurance and research in real-world data on medical therapy in Danish melanoma patients. Cancer Epidemiol 2021; 73:101943. [PMID: 33962356 DOI: 10.1016/j.canep.2021.101943] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/18/2021] [Accepted: 04/23/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Clinical trials enroll patients with specific diseases based on certain pre-defined eligibility criteria. Disease registries are crucial to evaluate the efficacy and safety of new expensive oncology medicines in broad non-trial patient populations. METHODS We provide detailed information on the structure, including variables, and the scientific results from a nation-wide Danish database covering advanced melanoma, illustrating the importance of continuous real-world data registration. Disease status and treatment-related information on all patients with American Joint Committee on Cancer (AJCC) 8th edition stage III or IV melanoma candidates to medical treatment in Denmark are prospectively registered in the Danish Metastatic Melanoma Database (DAMMED). RESULTS By January 1st, 2021, DAMMED includes 4156 patients and 7420 treatment regimens. Response rates and survival data from published randomized clinical trial data are compared with real-world efficacy data from DAMMED and presented. Overall, nine independent manuscripts highlighting similarities and discrepancies between real-world and clinical trial results are already reported to date. CONCLUSION Nation-wide disease registries take into consideration the complexity of daily clinical practice. We show a concrete example of how disease registries can complement clinical trials' information, improving clinical practice, and support health-related technology assessment.
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Affiliation(s)
- Eva Ellebaek
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark.
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Henrik Schmidt
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Marco Donia
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Lise Hoejberg
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | | | | | | | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Odense, Denmark
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Board R, Smittenaar R, Lawton S, Liu H, Juwa B, Chao D, Corrie P. Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018. Int J Cancer 2020; 148:868-875. [PMID: 32838478 PMCID: PMC7821238 DOI: 10.1002/ijc.33266] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/20/2020] [Accepted: 08/04/2020] [Indexed: 12/11/2022]
Abstract
Immune checkpoint inhibitors (CPIs) have radically changed outcomes for patients diagnosed with metastatic melanoma globally in the last 10 years, based on evidence of overall survival (OS) benefits generated from international randomised controlled trials (RCTs). Since RCTs do not always reflect real‐world prescribing, we interrogated established national databases to track prescribing of CPIs approved for first line treatment of metastatic melanoma patients in England since 2014 and determined patient outcomes associated with OS, as well as treatment‐related toxicity. Between April 2014 and March 2018, 5465 melanoma patients were diagnosed and treated with systemic anticancer therapy (SACT), 2322 of which received first‐line CPIs. There was good 3‐year OS concordance with RCT outcomes for ipilimumab (32%), ipinivo (56%) and nivolumab (51%), but OS was lower than expected for pembrolizumab (40%). Comparing patients prescribed ipinivo with those prescribed pembrolizumab, ipinivo‐treated patients were younger (88% vs 49% patients <70 years, P < .001) and fitter (60% vs 38% patients with Eastern Cooperative Oncology Group [ECOG] performance status 0, P < .0001). Emergency hospital admission rates from the earliest and last treatment dates were higher for patients prescribed ipinivo (37% and 55%) compared to those prescribed pembrolizumab (17% and 29%). The 30‐day mortality rates favoured ipinivo patients (3.8% ipinivo, 9.1% pembrolizumab, P < .0001) and likely reflected marked differences in median treatment durations: 63 (range 7‐440) days for ipinivo and 192 (range 5‐943) days for pembrolizumab. The dominant treatment‐related condition linked to hospital admission was colitis, recorded for 25% of patients prescribed ipinivo compared to 4% of patients prescribed pembrolizumab. Our population data has demonstrated that RCT outcomes can be achieved in routine care settings with careful patient selection. What's new? Immune checkpoint inhibitors (CPIs) greatly impact overall survival in metastatic melanoma. In England, CPIs have been used as first‐line therapy for this malignancy since 2014. This retrospective study assessed survival and toxicity among English metastatic melanoma patients prescribed CPIs between 2014 and 2018. For the CPIs ipilimumab, nivolumab, and ipinivo, survival outcomes were remarkably similar to registration trials. Poorer outcomes were associated with pembrolizumab, possibly because patients who received this drug were older and relatively less fit. Ipinivo generated the highest rates of emergency hospital visits and admissions, although 30‐day mortality was unchanged, potentially reflecting effective management of complications.
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Affiliation(s)
- Ruth Board
- Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK
| | - Rebecca Smittenaar
- National Cancer Registration and Analysis Service, Health Improvement Directorate, Public Health England, London, UK
| | - Sarah Lawton
- National Cancer Registration and Analysis Service, Health Improvement Directorate, Public Health England, London, UK
| | - Hanhua Liu
- National Cancer Registration and Analysis Service, Health Improvement Directorate, Public Health England, London, UK
| | - Bukky Juwa
- National Cancer Registration and Analysis Service, Health Improvement Directorate, Public Health England, London, UK
| | - David Chao
- Department of Oncology, Royal Free London NHS Foundation Trust, London, UK
| | - Pippa Corrie
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Asher N, Ben-Betzalel G, Lev-Ari S, Shapira-Frommer R, Steinberg-Silman Y, Gochman N, Schachter J, Meirson T, Markel G. Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma. Cancers (Basel) 2020; 12:cancers12082329. [PMID: 32824780 PMCID: PMC7464656 DOI: 10.3390/cancers12082329] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 08/06/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database—a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-naïve. The median follow-up was 12 months. The response rates for treatment-naïve and previously-treated patients were 61% and 25%, respectively; median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-naïve patients was 58% (95% CI 42–65). At data cutoff, 22% were still on-treatment. Grade 3–4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%); AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.
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Affiliation(s)
- Nethanel Asher
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
- Correspondence: (N.A.); (G.M.); Tel.: +972-526669283 (N.A.); Fax: +972-35304934 (N.A.)
| | - Guy Ben-Betzalel
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
| | - Shaked Lev-Ari
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
| | - Ronnie Shapira-Frommer
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
| | - Yael Steinberg-Silman
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
| | - Neta Gochman
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
| | - Jacob Schachter
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Tomer Meirson
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1589, Israel
| | - Gal Markel
- Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan 52621, Israel; (G.B.-B.); (S.L.-A.); (R.S.-F.); (Y.S.-S.); (N.G.); (J.S.); (T.M.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Correspondence: (N.A.); (G.M.); Tel.: +972-526669283 (N.A.); Fax: +972-35304934 (N.A.)
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