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Article ; Online: Evolving Management of Stage IV Melanoma.

Switzer, Benjamin / Piperno-Neumann, Sophie / Lyon, James / Buchbinder, Elizabeth / Puzanov, Igor

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting

2023 Volume 43, Page(s) e397478

Abstract: Significant advancements have been made in the treatment of advanced melanoma with the use of immune checkpoint inhibitors, novel immunotherapies, and BRAF/MEK-targeted therapies with numerous frontline treatment options. However, there remains ... ...

Abstract	Significant advancements have been made in the treatment of advanced melanoma with the use of immune checkpoint inhibitors, novel immunotherapies, and BRAF/MEK-targeted therapies with numerous frontline treatment options. However, there remains suboptimal evidence to guide treatment decisions in many patients. These include patients with newly diagnosed disease, immune checkpoint inhibitor (ICI)-resistant/ICI-refractory disease, CNS metastases, history of autoimmune disease, and/or immune-related adverse events (irAEs). Uveal melanoma (UM) is a rare melanoma associated with a poor prognosis in the metastatic setting. Systemic treatments, including checkpoint inhibitors, failed to demonstrate any survival benefit. Tebentafusp, a bispecific molecule, is the first treatment to improve overall survival (OS) in patients with HLA A*02:01-positive metastatic UM.
MeSH term(s)	Humans ; Melanoma/drug therapy ; Immunotherapy ; Uveal Neoplasms
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2431126-1
ISSN	1548-8756 ; 1548-8748
ISSN (online)	1548-8756
ISSN	1548-8748
DOI	10.1200/EDBK_397478
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Article ; Online: Metastatic uveal melanoma: The final frontier.

Rantala, Elina S / Hernberg, Micaela M / Piperno-Neumann, Sophie / Grossniklaus, Hans E / Kivelä, Tero T

Progress in retinal and eye research

2022 Volume 90, Page(s) 101041

Abstract: Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. ... ...

Abstract	Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
MeSH term(s)	Clinical Trials, Phase III as Topic ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/secondary ; Melanoma ; Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; Recombinant Fusion Proteins ; Retrospective Studies ; Uveal Neoplasms/diagnosis ; Uveal Neoplasms/therapy
Chemical Substances	Recombinant Fusion Proteins ; tebentafusp (N658GY6L3E)
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1182683-6
ISSN	1873-1635 ; 1350-9462
ISSN (online)	1873-1635
ISSN	1350-9462
DOI	10.1016/j.preteyeres.2022.101041
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Article ; Online: From rare to well-done: importance of rare tumors in cancer therapeutic advances.

Duffaud, Florence / Piperno-Neumann, Sophie / Penel, Nicolas / Blay, Jean-Yves

Oncotarget

2019 Volume 10, Issue 40, Page(s) 3998–3999

Language	English
Publishing date	2019-06-18
Publishing country	United States
Document type	Editorial
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27020
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Article: Avancées concernant le mélanome uvéal.

Piperno-Neumann, Sophie / Desjardins, Laurence

La Revue du praticien

2014 Volume 64, Issue 1, Page(s) 83–84

Title translation	Advances in uveal melanoma.
MeSH term(s)	Disease Progression ; Genetic Predisposition to Disease ; Humans ; Liver Neoplasms/diagnosis ; Liver Neoplasms/secondary ; Liver Neoplasms/therapy ; Melanoma/genetics ; Melanoma/pathology ; Melanoma/therapy ; Mutation ; Neoplasm Metastasis ; Uveal Neoplasms/genetics ; Uveal Neoplasms/pathology ; Uveal Neoplasms/therapy
Language	French
Publishing date	2014-01
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	205365-2
ISSN	2101-017X ; 0035-2640
ISSN (online)	2101-017X
ISSN	0035-2640
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Article: A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma.

Bauer, Sebastian / Larkin, James / Hodi, F Stephen / Stephen, Frank / Kapiteijn, Ellen H W / Schwartz, Gary K / Calvo, Emilano / Yerramilli-Rao, Padmaja / Piperno-Neumann, Sophie / Carvajal, Richard D

Frontiers in oncology

2023 Volume 12, Page(s) 975642

Abstract: Background: Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been ... ...

Abstract	Background: Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK. Method: We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis. Results: Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1. Conclusions: Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.
Language	English
Publishing date	2023-06-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.975642
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Article ; Online: Advances in the clinical management of uveal melanoma.

Carvajal, Richard D / Sacco, Joseph J / Jager, Martine J / Eschelman, David J / Olofsson Bagge, Roger / Harbour, J William / Chieng, Nicholas D / Patel, Sapna P / Joshua, Anthony M / Piperno-Neumann, Sophie

Nature reviews. Clinical oncology

2023 Volume 20, Issue 2, Page(s) 99–115

Abstract: Melanomas arising in the uveal tract of the eye are a rare form of the disease with a biology and clinical phenotype distinct from their more common cutaneous counterparts. Treatment of primary uveal melanoma with radiotherapy, enucleation or other ... ...

Abstract	Melanomas arising in the uveal tract of the eye are a rare form of the disease with a biology and clinical phenotype distinct from their more common cutaneous counterparts. Treatment of primary uveal melanoma with radiotherapy, enucleation or other modalities achieves local control in more than 90% of patients, although 40% or more ultimately develop distant metastases, most commonly in the liver. Until January 2022, no systemic therapy had received regulatory approval for patients with metastatic uveal melanoma, and these patients have historically had a dismal prognosis owing to the limited efficacy of the available treatments. A series of seminal studies over the past two decades have identified highly prevalent early, tumour-initiating oncogenic genomic aberrations, later recurring prognostic alterations and immunological features that characterize uveal melanoma. These advances have driven the development of a number of novel emerging treatments, including tebentafusp, the first systemic therapy to achieve regulatory approval for this disease. In this Review, our multidisciplinary and international group of authors summarize the biology of uveal melanoma, management of primary disease and surveillance strategies to detect recurrent disease, and then focus on the current standard and emerging regional and systemic treatment approaches for metastatic uveal melanoma.
MeSH term(s)	Humans ; Neoplasm Recurrence, Local ; Uveal Neoplasms/genetics ; Uveal Neoplasms/therapy ; Prognosis ; Melanoma/therapy ; Melanoma/drug therapy
Language	English
Publishing date	2023-01-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-022-00714-1
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Article: Impact of the coronavirus disease 2019 pandemic on sarcoma management in France: a 2019 and 2020 comparison.

Penel, Nicolas / Cantarel, Coralie / Chemin-Airiau, Claire / Ducimetiere, Françoise / Gouin, François / Le Loarer, François / Toulmonde, Maud / Piperno-Neumann, Sophie / Bellera, Carine / Honore, Charles / Blay, Jean-Yves / Mathoulin-Pelissier, Simone

Therapeutic advances in medical oncology

2023 Volume 15, Page(s) 17588359231192400

Abstract: Background: The coronavirus disease 2019 (COVID-19) pandemic was an unprecedented shock to the healthcare systems, and its consequences on managing rare cancers are unknown. We investigated COVID-19's impact on the activity of sarcoma-labeled networks ... ...

Abstract	Background: The coronavirus disease 2019 (COVID-19) pandemic was an unprecedented shock to the healthcare systems, and its consequences on managing rare cancers are unknown. We investigated COVID-19's impact on the activity of sarcoma-labeled networks by comparing key indicators in 2019-2020 (before and during the pandemic, respectively). Methods: We compared the incidence of limb and trunk soft tissue sarcomas, surgery rate, surgery center, surgery quality, and surgery delays nationally and in various regions, focusing on the three most severely affected regions. Findings: In this study, sarcoma incidence did not decrease, and the tumor and patient characteristics were similar in both years. The number of patients who underwent surgery in the labeled centers increased significantly (63% Interpretation: The model of the labeled center network for managing rare tumors was resilient. Paradoxically, the quality indicators improved during the pandemic due to the direct referral of patients with sarcomas to the labeled centers. Summary: This study shows that a nationwide network organization has made it possible to maintain care for these rare tumors during the pandemic.
Language	English
Publishing date	2023-08-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2503443-1
ISSN	1758-8359 ; 1758-8340
ISSN (online)	1758-8359
ISSN	1758-8340
DOI	10.1177/17588359231192400
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Article ; Online: Divergent local and systemic antitumor response in primary uveal melanomas.

The Journal of experimental medicine

2024 Volume 221, Issue 6

Abstract: Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types ... ...

Abstract	Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.
MeSH term(s)	Humans ; Melanoma/therapy ; Uveal Neoplasms ; CD8-Positive T-Lymphocytes ; Drainage
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20232094
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Article: FAK Inhibitor-Based Combinations with MEK or PKC Inhibitors Trigger Synergistic Antitumor Effects in Uveal Melanoma.

Tarin, Malcy / Némati, Fariba / Decaudin, Didier / Canbezdi, Christine / Marande, Benjamin / Silva, Lisseth / Derrien, Héloïse / Jochemsen, Aart G / Gardrat, Sophie / Piperno-Neumann, Sophie / Rodrigues, Manuel / Mariani, Pascale / Cassoux, Nathalie / Stern, Marc-Henri / Roman-Roman, Sergio / Alsafadi, Samar

Cancers

2023 Volume 15, Issue 8

Abstract: Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment ... ...

Abstract	Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM.
Language	English
Publishing date	2023-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15082280
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Article ; Online: Circulating Tumor DNA as a Prognostic Factor in Patients With Resectable Hepatic Metastases of Uveal Melanoma.

Mariani, Pascale / Bidard, François-Clément / Rampanou, Aurore / Houy, Alexandre / Servois, Vincent / Ramtohul, Toulsie / Pierron, Gaelle / Chevrier, Marion / Renouf, Benjamin / Lantz, Olivier / Gardrat, Sophie / Vincent-Salomon, Anne / Roman-Roman, Sergio / Rodrigues, Manuel / Piperno-Neumann, Sophie / Cassoux, Nathalie / Stern, Marc-Henri / Renault, Shufang

Annals of surgery

2023 Volume 278, Issue 4, Page(s) e827–e834

Abstract: Objective: We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145).: Background: In UM patients, the liver is the most common and ...

Abstract	Objective: We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145). Background: In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients. Methods: Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes. Results: Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS. Conclusions: This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.
MeSH term(s)	Humans ; Circulating Tumor DNA/genetics ; Prognosis ; Prospective Studies ; Neoplasm Recurrence, Local ; Liver Neoplasms/genetics ; Liver Neoplasms/surgery ; Biomarkers, Tumor/genetics ; Mutation
Chemical Substances	Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0000000000005822
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