Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
5.2
Journals
Cancers
Special Issues
Systemic Therapies in Melanoma
share announcement

Systemic Therapies in Melanoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 39264

Special Issue Editors

Dr. Alexandre Moulin

E-Mail Website
Guest Editor
Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
Interests: ocular tumors; conjunctival melanoma; uveal melanoma; targeted therapy; immunotherapy
Prof. Olivier Michielin

E-Mail Website
Guest Editor
Oncology Department, Lausanne University Hospital (CHUV), Lausanne, Swizterland

Special Issue Information

Dear Colleagues,

In the last few years, the appraisal of the genetic background of melanoma has allowed us to identify key driver genes with oncogenic mutations and develop targeted therapies for advanced melanomas. The significant rate of response of the high mutation burden identified in skin melanomas to immunotherapy and combined therapy with checkpoint inhibitors has recently led to an impressive improvement in the 5-year overall survival in advanced skin melanoma patients. These changes, however, were not observed in metastatic uveal melanomas. This Special Issue aims to present articles assessing recent advances in systemic therapy for advanced skin and other melanomas.

Dr. Alexandre Moulin
Prof. Olivier Michielin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cutaneous melanoma
  • targeted therapy
  • immunotherapy
  • conjunctival melanoma
  • uveal melanoma
  • mucosal melanoma
  • genetic landscape

Published Papers (12 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

13 pages, 927 KiB  
Article
Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma
by Krisztian Homicsko, Reinhard Dummer, Christoph Hoeller, Jedd D. Wolchok, F. Stephen Hodi, James Larkin, Paolo A. Ascierto, Victoria Atkinson, Caroline Robert, Michael A. Postow, Sandra Re, David Paulucci, Darin Dobler and Olivier Michielin
Cancers 2022, 14(9), 2300; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092300 - 05 May 2022
Cited by 7 | Viewed by 2426
Abstract
The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line [...] Read more.
The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6–58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

16 pages, 2695 KiB  
Article
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening
by Katya Nardou, Michael Nicolas, Fabien Kuttler, Katarina Cisarova, Elifnaz Celik, Mathieu Quinodoz, Nicolo Riggi, Olivier Michielin, Carlo Rivolta, Gerardo Turcatti and Alexandre Pierre Moulin
Cancers 2022, 14(6), 1575; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061575 - 19 Mar 2022
Viewed by 2798
Abstract
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity [...] Read more.
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

18 pages, 2137 KiB  
Article
Safety and Efficacy of Ipilimumab plus Nivolumab and Sequential Selective Internal Radiation Therapy in Hepatic and Extrahepatic Metastatic Uveal Melanoma
by Veronica Aedo-Lopez, Camille L. Gérard, Sarah Boughdad, Bianca Gautron Moura, Gregoire Berthod, Antonia Digklia, Krisztian Homicsko, Niklaus Schaefer, Rafael Duran, Michel A. Cuendet and Olivier Michielin
Cancers 2022, 14(5), 1162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051162 - 24 Feb 2022
Cited by 9 | Viewed by 2127
Abstract
To assess the safety and efficacy of ipilimumab plus nivolumab around selective internal radiation therapy (SIRT) in patients with metastatic uveal melanoma (mUM). We present a retrospective, single center study of 32 patients with mUM divided into two groups based on the treatment [...] Read more.
To assess the safety and efficacy of ipilimumab plus nivolumab around selective internal radiation therapy (SIRT) in patients with metastatic uveal melanoma (mUM). We present a retrospective, single center study of 32 patients with mUM divided into two groups based on the treatment received between April 2013 and April 2021. The SIRT_IpiNivo cohort was treated with Yttrium-90 microspheres and ipilimumab plus nivolumab before or after the SIRT (n = 18). The SIRT cohort underwent SIRT but did not receive combined immunotherapy with ipilimumab plus nivolumab (n = 14). Twelve patients (66.7%) of the SIRT_IpiNivo arm received SIRT as first-line treatment and six patients (33.3%) received ipilimumab plus nivolumab prior to SIRT. In the SIRT group, seven patients (50.0%) received single-agent immunotherapy. One patient treated with combined immunotherapy 68 months after the SIRT was included in this group. At the start of ipilimumab plus nivolumab, 94.4% (n = 17) presented hepatic metastases and 72.2% (n = 13) had extra liver disease. Eight patients (44.4%) of the SIRT_IpiNivo group experienced grade 3 or 4 immune related adverse events, mainly colitis and hepatitis. Median overall survival from the diagnosis of metastases was 49.6 months (95% confidence interval (CI); 24.1-not available (NA)) in the SIRT_IpiNivo group compared with 13.6 months (95% CI; 11.5-NA) in the SIRT group (log-rank p-value 0.027). The presence of extra liver metastases at the time of SIRT, largest liver lesion more than 8 cm (M1c) and liver tumor volume negatively impacted the survival. This real-world cohort suggests that a sequential treatment of ipilimumab plus nivolumab and SIRT is a well-tolerated therapeutic approach with promising survival rates. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

22 pages, 3387 KiB  
Article
Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial
by Julia Katharina Schwarze, Soizic Garaud, Yanina J. L. Jansen, Gil Awada, Valérie Vandersleyen, Jens Tijtgat, Alexandre de Wind, Paulus Kristanto, Teofila Seremet, Karen Willard-Gallo and Bart Neyns
Cancers 2022, 14(3), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030682 - 28 Jan 2022
Cited by 8 | Viewed by 3232
Abstract
Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. [...] Read more.
Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

13 pages, 515 KiB  
Article
A Retrospective Analysis of Dabrafenib and/or Dabrafenib Plus Trametinib Combination in Patients with Metastatic Melanoma to Characterize Patients with Long-Term Benefit in the Individual Patient Program (DESCRIBE III)
by Victoria G. Atkinson, Pietro Quaglino, Massimo Aglietta, Michele Del Vecchio, Roberta Depenni, Francesca Consoli, Dimitrios Bafaloukos, Pier Francesco Ferrucci, Skaiste Tulyte, Ivana Krajsová, Paolo A. Ascierto, Rossana Gueli, Ana Arance, Helen Gogas, Hiya Banerjee, Teddy Saliba, Egbert de Jong and Bart Neyns
Cancers 2021, 13(10), 2466; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102466 - 18 May 2021
Cited by 6 | Viewed by 3039
Abstract
The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with BRAF V600–mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with [...] Read more.
The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with BRAF V600–mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with unresectable or metastatic melanoma treated with dab monotherapy and/or dab + tram combination therapy as part of the Named Patient Program or Individual Patient Program. Overall, 509 patients were enrolled. Patients were categorized into three groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and <12 months), and short-term (on therapy <6 months) duration of benefit. More patients in the short-term duration of benefit group had baseline characteristics associated with poor prognosis compared with the other two groups. Median lactate dehydrogenase (LDH) levels (368 U/L) at baseline were also higher in the short-term duration of benefit group. No new safety signals were identified. DESCRIBE III identified baseline characteristics associated with long-term benefit of dab + tram. Lower LDH level and <3 metastatic sites at baseline were associated with a longer duration of benefit, confirming that the findings from COMBI-d and COMBI-v are relevant to patients treated in a real-world setting. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

7 pages, 679 KiB  
Communication
Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants
by Francesco Spagnolo, Bruna Dalmasso, Enrica Tanda, Miriam Potrony, Susana Puig, Remco van Doorn, Ellen Kapiteijn, Paola Queirolo, Hildur Helgadottir and Paola Ghiorzo
Cancers 2021, 13(10), 2440; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102440 - 18 May 2021
Cited by 8 | Viewed by 2512
Abstract
Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, [...] Read more.
Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

13 pages, 1605 KiB  
Article
A Phase 2 Clinical Trial of Trametinib and Low-Dose Dabrafenib in Patients with Advanced Pretreated NRASQ61R/K/L Mutant Melanoma (TraMel-WT)
by Gil Awada, Julia Katharina Schwarze, Jens Tijtgat, Giuseppe Fasolino, Hendrik Everaert and Bart Neyns
Cancers 2021, 13(9), 2010; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092010 - 22 Apr 2021
Cited by 7 | Viewed by 2468
Abstract
Background: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown [...] Read more.
Background: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. Methods: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. Results: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

10 pages, 1716 KiB  
Article
Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy
by John M. Rieth, Umang Swami, Sarah L. Mott, Mario Zanaty, Michael D. Henry, Aaron D. Bossler, Jeremy D. Greenlee, Yousef Zakharia, Marion Vanneste, Brooke Jennings and Mohammed M. Milhem
Cancers 2021, 13(7), 1489; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071489 - 24 Mar 2021
Cited by 7 | Viewed by 2535
Abstract
Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different [...] Read more.
Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2–4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45–0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32–0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

18 pages, 4387 KiB  
Article
CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway
by Nancy T. Santiappillai, Shatha Abuhammad, Alison Slater, Laura Kirby, Grant A. McArthur, Karen E. Sheppard and Lorey K. Smith
Cancers 2021, 13(3), 524; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030524 - 29 Jan 2021
Cited by 8 | Viewed by 3115
Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical [...] Read more.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 806 KiB  
Review
PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?
by Wei Yen Chan, Lauren J. Brown, Lee Reid and Anthony M. Joshua
Cancers 2021, 13(18), 4520; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184520 - 08 Sep 2021
Cited by 8 | Viewed by 8188
Abstract
Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients [...] Read more.
Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

18 pages, 898 KiB  
Review
Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients
by Sarah Zhou, Daniel Sikorski, Honghao Xu, Andrei Zubarev, May Chergui, François Lagacé, Wilson H. Miller, Jr., Margaret Redpath, Stephanie Ghazal, Marcus O. Butler, Teresa M. Petrella, Joël Claveau, Carolyn Nessim, Thomas G. Salopek, Robert Gniadecki and Ivan V. Litvinov
Cancers 2021, 13(9), 2282; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092282 - 10 May 2021
Cited by 6 | Viewed by 3347
Abstract
Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated [...] Read more.
Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

Other

Jump to: Research, Review

15 pages, 1796 KiB  
Systematic Review
Contemporary Neoadjuvant Therapies for High-Risk Melanoma: A Systematic Review
by Kerianne Boulva, Sameer Apte, Ashley Yu, Alexandre Tran, Risa Shorr, Xinni Song, Michael Ong and Carolyn Nessim
Cancers 2021, 13(8), 1905; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081905 - 15 Apr 2021
Cited by 7 | Viewed by 2389
Abstract
Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. [...] Read more.
Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. We conducted a systematic review of trials performed in the last decade evaluating neoadjuvant targeted, immuno- or intralesional therapy for resectable stage III or IV melanoma. Database searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception to 13 February 2020. Two reviewers assessed titles, abstracts, and full texts. Trials investigating contemporary neoadjuvant therapies in high-risk melanoma were included. Eight phase II trials (4 randomized and 4 single-arm) involving 450 patients reported on neoadjuvant anti-BRAF/MEK targeted therapy (3), anti-PD-1/CTLA-4 immunotherapy (3), and intralesional therapy (2). The safest and most efficacious regimens were dabrafenib/trametinib and combination ipilimumab (1 mg/kg) + nivolumab (3 mg/kg). Pathologic complete response (pCR) and adverse events were comparable. Ipilimumab + nivolumab exhibited longer RFS. Contemporary neoadjuvant therapies are not only safe, but also demonstrate remarkable pCR and RFS—outcomes which are regarded as meaningful surrogates for long-term survival. Studies defining predictors of pCR, its correlation with oncologic outcomes, and phase III trials comparing neoadjuvant therapy to standard of care will be crucial. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-12
Back to TopTop