We present the case of a 74 year old man who achieved a complete response and stabilization of hi... more We present the case of a 74 year old man who achieved a complete response and stabilization of his hepatic and lymph node metastases respectively after treatment with ipilimumab at 10 mg/Kg. The patient was diagnosed with right foot cutaneous melanoma in February 2004 (pT4apN2a according to the 2009 AJCC melanoma staging and classification). In October 2004, he started a first line chemotherapy treatment with fotemustine 100mg/Kg q21 as some inguinal, iliac and interaortocaval lymph node metastases had appeared. After 8 cycles of fotemustine, he experienced a relapse of his lymph node metastases, so a second line treatment with dacarbazin 1000 mg/m 2 q21 was administered until a new progression was noted (after 6 cycles). A third line treatment with weekly carboplatin and thalidomide kept the patient stable for almost 8 months, but then a further new progression was noted with the appearance of multiple cutaneous metastases on his right leg and a 25-mm hepatic metastasis (Figure ). Therefore, the patient was enrolled in Protocol CA180008 and treated with ipilimumab 10mg/Kg every 3 weeks for 4 cycles. The only drug-related toxicity was grade 1 diarrhea and vitiligo. The first tumor assessment was performed with a CT-scan two weeks after the fourth ipilimumab administration (week 12), and then every 4-6 months. Initially, a partial response of the index hepatic
We present the case of a 58 year old woman, who achieved complete response for her cutaneous mela... more We present the case of a 58 year old woman, who achieved complete response for her cutaneous melanoma metastasis after treatment with ipilimumab at 3 mg/Kg. The patient was given dacarbazine as a first line treatment for her cutaneous metastasis and a partial response was achieved. However, after 26 cycles of chemotherapy, the cutaneous lesions progressed, so ipilimumab was chosen as a second line treatment. The patient was eligible for the compassionate use of ipilimumab.Two weeks after the fourth cycle with ipilimumab, a complete response of most cutaneous metastasis was noted, with a partial response of the remaining lesions, which were still regressing at the last follow-up visit. Ipilimumab, which was recently reported to improve survival in patients with metastatic melanoma, represents a most promising immunotherapeutic drug and it has been approved for patients with advanced melanoma as a first-and second-line treatment by the FDA and as a second-line treatment by the European Medicines Agency (EMA).
Background: Following the increased survival of patients with metastatic melanoma thanks to immun... more Background: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma. The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) Frontiers in Oncology frontiersin.org 01
In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic varia... more In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic variants who received targeted therapy for advanced melanoma across four European centers. Since loss of CDKN2A function may intrinsically limit the activity of MAPK-directed targeted therapy, we decided to assess whether patients with germline CDKN2A pathogenic variants may achieve suboptimal results with BRAF and MEK inhibitors. To the best of our knowledge, this is the first study reporting on patients with BRAF-mutant advanced melanoma and a germline CDKN2A pathogenic variant who received treatment with BRAF with or without MEK inhibitors. Despite the limitations of our study, mostly due to the rare frequency of CDKN2A pathogenic variants, a challenge for the conduction of prospective trials with proper sample size, our results support treatment with targeted therapy in this subset of patients.
Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumo... more Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumors. In most cases, the diagnosis and treatments are made on small, low-risk lesions. However, in about 5% of cases, CSCC may present as either locally advanced or metastatic (i.e. with locoregional lymph nodes metastases or distant localizations). Prior to the introduction of immunotherapy in clinical practice, the standard treatment of advanced CSCC was not clearly defined, and up to 60% of patients received no systemic therapy. Thanks to a strong pre-clinical rationale, clinical trials led to the FDA (Food and Drug Administration) and EMA (European Medicines Agency) registration of cemiplimab, a PD-1 inhibitor that achieved encouraging results in terms of objective response, overall survival, and quality of life. Subsequently, the anti-PD-1 pembrolizumab received the approval for the treatment of advanced CSCC by the FDA only. In this review, we will focus on the definition of advanced CSCC and on the current and future therapeutic options, with a particular regard for immunotherapy.
Journal of The American Academy of Dermatology, May 1, 2019
Background: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently b... more Background: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently been associated with poor survival in patients with melanoma. Despite the high mutation rate in our cohort (up to 10% in patients with apparently sporadic melanoma), information on the impact of CDKN2A on survival in this cohort is lacking. Objective: To investigate whether poor survival associated with CDKN2A germline mutations was confirmed in a high mutationeprevalence cohort of Italian patients with melanoma undergoing a mutation-based follow-up. Methods: A total of 1239 patients with cutaneous melanoma were tested for CDKN2A mutational status and then assigned to a follow-up scheme according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A germline mutationepositive (MUT 1 ) patients. From this cohort, we selected 106 MUT 1 patients (with familial melanoma or apparently sporadic melanoma) and 199 CDKN2A germline mutationenegative (MUT e ) patients with sporadic melanoma who were matched by age and sex and had a similar tumor stage distribution. We found no difference in overall survival (hazard ratio, 0.85; 95% confidence interval, 0.48-1.52; P = .592,) or melanoma-specific survival (hazard ratio, 0.86; 95% confidence interval, 0.38-1.95; P = .718,) between MUT 1 and MUT e patients. MUT 1 patients were more likely to develop multiple melanomas and to undergo surgical excision of dysplastic nevi than were MUT e patients. Limitations: Retrospective study. Conclusion: CDKN2A mutations were not associated with survival in our cohort. ( J Am Acad Dermatol
In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progres... more In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported. Methods The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAF V600E/Kmutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol. Results Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet. Conclusion In BRAF V600E/K -mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
7528 Background: Due to the low incidence frequency of melanoma in Italy, recruitment of cases an... more 7528 Background: Due to the low incidence frequency of melanoma in Italy, recruitment of cases and kindreds through individual centers generally yields small numbers. We have therefore initiated an...
Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been i... more Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF-), including dermoscopic findings of melanomas and dysplastic nevi. Methods: we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/ research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available. After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF-. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF-). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF-patients, whose most prevalent pattern was the multicomponent. Conclusions: MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF-patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.
background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, ca... more background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. Methods CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. the carriers' responses were compared with responses reported in phase III clinical trials for CtLA-4 and pD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. results eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). Conclusion patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germli... more PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with ( CDKN2A +) and without ( CDKN2A–) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A–. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A– patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A– patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A– patients.
Riassunto. Negli ultimi anni il trattamento del melanoma è entrato in una nuova era grazie all'in... more Riassunto. Negli ultimi anni il trattamento del melanoma è entrato in una nuova era grazie all'introduzione dell'immunoterapia con gli inibitori dei checkpoint immunologici, in particolare con anticorpi anti PD-1, e delle terapie a bersaglio molecolare dirette verso BRAF e MEK. In assenza di studi di confronto diretto, la scelta della strategia terapeutica di prima linea deve basarsi sulle caratteristiche cliniche del paziente e su quelle biologiche del tumore. Per cercare di definire un algoritmo di trattamento dei pazienti con melanoma sulla base dei dati attualmente disponibili, abbiamo analizzato e confrontato i dati di sopravvivenza libera da progressione e sopravvivenza globale a 3 e 4 anni delle analisi per sottogruppi dei principali studi con inibitori di BRAF+MEK e anticorpi anti PD-1. Parole chiave. Adiuvante, algoritmo, immunoterapia, melanoma, terapie a bersaglio molecolare. Melanoma: which therapy for which patient. Summary. The introduction of anti PD-1 immunotherapy and BRAF+MEK-directed targeted therapy have been a breakthrough for the treatment of melanoma. Because no direct comparison exist between such strategies, the choice of front-line therapy relies on patients characteristics and tumor biology. To define an algorithm for the management of patients with high-risk or metastatic melanoma based on currently available data, we analyzed and compared 3-year and 4-year OS and PFS results from subgroup analyses of clinical trials with anti PD-1 drugs and BRAF+MEK inhibitors.
Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcom... more Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes. Results: A total of 1,395 patients were included. Primary tumors included non–small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07–1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03–1.43) independent of numb...
Considering the continuously expanding indication for ICI therapy, these findings are of the utmo... more Considering the continuously expanding indication for ICI therapy, these findings are of the utmost importance to ensure effective utilization of this therapy during and beyond the SARS-CoV-2 global pandemic.
ImportanceThe association of immune checkpoint inhibitors (ICIs) with patient quality of life has... more ImportanceThe association of immune checkpoint inhibitors (ICIs) with patient quality of life has been poorly explored.ObjectiveTo evaluate patient-reported outcomes (PROs) assessed in randomized clinical trials (RCTs) of immunotherapy-based treatments.Data SourcesThis systematic review and random-effects meta-analysis used RCTs identified in PubMed, MEDLINE, Embase, and Scopus from database inception to June 1, 2021.Study SelectionA total of 2259 RCTs were identified that assessed ICIs as monotherapy or in combination with chemotherapy or combined with another ICI and/or targeted therapy vs control groups not containing immunotherapy in patients with advanced solid tumors. Studies were reviewed independently by 2 authors.Data Extraction and SynthesisThis meta-analysis followed the PRISMA guidelines and recommendations of the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium.Main Outcomes and MeasuresThe coprimary ai...
BackgroundTo evaluate the capability of basal and one-month differed white blood cells (WBC), neu... more BackgroundTo evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response toimmune checkpoint inhibitors (ICI) in metastatic melanoma (MM).MethodsWe performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve.ResultsAt baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neu...
We present the case of a 74 year old man who achieved a complete response and stabilization of hi... more We present the case of a 74 year old man who achieved a complete response and stabilization of his hepatic and lymph node metastases respectively after treatment with ipilimumab at 10 mg/Kg. The patient was diagnosed with right foot cutaneous melanoma in February 2004 (pT4apN2a according to the 2009 AJCC melanoma staging and classification). In October 2004, he started a first line chemotherapy treatment with fotemustine 100mg/Kg q21 as some inguinal, iliac and interaortocaval lymph node metastases had appeared. After 8 cycles of fotemustine, he experienced a relapse of his lymph node metastases, so a second line treatment with dacarbazin 1000 mg/m 2 q21 was administered until a new progression was noted (after 6 cycles). A third line treatment with weekly carboplatin and thalidomide kept the patient stable for almost 8 months, but then a further new progression was noted with the appearance of multiple cutaneous metastases on his right leg and a 25-mm hepatic metastasis (Figure ). Therefore, the patient was enrolled in Protocol CA180008 and treated with ipilimumab 10mg/Kg every 3 weeks for 4 cycles. The only drug-related toxicity was grade 1 diarrhea and vitiligo. The first tumor assessment was performed with a CT-scan two weeks after the fourth ipilimumab administration (week 12), and then every 4-6 months. Initially, a partial response of the index hepatic
We present the case of a 58 year old woman, who achieved complete response for her cutaneous mela... more We present the case of a 58 year old woman, who achieved complete response for her cutaneous melanoma metastasis after treatment with ipilimumab at 3 mg/Kg. The patient was given dacarbazine as a first line treatment for her cutaneous metastasis and a partial response was achieved. However, after 26 cycles of chemotherapy, the cutaneous lesions progressed, so ipilimumab was chosen as a second line treatment. The patient was eligible for the compassionate use of ipilimumab.Two weeks after the fourth cycle with ipilimumab, a complete response of most cutaneous metastasis was noted, with a partial response of the remaining lesions, which were still regressing at the last follow-up visit. Ipilimumab, which was recently reported to improve survival in patients with metastatic melanoma, represents a most promising immunotherapeutic drug and it has been approved for patients with advanced melanoma as a first-and second-line treatment by the FDA and as a second-line treatment by the European Medicines Agency (EMA).
Background: Following the increased survival of patients with metastatic melanoma thanks to immun... more Background: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma. The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) Frontiers in Oncology frontiersin.org 01
In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic varia... more In our study, we retrospectively collected data of patients with germline CDKN2A pathogenic variants who received targeted therapy for advanced melanoma across four European centers. Since loss of CDKN2A function may intrinsically limit the activity of MAPK-directed targeted therapy, we decided to assess whether patients with germline CDKN2A pathogenic variants may achieve suboptimal results with BRAF and MEK inhibitors. To the best of our knowledge, this is the first study reporting on patients with BRAF-mutant advanced melanoma and a germline CDKN2A pathogenic variant who received treatment with BRAF with or without MEK inhibitors. Despite the limitations of our study, mostly due to the rare frequency of CDKN2A pathogenic variants, a challenge for the conduction of prospective trials with proper sample size, our results support treatment with targeted therapy in this subset of patients.
Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumo... more Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumors. In most cases, the diagnosis and treatments are made on small, low-risk lesions. However, in about 5% of cases, CSCC may present as either locally advanced or metastatic (i.e. with locoregional lymph nodes metastases or distant localizations). Prior to the introduction of immunotherapy in clinical practice, the standard treatment of advanced CSCC was not clearly defined, and up to 60% of patients received no systemic therapy. Thanks to a strong pre-clinical rationale, clinical trials led to the FDA (Food and Drug Administration) and EMA (European Medicines Agency) registration of cemiplimab, a PD-1 inhibitor that achieved encouraging results in terms of objective response, overall survival, and quality of life. Subsequently, the anti-PD-1 pembrolizumab received the approval for the treatment of advanced CSCC by the FDA only. In this review, we will focus on the definition of advanced CSCC and on the current and future therapeutic options, with a particular regard for immunotherapy.
Journal of The American Academy of Dermatology, May 1, 2019
Background: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently b... more Background: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently been associated with poor survival in patients with melanoma. Despite the high mutation rate in our cohort (up to 10% in patients with apparently sporadic melanoma), information on the impact of CDKN2A on survival in this cohort is lacking. Objective: To investigate whether poor survival associated with CDKN2A germline mutations was confirmed in a high mutationeprevalence cohort of Italian patients with melanoma undergoing a mutation-based follow-up. Methods: A total of 1239 patients with cutaneous melanoma were tested for CDKN2A mutational status and then assigned to a follow-up scheme according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A germline mutationepositive (MUT 1 ) patients. From this cohort, we selected 106 MUT 1 patients (with familial melanoma or apparently sporadic melanoma) and 199 CDKN2A germline mutationenegative (MUT e ) patients with sporadic melanoma who were matched by age and sex and had a similar tumor stage distribution. We found no difference in overall survival (hazard ratio, 0.85; 95% confidence interval, 0.48-1.52; P = .592,) or melanoma-specific survival (hazard ratio, 0.86; 95% confidence interval, 0.38-1.95; P = .718,) between MUT 1 and MUT e patients. MUT 1 patients were more likely to develop multiple melanomas and to undergo surgical excision of dysplastic nevi than were MUT e patients. Limitations: Retrospective study. Conclusion: CDKN2A mutations were not associated with survival in our cohort. ( J Am Acad Dermatol
In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progres... more In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported. Methods The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAF V600E/Kmutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol. Results Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet. Conclusion In BRAF V600E/K -mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
7528 Background: Due to the low incidence frequency of melanoma in Italy, recruitment of cases an... more 7528 Background: Due to the low incidence frequency of melanoma in Italy, recruitment of cases and kindreds through individual centers generally yields small numbers. We have therefore initiated an...
Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been i... more Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF-), including dermoscopic findings of melanomas and dysplastic nevi. Methods: we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/ research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available. After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF-. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF-). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF-patients, whose most prevalent pattern was the multicomponent. Conclusions: MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF-patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.
background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, ca... more background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. Methods CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. the carriers' responses were compared with responses reported in phase III clinical trials for CtLA-4 and pD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. results eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). Conclusion patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germli... more PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with ( CDKN2A +) and without ( CDKN2A–) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A–. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A– patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A– patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A– patients.
Riassunto. Negli ultimi anni il trattamento del melanoma è entrato in una nuova era grazie all'in... more Riassunto. Negli ultimi anni il trattamento del melanoma è entrato in una nuova era grazie all'introduzione dell'immunoterapia con gli inibitori dei checkpoint immunologici, in particolare con anticorpi anti PD-1, e delle terapie a bersaglio molecolare dirette verso BRAF e MEK. In assenza di studi di confronto diretto, la scelta della strategia terapeutica di prima linea deve basarsi sulle caratteristiche cliniche del paziente e su quelle biologiche del tumore. Per cercare di definire un algoritmo di trattamento dei pazienti con melanoma sulla base dei dati attualmente disponibili, abbiamo analizzato e confrontato i dati di sopravvivenza libera da progressione e sopravvivenza globale a 3 e 4 anni delle analisi per sottogruppi dei principali studi con inibitori di BRAF+MEK e anticorpi anti PD-1. Parole chiave. Adiuvante, algoritmo, immunoterapia, melanoma, terapie a bersaglio molecolare. Melanoma: which therapy for which patient. Summary. The introduction of anti PD-1 immunotherapy and BRAF+MEK-directed targeted therapy have been a breakthrough for the treatment of melanoma. Because no direct comparison exist between such strategies, the choice of front-line therapy relies on patients characteristics and tumor biology. To define an algorithm for the management of patients with high-risk or metastatic melanoma based on currently available data, we analyzed and compared 3-year and 4-year OS and PFS results from subgroup analyses of clinical trials with anti PD-1 drugs and BRAF+MEK inhibitors.
Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcom... more Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes. Results: A total of 1,395 patients were included. Primary tumors included non–small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07–1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03–1.43) independent of numb...
Considering the continuously expanding indication for ICI therapy, these findings are of the utmo... more Considering the continuously expanding indication for ICI therapy, these findings are of the utmost importance to ensure effective utilization of this therapy during and beyond the SARS-CoV-2 global pandemic.
ImportanceThe association of immune checkpoint inhibitors (ICIs) with patient quality of life has... more ImportanceThe association of immune checkpoint inhibitors (ICIs) with patient quality of life has been poorly explored.ObjectiveTo evaluate patient-reported outcomes (PROs) assessed in randomized clinical trials (RCTs) of immunotherapy-based treatments.Data SourcesThis systematic review and random-effects meta-analysis used RCTs identified in PubMed, MEDLINE, Embase, and Scopus from database inception to June 1, 2021.Study SelectionA total of 2259 RCTs were identified that assessed ICIs as monotherapy or in combination with chemotherapy or combined with another ICI and/or targeted therapy vs control groups not containing immunotherapy in patients with advanced solid tumors. Studies were reviewed independently by 2 authors.Data Extraction and SynthesisThis meta-analysis followed the PRISMA guidelines and recommendations of the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium.Main Outcomes and MeasuresThe coprimary ai...
BackgroundTo evaluate the capability of basal and one-month differed white blood cells (WBC), neu... more BackgroundTo evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response toimmune checkpoint inhibitors (ICI) in metastatic melanoma (MM).MethodsWe performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve.ResultsAt baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neu...
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Papers by Paola Queirolo