Risultati per: Raccomandazioni cliniche per il melanoma cutaneo

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This genome-wide association study meta-analysis evaluates whether differences in risk of in situ melanoma and invasive melanoma are heritable.

Heritability is a factor that has been demonstrated to be strongly associated with the diagnosis of cutaneous melanoma, and there are several inherited gene variants that have been identified as melanoma risk alleles. Previous studies have mainly focused on invasive melanoma or on melanoma irrespective of invasiveness. In this issue of JAMA Dermatology, Ingold et al present their investigation on the influence of germline genetic variation on the risk of developing in situ vs invasive melanoma. The study by Ingold et al is a notable attempt to unravel a complicated biology as melanoma in situ traditionally is considered as a precursor to invasive melanomas, and the idea that these lesions in a sense represent different class of tumors with different etiology is unproven. The authors conducted this study using 5 different datasets of populations with European ancestry (from the UK, Finland, and Australia), with more than 10 000 and more than 3000 patients in total with invasive and in situ melanomas, respectively, together with more than 500 000 controls. The study is a meta-analysis of the different cohorts, assessing associations between common single-nucleotide variant (SNV) genotypes, comparing (1) invasive melanoma with controls, (2) in situ melanoma with controls, and (3) invasive melanoma with in situ melanoma (case-case analysis). Further, 3 separate bioinformatics approaches were applied: (1) genome-wide association study (GWAS) to identify significant chromosomal risk loci, (2) polygenic risk score (PRS) analyses based on 64 497 SNVs to identify joint score combining identified variants that had a P value threshold less than .10 in the case-case GWAS meta-analysis, and (3) SNV-based heritability, which is a method to assess how much of the variation in a trait can be explained by the cumulative effect of SNVs.

Objective
This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).

Design, setting and participants
This is a phase 1–1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion.

Interventions
Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation.

Outcome measures
The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab.

Results
33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study.

Conclusions
Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types.

Trial registration number
NCT02608268.

The recommendations for treating invasive melanoma have evolved dramatically during the past century. The surgical practices of radically wide margins and amputations were abandoned when evidence from randomized clinical trials (RCTs) showed that surgical margins as narrow as 1 cm were safe for most melanomas. In contrast, the recommendations for surgical margins for melanoma in situ (MIS) are not based on RCTs and exist with some controversy. The earliest recommendations of a 5-mm surgical margin for MIS was suggested by the National Institutes of Health by a panel of dermatologists in 1991 based on their experience rather than scientific evidence, and this became the recommended excision margin adopted by many national and international groups writing clinical guidelines. At the same time, the experience of Mohs surgeons and others looking carefully at the width of surgical margins necessary to achieve negative histologic margins led to a different conclusion. Multiple studies from various institutions showed that MIS often extends beyond a 5-mm clinical margin, and wider margins were necessary to avoid local recurrence and tumor progression. Although no RCTs were performed to my knowledge, the preponderance of evidence from these sources came to the same conclusion that margins wider than 5 mm for MIS are necessary to provide negative histologic margins in 97% of real-world lesions of MIS. However, the controversy continued about surgical margins for subgroups of MIS based on histology (MIS vs lentigo maligna), location (head and neck vs trunk and extremity), and other clinical parameters. Today, most clinical guidelines recommend a range of margins of 0.5 to 1 cm for all MIS, noting that the goal of excision is negative histologic margins.

This case series investigates the recurrence rate of melanoma in situ treated with a 5-mm margin in low-risk body sites.

This Viewpoint discusses use of anti–PD-1 monotherapy as the primary treatment option for patients with treatment-naive metastatic melanoma staining positive for PD-L1 over dual checkpoint inhibition therapy.

New England Journal of Medicine, Ahead of Print.

New England Journal of Medicine, Ahead of Print.

This case series describes a constellation of novel adverse reactions in 3 of 9 patients with uveal melanoma receiving treatment targeting activity of the Brahma-associated factor chromatin remodeling complex.

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