Risultati per: Linee guida sul melanoma cutaneo

Gli obiettivi di Curigliano, nuovo presidente eletto di Esmo

Gli obiettivi di Curigliano, nuovo presidente eletto di Esmo

Caressa e Bergomi, in ogni campo fondamentale gioco di squadra

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.

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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.