Introduction Les résultats de l’essai pivot multicentrique randomisé de phase 3 CheckMate 067 chez des patients atteints de mélanome avancé ont montré des améliorations de la survie sans progression et de la survie globale (OS) avec nivolumab (NIVO) plus ipilimumab (IPI) ou NIVO en monothérapie par rapport à IPI en monothérapie. Nous présentons maintenant les résultats finaux de l’étude CheckMate 067, avec un suivi minimum de 10ans, représentant la durée de suivi la plus longue jamais rapportée pour une étude de phase 3 impliquant un traitement à base d’anti-PD-1 (NIVO), toutes tumeurs confondues. Matériel et méthodes Les patients éligibles atteints d’un mélanome non résécable de stade III ou IV et naïfs de traitement (n=945) ont été répartis de manière aléatoire 1:1:1 et stratifiés selon le statut PD-L1, le statut mutationnel BRAF et le stade AJCC. Les patients ont reçu NIVO 1mg/kg+IPI 3mg/kg pour 4 doses toutes les 3 semaines, suivi de NIVO 3mg/kg toutes les 2 semaines (n=314), NIVO 3mg/kg toutes les 2 semaines+placebo (n=316), ou IPI 3mg/kg toutes les 3 semaines pour 4 doses+placebo (n=315) jusqu’à progression ou toxicité inacceptable. Le critère d’évaluation principal comprenait la survie globale avec NIVO+IPI ou NIVO versus IPI. Les critères d’évaluation secondaires comprenaient des évaluations descriptives de l’efficacité de NIVO+IPI versus NIVO seul ainsi que la tolérance. La survie spécifique au mélanome (MSS), qui exclut les décès non liés au mélanome, était un critère d’évaluation exploratoire. Résultats Avec un suivi minimum de 10ans, les données finales d’OS et de MSS de l’étude CheckMate 067 seront rapportées en incluant des détails sur toute nouvelle progression de la maladie ou décès dus au mélanome depuis les dernières clôtures des données. Les résultats dans les sous-groupes clés, en fonction du statut mutationnel BRAF, des niveaux d’expression de PD-L1 et des niveaux de lactate déshydrogénase, seront également présentés. Nous actualiserons enfin les données de tolérance. Discussion Il s’agit des résultats finaux de l’étude historique CheckMate 067, représentant le suivi le plus long de tous les essais de phase 3 portant sur une thérapie à base d’anti-PD-1 en première ligne, tous types de tumeurs confondus. Conclusion Cet essai a permis à l’association NIVO+IPI et à la monothérapie NIVO de devenir des traitements de référence pour les patients atteints d’un mélanome avancé, en transformant leur pronostic et leur survie. Nous nous attendons à ce que ces données à 10ans de suivi renforcent les conclusions précédentes de l’étude CheckMate 067.Previously presented at ESMO 2024, “FPN LBA43”, “James Larkin et al.” - Reused with permission.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care.

•First analysis of predictive and prognostic role of PD-(L)1 SNVs in 125 advanced melanoma patients treated with anti-PD-1.•PD-L1 +8293 C/A genotype and PD1.5 T allele associated with lower risk of irAEs.•Survival benefit observed in patients harbouring the PD1.7 C/C genotype.

D + T has shown long-term efficacy and a well-characterised safety profile in pts with BRAF-mutant melanoma in clinical trials; however, real-world evidence (RWE) is limited. ePROs compiled with digital solutions can allow for collection of symptom data, prompt reaction to medical events, and improved quality of life (QOL). Novartis and Kaiku Health codeveloped a platform for pts with high-risk stage III or unresectable/metastatic BRAF V600E/K–mutant melanoma to describe PROs during treatment with D + T and provide pt educational materials. 40 to 100 pts will be enrolled during treatment with D + T and followed for ≥ 6 mo to collect longitudinal PRO and clinical data. The primary endpoint is incidence of key symptoms such as fever, chills, fatigue, and nausea. Secondary endpoints include frequency, severity, and duration of symptoms; platform feasibility and impact on treatment interruptions and/or reductions and time on treatment; and machine learning (ML) modelling aimed at predicting symptom onset and continuity. At data cutoff for the interim analysis (22 Mar 2022), 49 pts were enrolled from 5 sites. The adoption rate was 92%, with 45/49 invited pts registered, with 66% using the module for ≥ 12 wk. The majority (65%) used mobile versions, and 76% read electronic educational materials. 39/45 pts reported a total of 7217 symptoms using the module with a 71% average weekly compliance, and 39 pts completed ≥ 1 QOL questionnaire. Median time spent on questionnaires ranged from ≈ 2-3 minutes. Common symptoms were fatigue (82%), headache (56%), cough (51%), and muscle pain (51%). 10 pts reported 19 cases of acute fever and were monitored using a fever management algorithm until resolution. ML models predicted symptom onset and continuity for 9 symptoms with good to excellent performance. Interim data suggest that modules are supporting pts while generating RWE, which opens the possibility of understanding safety profiles and QOL in this setting. Continued data collection and investigation of ML aim to better predict symptoms for earlier intervention.

Primary analysis of the phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line combination treatment with A+V+C vs P+V+C in patients (pts) with previously untreated BRAFV600 mutation–positive advanced melanoma. At the time of primary analysis (median follow-up 18.9 months), numerically lower rates of interval development of CNS mets were also seen with A+V+C vs P+V+C. Here we report updated exploratory analyses of incidence and time to development of CNS mets with A+V+C vs P+V+C with longer follow-up in the IMspire150 study. Eligible pts were randomized 1:1 to receive A+V+C or P+V+C. Pts received V+C in cycle 1; A or P were given on day 1 and 15 of each 28-day cycle starting from cycle 2 onwards. Incidence and time to development of CNS mets were evaluated in pts with no history of CNS mets at baseline confirmed by magnetic resonance imaging/computed tomography (MRI/CT). Follow-up MRI/CT assessments were performed during the study as clinically indicated. Time-to-event outcomes were estimated using the Kaplan-Meier method and competing risks analysis. 514 pts were randomly assigned to A+V+C (n=256) or P+V+C (n=258); 244 and 247 pts, respectively, had no history of CNS mets at baseline. With median follow-up of 29.8 months in the A+V+C arm and 22.8 months in the P+V+C arm, CNS mets had developed in 61/244 pts (25%) in the A+V+C arm and 70/247 pts (28%) in the P+V+C arm. Cumulative incidence of CNS mets as site of first progressive disease with A+V+C vs P+V+C was 16% vs 19%, 24% vs 26%, 25% vs 28%, and 28% vs 29% at 12, 24, 36, and 48 months, respectively (stratified hazard ratio [HR] 0.91; 95% CI, 0.64-1.29). Time to first CNS mets was delayed with A+V+C vs P+V+C (HR 0.80; 95% CI, 0.57-1.13). Median time from first detection of CNS mets until death was similar between A+V+C and P+V+C (median 5.3 vs 5.2 months; HR 0.96; 95% CI, 0.65-1.41). Addition of A to V+C is associated with numerically lower rates for development of CNS mets. The observed risk reduction for CNS mets is consistent with the overall benefit observed for A+V+C in the IMspire150 study.

Background: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date. Materials and methods: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors. Results: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together. Conclusions: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

Cemiplimab is the first approved systemic treatment for patients with advanced cutaneous squamous cell carcinoma (cSCC). We have already reported previously acute toxicities and overall responses from a real-world experience of 18 Italian centers. We analyzed the long-term follow up of the 134 patients previously analyzed in the retrospective, observational study REAL CEMI. We assessed late toxicities rate, considering treatment-related adverse events (trAEs) that occurred after at least 6 months since cemiplimab start, the updated objective response rate (ORR) and disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). We explored correlations between clinical outcomes and baseline clinical-pathological characteristics, and we carried out a descriptive analysis of patients who obtained a complete response (CR). At a median follow up (range 1-32) of 14 months, cemiplimab was ongoing in 29 patients (21,6%) with a median duration of treatment of 7 months (1-29+). Late trAEs occurred in 11,2% of cases, with a median time to onset of 12 months. Most of them were grade (G) 1/2 (73,3%), but two patients stopped cemiplimab due to a late adverse event (G3 maculopapular rash pemphigoid-like and G3 nausea and vomiting). Updated ORR was 58,9% and DCR was 72,4%. Median PFS was 9 (95% confidence interval (CI) 2.45-15.55) months and median OS was 21 (95% CI 9.41-32.59) months. In the multivariate analysis, the best response obtained, and Performance Status were found to be significantly related to both PFS and OS, while chronic intake of steroids was only related to PFS. Considering the subgroup of 26 (19,4%) patients with CR: median time to CR was 4 months (1-23) and median duration of treatment after obtaining CR 8 months (0-35+); at the data cut-off, 19 (73,1%) patients had stopped treatment with cemiplimab, and all these patients had ongoing complete response. At a longer follow up of a real-world study, the activity of cemiplimab is confirmed, with a relatively low number of late toxicities. However, some trAEs may occur even after several months from the start of treatment. Complete response is often maintained for long time.

Background: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. Methods: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. Results: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. Conclusions: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

Current standard of care for patients (pts) after resection of high-risk stage II melanoma is observation. In the phase 3 double-blind KEYNOTE-716 trial we evaluated pembrolizumab (pembro) versus placebo in pts with resected AJCC-8 stage IIB or IIC melanoma. We present results of the first recurrence-free survival (RFS) interim analysis. Eligible pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma with negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (up to 1 year). Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. The primary endpoint was RFS per investigator assessment. Safety was also evaluated. The data cutoff date for the interim analysis was December 4, 2020. Overall, 976 pts (64% stage IIB; 34.8% stage IIC) were randomized (487 pembro; 489 placebo). At median follow-up of 14.4 months, pembro significantly prolonged RFS vs placebo (HR 0.65, 95% CI 0.46-0.92; P=0.00658; median not reached for both). 54 (11.1%) vs 82 (16.8%) pts had a recurrence with almost halving of distant recurrence events in the pembro (23) vs placebo (38) group. The 12-month RFS rate was 90.5% vs 83.1%. Grade ≥3 any-cause AEs occurred in 125 (25.9%) vs 83 (17.1%) pts in the pembro vs placebo group. Grade ≥3 drug-related AEs occurred in 78 (16.1%) vs 21 (4.3%) pts; 74 (15.3%) vs 12 (2.5%) discontinued due to a drug-related AE. No deaths due to any-cause AE or drug-related AEs occurred with pembro; four deaths due to any-cause AEs occurred with placebo. Immune-mediated AEs occurred in 36.2% vs 8.4%, most commonly hypothyroidism (15.7% vs 3.5%) and hyperthyroidism (10.4% vs 0.6%). Most were grade 1-2 in severity. Adjuvant pembrolizumab for resected stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo and was associated with significantly prolonged RFS and a favorable benefit-risk profile.

Background: In our previous works, we demonstrated that patients' sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors. Here, we assessed the sex-based heterogeneity of efficacy of anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) given as monotherapy, for advanced non-small-cell lung cancer (NSCLC) expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. Methods: We carried out a systematic review and meta-analysis including all randomized, controlled trials testing anti-PD-1/anti-PD-L1 drugs inmonotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) log [hazard ratio (HR)] reported in male and female study participants. Results: We analyzed four randomized, controlled trials, including 1672 patients, of whom 1224 (73.2%) were men and 448 (26.8%) were women. The pooled OS-HR comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 [95% confidence interval (CI), 0.50-0.69] for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS-HRs reported in men versus women was 0.71 (95% CI, 0.52-0.98; P-heterogeneity: 0.04), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male patients (Q = 2.39, P = 0.50, I-2 = 0%) or in female patients (Q = 1.13, P = 0.50, I-2 = 0%). Conclusion: Evidence available indicates anti-PD-1/anti-PD-L1 monotherapy as highly effective in men but not in women, even in NSCLCs expressing high PD-L1 levels. Prospective trials testing sex-based tailored immunotherapy strategies are needed.

Background A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients. Objective We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents. Methods One-hundred-twenty-three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated. Results Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (<= 12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi. Conclusion Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

Chronic hyperglycemia is known to induce immune dysfunctions and multiple studies has identified resistance/adherence to insulin therapy as barriers to achieving an optimal glycaemic control in patients with diabetes mellitus (DM) after front line metformin failure. How DM affects the efficacy of immune checkpoint inhibitors (ICI) is yet to be defined.

The long-term impact of COVID-19 in cancer patients (pts) is undefined. Among 2795 consecutive pts with COVID-19 and cancer registered to OnCovid between 01/2020 and 02/2021, we examined clinical outcomes of pts reassessed post COVID-19 recovery. Among 1557 COVID-19 survivors, 234 (15%) reported sequelae including respiratory symptoms (49.6%), fatigue (41%) and cognitive/psychological dysfunction (4.3%). Persisting COVID-19 sequelae were more likely found in males (p=0.0407) aged ≥65 years (p=0.0489) with ≥2 comorbidities (p=0.0006) and positive smoking history (p=0.0004). Sequelae were associated with history of prior hospitalisation (p<0.0001), complicated disease (p<0.0001) and COVID-19 therapy (p=0.0002). With a median post-COVID-19 follow up of 128 days (95%CI 113-148), multivariable analysis of survival revealed COVID-19 sequelae to be associated with an increased risk of death (HR 1.76, 95%CI 1.16-2.66) after adjusting for sex, age, comorbidities, tumour characteristics, anticancer therapy and COVID-19 severity. Out of 473 patients who were on systemic anticancer therapy (SACT) at COVID-19 diagnosis; 62 (13.1%) permanently discontinued therapy and 75 (15.8%) received SACT adjustments, respectively. Discontinuations were due to worsening performance status (45.1%), disease progression (16.1%) and residual organ disfunction (6.3%). SACT adjustments were pursued to avoid hospital attendance (40%), prevent immunosuppression (57.3%) or adverse events (20.3%). Multivariable analyses showed permanent discontinuation to be associated with an increased risk of death (HR 4.2, 95%CI: 1.62-10.7), whereas SACT adjustments did not adversely affect survival. Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely influence survival and oncological outcomes after recovery. SACT adjustments can be safely pursued to preserve oncological outcomes in patients who remain eligible to treatment.

The phase III IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line A vs placebo (P) combined with V+C in patients (pts) with BRAFV600 mutation–positive advanced melanoma. Safety profiles of A and V+C partially overlap. Here we report incidence, time course, and outcomes of select AEs of special interest (AESIs) in IMspire150. 514 pts were randomized 1:1 to A+V+C or P+V+C. Pts received V+C from cycle 1; A or P was added from cycle 2 onward. Incidence (overall and by cycle), time to onset/resolution, and recurrence of select AESIs were evaluated in the safety population (A+V+C, n=230; P+V+C, n=281). Rash and hepatitis were analyzed as overall combined medical concepts. Median follow-up was 18.9 mo. AESI rates were numerically higher with A+V+C vs P+V+C (rash, 81% vs 77%; elevated creatine phosphokinase [eCPK], 53% vs 47%; pyrexia, 49% vs 35%; and hepatitis [clinical diagnosis and asymptomatic lab abnormalities], 53% vs 38%), excepting diarrhea (50% vs 56%). Incidences of diarrhea, rash, and eCPK were highest in cycle 1 and decreased thereafter. Incidences of pyrexia and hepatitis peaked in cycle 2 after addition of A in the A+V+C arm then similarly declined. Median time to onset was similar with A+V+C vs P+V+C for diarrhea (0.4 vs 0.4 mo) and rash (0.5 vs 0.4 mo), but was numerically longer with A+V+C for eCPK (1.4 vs 0.7 mo), pyrexia (1.2 vs 0.7 mo), and hepatitis (1.6 vs 1.2 mo). Median time to resolution was similar between arms (diarrhea, 0.3 vs 0.2 mo; rash, 0.8 vs 0.8 mo; eCPK, 0.5 vs 0.5 mo; pyrexia, 0.1 vs 0.1 mo; hepatitis, 0.7 vs 0.7 mo). In pts who had first occurrence of an AESI with A+V+C vs P+V+C, incidences of recurrent AESIs were diarrhea (58/115 vs 64/157), rash (65/187 vs 62/215), eCPK (62/121 vs 61/133), pyrexia (53/112 vs 29/98), and hepatitis (38/122 vs 25/107). Recurrent AESIs were generally grade 1/2 with median times to recurrence of 0.8-1.5 mo. These data indicate that key AESIs with A+V+C occur early during treatment; are manageable, with resolution times similar to those with V+C; and have low to moderate risk of recurrence. Recurrent AESIs are generally mild to moderate in severity with no evidence of cumulative effect.

At present, the standard treatment for NRAS mutated MM is the same as for BRAF wild type MM with immune checkpoint inhibitors (ICIs) used as first line. It is thought that NRAS mutation is associated with better outcomes to immunotherapy. Nevertheless, retrospective studies reported controversial findings. To better understand the predictive role of NRAS mutation to ICIs, we assessed retrospectively clinical outcomes in two cohorts of pts homogeneously treated with ICIs as first line therapy: NRAS mutated/BRAF wild type MM (mut/wt) and NRAS wild/BRAF wild type MM (wt/wt). A total of 331 pts including 163 mut/wt and 168 wt/wt were recruited in 11 Centres in Italy. The main evaluated pts features included: sex, age, origin and characteristics of primary cancer, previous adjuvant therapy, ECOG PS, M stage, metastatic sites, lactate dehydrogenase (LDH) level, basal count of white blood cells, lymphocyte and platelet, and subsequent therapies. In the wt/wt population, 35 pts received ipilimumab, 131 antiPD-1or antiPD-L1 and 2 the combination of both. In the cohort mut/wt, 45 patients received ipilimumab, 115 antiPD-1 and 3 the combination. As regard the primary, mut/wt was more frequently ulcerated (p.0038) and arose more frequently on the trunk (p.003) with respect wt/wt. At the onset of advanced stages, mut/wt had a higher M1c rate (p.001) involving less frequently lung (p.007) and brain (p.011) and progressing less to the brain if case be so (p.011). There was no significant difference in ORR, PFS and OS between the two groups (41.4%, 11 months [6-20, 95% CI] and 32 months [23-61, 95% CI] in mut/wt and 36,1%, 9 months [6-17, 95% CI] and 27 months [16-35, 95% CI] in wt/wt). Univariate analysis across the entire population showed a better ORR significatively associated with normal LDH, <3 sites of metastases, N/L ratio under 2.5 and the use of antiPD-1 than antiCTLA-4. A longer PFS and OS were also correlated with normal LDH, <3 sites of metastases, N/L ratio <2,5, lower platelet count and the use of antiPD-1 than antiCTLA-4. We provide evidence that ICIs used as first line therapy are equally effective in mut/wt and wt/wt MM.

The aim of neo-adjuvant therapy in locally advanced or oligometastatic melanoma is to facilitate radical resection, improve outcomes and undertake research to identify biomarkers of response and resistance. Recently, pathological response has been indicated as a surrogate of survival. We investigate the efficacy of Ipilimumab/Nivolumab combination as primary treatment of locally advanced or oligometastatic melanoma patients (pts), within an open label, single arm, two centres study. Treatment schedule consists in 4 neoadjuvant cycles of Ipilimumab 1 mg/kg and Nivolumab 3 mg/kg every 3 weeks, followed by surgery and adjuvant Nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective is pathological complete remission (pCR) rate. Secondary objectives are: safety, feasibility and efficacy; health related quality of life; identification of molecular and immunological biomarkers of response and resistance (somatic genetic drivers, tumor mutational burden (TMB), mutational signatures, predicted neoantigens, germline HLA typing, somatic HLA mutations and liquid biopsy); degree of immune activation; evaluation of microbioma. From March 2019, 26 out of 35 pts were enrolled. In the ITT population (22 pts), 21 pts were stage III and 1 stage IV-M1b cutaneous melanoma; 17 pts concluded neoadjuvant therapy and received surgery; 4 pts concluded the adjuvant treatment. pCR was reached in 9/17 (52%), pathological partial remission in 4/17 (24%) and pathological no response (pNR) in 4/17 (24%) pts. With a median follow-up of 5 months, all pts are alive; one, with pNR at surgery, relapsed during adjuvant phase. In the neoadjuvant phase 4 pts (18%) developed G3-4 adverse events (AE): 2 transaminitis, 1 myocarditis and 1 asyntomatic CPK increase after 4, 3 and 2 cycles; 3 of them underwent to surgery after toxicity resolution. No G3-4 AE were observed during adjuvant phase. Primary Ipilimumab/Nivolumab is effective and feasible, showing high pCR rate. Toxicity was superimposable to that already observed with this schedule. Longer follow-up is needed to assess a correlation between pathological response and survival. Translational data will be available and presented at ESMO.