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Background: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM., Methods: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS)., Results: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed., Conclusion: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44)., (© 2024. Society of Surgical Oncology.)

Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients., Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C)., Results: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76)., Conclusions: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).

Background: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab., Methods: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study., Results: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQ-Brain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab., Conclusions: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL., Competing Interests: Declaration of Competing Interest AMDG has served as a consultant and/or advisor to Incyte, Pierre Fabre, Glaxo Smith Kline, Bristol-Myers Squibb, Merck Sharp Dohme, Sunpharma, Immunocore and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre and Sanofi; VCS has served as advisor to Merk Serono, Novartis, and Pierre Fabre and has received travel accommodation from Bristol-Myers Squibb, and Pierre Fabre and has received personal fees as invited speaker from Sanofi, Merck Sharp Dohme, and Pierre Fabre; MDV has served as consultant and/or advisor to Bristol-Myers Squibb, Merck Sharp Dohme, Novartis, Pierre Fabre, Sanofi, and Roche; PFF has served as consultant and/or advisor to Bristol-Myers Squibb, Pierre Fabre, Merck Sharp Dohme, Roche and Novartis; MG has served as a consultant and/or advisor to Bristol-Myers Squibb, Merck Sharp Dohme, and Novartis; PQ has served as consultant and/or advisor to Bristol-Myers Squibb, Merck Sharp Dohme, Novartis, Roche, Pierre Fabre, and Igea and has received personal fees as invited speaker from Bristol-Myers Squibb, Merck Sharp Dohme, Novartis, Roche, Pierre Fabre, and Igea; M Guidoboni has served as consultant and/or advisor to Bristol-Myers Squibb, Merck Sharp Dohme, Novartis, Pierre Fabre and has received grant support from Merck Sharp Dohme; PM has served as a consultant and/or advisor to Roche, Bristol-Myers Squibb, Novartis, Pfizer, Merck Sharp Dohme, AstraZeneca and has received research funding from Bristol-Myers Squibb, Novartis, Pfizer, Merck Sharp Dohme, AstraZeneca, Boehringer, Celgene, and Roche; LC has served as consultant and/or advisor to Bristol-Myers Squibb, Roche, and Merck Sharp Dohme, and has received compensated educational activities from Bristol Myers Squibb, AstraZeneca and Sanofi; RD has served as a consultant and/or advisor to Merck Serono, Sciclone Pharmaceuticals, and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre; MM has served as consultant and/or advisor to Bristol-Myers Squibb, Pierre Fabre, Merck Serono, Sanofi Aventis and Novartis, and has received grant support from Novartis; M Maio has served as a consultant and/or advisor to Roche, Bristol-Myers Squibb, Merck Sharp Dohme, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, Glaxo Smith Kline, Sciclone, Sanofi, Alfasigma, and Merck Serono; M Maio, RC, and AC own shares in Epigen Therapeutics, Srl. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy., (© 2024. The Author(s).)

Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients does not respond to immune and/or targeted therapies owing to primary and acquired resistance, high-grade immune-related adverse events, and a lack of alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay on the basis of a drop-out genetic screen in metastatic melanoma patient-derived xenografts. We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of AURKA and MAPK/extracellular signal-regulated kinase kinase employing the combination of alisertib and trametinib is highly effective in a cohort of metastatic melanoma patient-derived xenografts, both ex vivo and in vivo. Alisertib and trametinib combination therapy outperforms standard-of-care therapy in both BRAF-mutant patient-derived xenografts and targeted therapy-resistant models. Furthermore, alisertib and trametinib treatment modulates several critical cancer pathways, including an early metabolic reprogramming that leads to the transcriptional upregulation of the fatty acid oxidation pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed, the triple combination of alisertib and trametinib with the fatty acid oxidation inhibitor etomoxir proved to be further beneficial, inducing tumor regression and remarkably prolonging the overall survival of the mice., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile., Materials and Methods: From November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%)., Results: After a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis-free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3-4 occurred in 11.5% of patients., Conclusion: This paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma., Methods: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype., Results: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup., Conclusion: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

Purpose: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma., Methods: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 10 6 plaque-forming unit (PFU) followed by ≤ 4 × 10 8 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis., Results: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm., Conclusion: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Purpose: Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600 -mutant metastatic melanoma., Methods: SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic BRAFV600 -mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication., Results: A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged., Conclusion: Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600 -mutant melanoma.

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration : NCT05309421 (ClinicalTrials.gov).

Introduction: Proto-oncogene KIT is the gene encoding the receptor tyrosine kinase protein KIT. Activating mutations are found in 2.9% of neoplasms, with the highest prevalence in gastrointestinal stromal tumour. Exon 17 mutations typically alter the kinase activation loop and are relatively rare, representing 11.7% of all activating KIT mutations. Recently, KIT exon 17 mutants turned out to be a potential molecular target for the type 1 kinase inhibitor avapritinib (BLU-285)., Objective: In this framework, we aimed at investigating the potential activity of avapritinib in mucosal melanoma and thymic carcinoma, two disease histologies with dismal prognosis, currently lacking evidence-based second line treatment options and in which KIT exon 17 activating mutations could represent a relevant therapeutic target., Results: In this series, we report the only four cases of patients affected by exon 17 mutant mucosal melanoma and thymic carcinoma that have been treated in Italy with avapritinib within a Compassionate Use Program. Two patients harboured mucosal melanoma and the other two were diagnosed with thymic carcinoma. We describe a differential activity of avapritinib (3/4 patients responded, 1/4 did not respond), along with possible hypotheses to justify such differences and potential implications for precision oncology., Conclusions: Taken together, the inactivity of imatinib on KIT exon 17 mutations, the general low clinical efficacy of immunotherapy, as well as the consequent formal lack of standard available and active second line systemic treatments in both mucosal melanoma and thymic carcinoma, support the implementation of avapritinib in the therapeutic armamentarium, even though further prospective evidence is warranted., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma., Methods: Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692)., Results: At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm., Conclusion: The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations., Competing Interests: Reinhard DummerHonoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, PfizerConsulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 PharmaceuticalsResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst) Georgina V. LongHonoraria: BMS, Pierre FabreConsulting or Advisory Role: Aduro Biotech, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, SkylineDx, Specialised Therapeutics, Array BioPharma, Evaxion Biotech A/S Caroline RobertConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer Hussein A. TawbiConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Genetech/Roche, Merck, Array BioPharma, Eisai, Iovance Biotherapeutics, Karyopharm Therapeutics, Boxer CapitalResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Merck (Inst), GlaxoSmithKline (Inst), Genentech/Roche (Inst), Celgene (Inst) Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics,Consulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharma Paolo A. AsciertoStock and Other Ownership Interests: PrimeVaxConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst)Travel Accommodations, Expenses: Merck Sharp & Dohme Paul D. NathanConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD, Immunocore, Pfizer, Pierre Fabre, Novartis, GlaxoSmithKline, Ipsen, 4SC, MerckSpeaker's Bureau: Bristol Myers Squibb, Novartis, MSD, Merck,Travel Accommodations, Expenses: Bristol Myers Squibb, MSD Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeaker's Bureau: Pfizer, Novartis, Pierre FabreResearch Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst)Travel Accommodations, Expenses: Orphan Europe, Pierre Fabre Caroline DutriauxHonoraria: Bristol Myers Squibb, MSD, Novartis, Pierre FabreConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Pierre FabreTravel Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre Mario MandalàHonoraria: MSD Oncology, Novartis, Pierre FabreConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre FabreResearch Funding: Novartis (Inst) Paul LoriganHonoraria: Novartis, Pierre Fabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, Oncology Education, NektarConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Novartis, NektarSpeaker's Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre Fabre, BMSTravel Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb Pier Francesco FerrucciConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, MSD Oncology, Pierre FabreResearch Funding: BMS (Inst)Travel Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb Jean Jacques GrobConsulting or Advisory Role: BMS, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, RocheSpeaker's Bureau: NovartisTravel Accommodations, Expenses: BMS, MSD Oncology, Novartis, Pierre Fabre Nicolas MeyerConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, Pierre Fabre, AbbVie, Sun Pharma, Merckle GmbHResearch Funding: Bristol Myers Squibb (Inst), MSD Oncology (Inst) Helen GogasHonoraria: Bristol Myers Squibb, MSD Oncology, Pierre Fabre, Sanofi/RegeneronConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Roche, MSD Oncology, Amgen (Inst), Novartis (Inst)Travel Accommodations, Expenses: Bristol Myers Squibb, MSD, Amgen, Pfizer Daniil StroyakovskiySpeaker's Bureau: Roche/Genentech, Bristol Myers Squibb, BioCad, AstraZenecaTravel Accommodations, Expenses: AstraZeneca, Novartis, Roche Ana AranceConsulting or Advisory Role: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, SanofiSpeaker's Bureau: Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, SanofiResearch Funding: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi, AmgenTravel Accommodations, Expenses: BMS, MSD, Novartis, Pierre Fabre, Roche, Merck, Sanofi Jan C. BraseEmployment: NovartisStock and Other Ownership Interests: NovartisPatents, Royalties, Other Intellectual Property: Coinventor on patent application Steven GreenEmployment: NovartisStock and Other Ownership Interests: Novartis Tomas HaasEmployment: NovartisStock and Other Ownership Interests: Novartis Aisha MasoodEmployment: NovartisStock and Other Ownership Interests: NovartisOther Relationship: Novartis Eduard GasalEmployment: Novartis, Innovent BiologicsLeadership: Innovent BiologicsStock and Other Ownership Interests: Novartis, Innovent Biologics, Revolution Medicines, Amgen, NateraTravel Accommodations, Expenses: Novartis, Innovent Biologics Antoni RibasLeadership: PACT Pharma, Arcus Biosciences, LutrisStock and Other Ownership Interests: Compugen, CytomX Therapeutics, Advaxis, Tango Therapeutics, PACT Pharma, Merus, ImaginAb, Lutris, Highlight Therapeutics, MapKure, 4c Biomed, Kite/Gilead, Isoplexis, Appia, Synthekine, Pluto, Inspirna, RAPT Therapeutics, ImmPACT-BioHonoraria: Merck Sharp & Dohme, Novartis, Amgen, Chugai/Roche, Genentech/Roche, Sanofi, Vedanta Biosciences, AstraZenecaConsulting or Advisory Role: Merck, Amgen, Novartis, Chugai Pharma, SanofiResearch Funding: Agilent (Inst), Bristol Myers Squibb (Inst)Patents, Royalties, Other Intellectual Property: Nonviral gene editing to Arsenal Bio Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharna, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, SandozConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, NektarSpeaker's Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaAResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst)Travel Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/RegeneronNo other potential conflicts of interest were reported.

Purpose: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes., Patients and Methods: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated., Results: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF -mutant tumors and 46%, 42%, and 22% in those with BRAF -wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed., Conclusion: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy., Competing Interests: Jedd D. WolchokStock and Other Ownership Interests: Tizona Therapeutics Inc, Adaptive Biotechnologies, Imvaq Therapeutics, Beigene, Linnaeus Therapeutics, Arsenal IO, Georgiamune, LLC, Apricity Therapeutics, Maverick Therapeutics, Trieza TherapeuticsConsulting or Advisory Role: Bristol Myers Squibb, Merck, Sellas Life Sciences, Lilly, Tizona Therapeutics, Inc, Amgen, Chugai Pharma, Adaptive Biotechnologies, Ascentage Pharma, PsiOxus Therapeutics, F-Star Biotechnology, Surface Oncology, Apricity Therapeutics, Astellas Pharma, Recepta Biopharma, Arsenal IO, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, IncDragonfly Therapeutics, Georgiamune, Kyowa Kirin Pharmaceutical, Maverick Therapeutics, Werewolf Therapeutics, Trishula Therapeutics, Idera, Imvaq Therapeutics, Bicara TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: I am a coinventor on an issued patent for DNA vaccines for treatment of cancer in companion animals. I am a coinventor on a patent for use of oncolytic Newcastle Disease virus. I am a coinventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells. I am coinventor and receive royalties for a patent for immune modulating antibodies. I am a coinventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer. I am a coinventor on a patent for Anti-CD40 agonist mAb fused to Monophosphoryl Lipid A (MPL) for cancer therapy. Alphavirus replicon particles expressing TRP2. Engineered Vaccinia Viruses for Cancer Immunotherapy. Recombinant poxviruses for cancer immunotherapy Vanna Chiarion-SileniConsulting or Advisory Role: MSD Oncology, Merck Serono, Bristol Myers Squibb, Novartis, Pierre Fabre, RocheSpeakers' Bureau: Bristol Myers Squibb, Novartis, Merck Serono, Pierre FabreTravel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre Rene GonzalezStock and Other Ownership Interests: AstraZeneca, GlaxoSmithKline, Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Procter & Gamble, SanofiConsulting or Advisory Role: AmgenResearch Funding: Millenium Pharamceuticals (Inst), Takeda (Inst), Boston Biomedical (Inst), Bristol Myers Squibb (Inst), Checkmate Pharmaceuticals (Inst), Incyte (Inst), Syndax (Inst), Roche/Genentech (Inst), Tesaro (Inst), Amgen (Inst), Morphotek (Inst), Checkmate Pharmaceuticals (Inst), Regeneron (Inst), Iovance Biotherapeutics (Inst), Nektar (Inst), Kartos Therapeutics (Inst), Taiga (Inst), Incyte (Inst), Exicure (Inst), Replimune (Inst), Alkermes (Inst), Ultimovacs (Inst), Moderna Therapeutics (Inst), OncoSec¸ Synlogic (Inst), Merck (Inst), Array BioPharma (Inst), Senhwa Biosciences (Inst), Immunocore (Inst), EMD Serono (Inst) Jean-Jacques GrobConsulting or Advisory Role: BMS, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, RocheSpeakers' Bureau: NovartisTravel, Accommodations, Expenses: BMS, MSD Oncology, Novartis, Pierre Fabre Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Christopher D. LaoConsulting or Advisory Role: Immunocore, BMSResearch Funding: Bristol Myers Squibb, Dynavax Technologies, GenentechTravel, Accommodations, Expenses: Immunocore, BMS C. Lance CoweyEmployment: Texas Oncology, US OncologyLeadership: US OncologyHonoraria: MerckConsulting or Advisory Role: Merck, Novartis, Pfizer¸ Iovance BiotherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Novartis (Inst), EMD Serono (Inst), Merck (Inst), Array BioPharma (Inst), Amgen (Inst), Regeneron (Inst), Celldex (Inst), Seattle Genetics (Inst) Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, SandozConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, NektarSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaAResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron John WagstaffHonoraria: Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, GlaxoSmithKline UK Ltd, PfizerConsulting or Advisory Role: Bristol Myers Squibb, Roche, Pfizer, Novartis, Pierre FabreSpeakers' Bureau: Bristol Myers Squibb Reinhard DummerHonoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, PfizerConsulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 PharmaceuticalsResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst) Pier Francesco FerrucciConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, MSD Oncology, Pierre FabreResearch Funding: BMSTravel, Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb Michael SmylieHonoraria: Bristol Myers Squibb, Novartis Canada Pharmaceuticals Inc, Merck, Roche Canada, Sanofi/RegeneronConsulting or Advisory Role: Merck Marcus O. ButlerHonoraria: Merck, Roche, Bristol Myers Squibb, NovartisConsulting or Advisory Role: Merck, Bristol Myers Squibb, Novartis, Immunovaccine, Immunocore, Adaptimmune, EMD Serono, GlaxoSmithKline, Genzyme, Sanofi, LaRoche Posay, Sun Pharma, Instil Bio, Iovance Biotherapeutics, Pfizer, AdaptimmuneResearch Funding: Merck, Takara BioExpert Testimony: Merck Andrew HillEmployment: Tasman OncologyStock and Other Ownership Interests: Tasman Oncology Ivan Márquez-RodasConsulting or Advisory Role: Bristol Myers Squibb, MSD¸ Novartis, Roche, Amgen, Sanofi, AstraZeneca, Merck Serono, Incyte, Bioncotech, Pierre Fabre, RegeneronTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD¸ Roche, Bioncotech John B. A. G. HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: MSD Oncology (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics (Inst), Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcel (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: MSD (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Massimo GuidoboniConsulting or Advisory Role: BMS, Novartis, Pierre FabreSpeakers' Bureau: BMS, Novartis, Pierre FabreResearch Funding: MSD Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre¸ Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA Hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor Kernenergie, Modus Outcomes, Advance Medical/Teladoc Health (Inst), Curio Science, SQZ Biotechnology, CRT Pioneer Fund LP, AdcendoResearch Funding: CoBioRes NV (Inst), Eisai (Inst), G1 Therapeutics (Inst), Novartis (Inst), PharmaMar (Inst)Travel, Accommodations, Expenses: MSD (Inst), Ipsen (Inst), Boehringer Ingelheim (Inst) Matteo S. CarlinoHonoraria: Bristol Myers Squibb, MSD, NovartisConsulting or Advisory Role: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron, QBiotics, Nektar, Eisai, OncoSec Céleste LebbéHonoraria: Roche, Bristol Myers Squibb, Novartis, Amgen, MSD, Pierre Fabre, Pfizer, IncyteConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre FabreSpeakers' Bureau: Roche, Bristol Myers Squibb, Novartis, Amgen, MSDResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Sanofi, Pierre FabreOther Relationship: Avantis Medical Systems Grant McArthurResearch Funding: Genentech/Roche (Inst), MSD (Inst), Roche (Inst) Paolo A. AsciertoStock and Other Ownership Interests: PrimeVaxConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca¸ Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics,Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Merck Sharp & Dohme Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/Regeneron,Research Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Viralytics (Inst), Nektar (Inst), Merck (Inst) Georgina V. LongHonoraria: BMS, Pierre FabreConsulting or Advisory Role: Aduro Biotech, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, SkylineDx, Specialised Therapeutics, Array BioPharma, Evaxion Biotech A/S Tuba BasEmployment: Bristol Myers Squibb (I), Merck, Fiore Healthcare Advisors (I)Stock and Other Ownership Interests: Merck Sharp & Dohme, Bristol Myers Squibb (I)Consulting or Advisory Role: Fiore Healthcare Advisors (I)Travel, Accommodations, Expenses: Merck Sharp & Dohme, Fiore Healthcare Advisors (I) Corey RitchingsEmployment: Bristol Myers SquibbStock and Other Ownership Interests: Bristol Myers Squibb James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais F. Stephen HodiEmployment: Dana-Farber Cancer InstituteLeadership: Bicara TherapeuticsStock and Other Ownership Interests: Apricity Health, Torque, Pionyr, Bicara TherapeuticsConsulting or Advisory Role: Merck Sharp & Dohme, Novartis, Genentech/Roche, EMD Serono, Sanofi, Bristol Myers Squibb, Surface Oncology, Compass Therapeutics, Partners Therapeutics, Pionyr, Torque, Rheos Medicines, Boston Pharmaceuticals, Checkpoint Therapeutics, Eisai, Bioentre, Gossamer Bio, Iovance Biotherapeutics, Trillium Therapeutics, Catalym¸ Amgen, Immunocore,Research Funding: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, Genentech/Roche, Novartis,Patents, Royalties, Other Intellectual Property: Patent pending as per institutional policy. Patent pending royalties received on MICA-related disorders application to institution per institutional IP policy. Angiopoietin-2 Biomarkers Predictive of Anti-immune checkpoint response. Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms. Methods of Using Pembrolizumab and TrebananibTravel, Accommodations, Expenses: Novartis, Bristol Myers SquibbOther Relationship: Bristol Myers Squibb, Genentech/RocheNo other potential conflicts of interest were reported.

Objectives: Parts 4 and 5 of the phase 1/2 KEYNOTE-022 study investigated the maximum tolerated dose (MTD), safety, and efficacy of pembrolizumab plus trametinib in solid tumours and BRAF wild-type melanoma., Patients and Methods: Patients received intermittent or concurrent dosing of pembrolizumab plus trametinib. Concurrent dosing was 2 or 4 weeks of trametinib run-in followed by concurrent pembrolizumab every 3 weeks (Q3W) plus trametinib once daily (QD). Intermittent dosing was 2 weeks of trametinib run-in followed by pembrolizumab plus intermittent trametinib (1 week off/2 weeks on). A 3 + 3 dose escalation was used, followed by dose confirmation., Results: Forty-two patients were enrolled. No dose-limiting toxicities (DLTs) occurred at initial dose levels (DL). At subsequent DLs, 10 of 38 evaluable patients had DLTs. For concurrent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg QD, with a 2-week trametinib 1.5 mg QD run-in (concurrent DL2a); in concurrent DL2a group, five (31%) patients had grade 3/4 treatment-related adverse events (TRAEs); the objective response rate (ORR) was 0%. ORR was 40% in concurrent DL1 and 0% in concurrent DL2b. For intermittent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 2 mg QD with a 2-week trametinib 2 mg QD run-in (intermittent DL2); in the intermittent DL2 group, seven (47%) patients had grade 3/4 TRAEs; ORR was 27%. ORR in intermittent DL1 was 33%., Conclusions: MTDs for concurrent and intermittent dosing of pembrolizumab with trametinib were identified. The combination had limited antitumour activity, numerically higher ORR with intermittent versus concurrent dosing, and manageable safety. CLINICALTRIALS., Gov Identifier: NCT02130466., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. reports serving as a consultant/adviser for Bristol Myers Squibb, AstraZeneca, Roche, Merck & Co., Inc., Kenilworth, NJ, USA, Amgen, Pierre Fabre, Alfasigma USA Inc., and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). M.S.C. reports serving as a consultant/adviser for MSD, Bristol Myers Squibb, Novartis, Amgen, Roche, Pierre Fabre, Sanofi, Merck Serono, Nektar, Regeneron, Eisai Co., Ltd., QBiotics, and Ideaya and has received honoraria from MSD, Bristol Myers Squibb, and Novartis. A.M.J. reports consultant/advisory role (recipient: his institution) for Neolukin, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol-Myers Squibb, Merck Serono, Eisai; has received research funding to his institution from Bristol-Myers Squibb, Janssen Oncology, MSD, Mayne Pharma, Roche/Genentech, Bayer, Macrogenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals; and stock and other ownership interests in Pricilium Therapeutics. E.M. reports serving as on advisory boards for MSD, Bristol Myers Squibb, Novartis, EMD Serono, and Sanofi. A.R. has received honoraria for consulting from Amgen, Chugai, Novartis, MSD, Sanofi, Vedanta, and Nurix; is a Science Advisory Board member and stockholder in Arcus, Highlight, Compugen, Merus, Rgenix, PACT Pharma, Tango Therapeutics, Apricity, ImaginAb, Isoplexis, Lutris Pharma, MapKure, and 4C Biomed; has previously been a Science Advisory Board member and stockholder in CytomX, Five Prime, RAPT, Advaxis, and Kite-Gilead; and declares institutional research grants from Agilent and Bristol Myers Squibb. P.A.A. reports serving as a consultant/advisor for Bristol Myers Squibb, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Boehringer-Ingelheim, Eisai Co., Ltd. and Regeneron; declares research funds from Bristol Myers Squibb, Roche-Genentech, and Array; and declares travel support from MSD. W.H.M. declares having received consultant fees from Bristol Myers Squibb, Merck Canada Inc., Kirkland, QC, Canada, Roche, Novartis, Amgen, and GlaxoSmithKline. M.O.B. reports serving as a consultant/advisor for MSD, Bristol Myers Squibb, Novartis, Sanofi, Pfizer, GlaxoSmithKline, Immunocore, and EMD Serono; serving as a Safety Review Board member for Adaptimmune, and GlaxoSmithKline; and receiving support for trials from MSD, Bristol Myers Squibb, Novartis, Adaptimmune, and Immunocore. P.F.F. reports serving on advisory boards for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Roche. R.Z. reports serving on advisory boards for Roche, Pfizer, and AstraZeneca; and receiving speaker payments from MSD and Bristol Myers Squibb. M.D.V. reports serving as a consultant/advisor for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. E.G. reports holding stocks in and reports receiving payment from Novartis. R.G. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S.J.D. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. E.C. was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, at the time of the study. O.H. declares having received speaker fees from Array, Pfizer, Bristol Myers Squibb, Novartis, and Sanofi Regeneron; having received consulting fees from Adura, Akeso, Amgen, Array, BeiGene, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, Merck & Co., Inc., Kenilworth, NJ, USA, Nextcure, Novartis, Sanofi Regeneron, Seattle Genetics, Tempus, and Zelluna; and contracted research for his institution from Arcus, Aduro, Akeso, Amgen, Array, Bristol Myers Squibb, CytomX, Exelixis, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance, Merck & Co., Inc., Kenilworth, NJ, USA, Moderna, Merck Serono, NextCure, Novartis, Sanofi Regeneron, Seattle Genetics, Torque, and Zelluna., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient's possible response to treatment or development of toxicities.

Purpose of Review: To review evidence on the efficacy and safety of combined BRAF-targeted therapy and immune checkpoint inhibitors in patients with BRAF-mutated metastatic melanoma., Recent Findings: Programmed death-1 pathway inhibitors administered with BRAF/MEK inhibitors showed promising anti-tumour activity in BRAF-mutated advanced melanoma and were investigated for safety and efficacy in three large international clinical trials. Although, in two out of those three randomized phase III studies, progression-free survival (PFS) did not reach statistical significance, results showed that duration of response (DOR) and overall survival (OS) were improved using combined therapy, sustaining the scientific rationale for its use at least in a subset of metastatic melanomas. However, the frequent occurrence of autoimmunity-induced toxicities should be considered since it is limiting the continuity and the wide application of these regimens. Novel treatment modalities combining targeted therapy with checkpoint inhibitors require further clinical investigation and elucidation of their effect on the immune system and cancer cell modulation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases., Patients and Methods: This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS)., Results: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths., Conclusions: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases., (©2021 American Association for Cancer Research.)

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC., Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs., Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs., Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men., (©2021 American Association for Cancer Research.)

Patients with newly resected stage II melanoma ( n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13-24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9-38.4) against placebo (median 19.05 ng/mL; IQ range 13.0-25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival ( p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44-16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.

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.

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.

Liver metastases are a major management problem; since they occur in tumors of different origin, they are often multiple, difficult to visualize and can lie dormant for many years. Patients with liver metastases usually die of their disease, mostly due to liver failure, since systemic treatments are unable to eradicate micro-metastasis, and interventional loco-regional procedures cannot treat all existing ones. Cholangiocarcinoma (CCA) is the second most common primary liver tumor, showing a poor overall prognosis. When resection is not possible, treatment options include tumor-focused or local ablative therapy, organ-focused or regional therapy and systemic therapy. We reviewed available loco-regional therapeutic options, with particular focus on the CHEMOSAT ® Melphalan/Hepatic Delivery System (CS-HDS), which is uniquely positioned to perform a percutaneous hepatic perfusion (PHP), in order to treat the entire liver as a standalone or as complementary therapy. This system isolates the liver circulation, delivers a high concentration of chemotherapy (melphalan), filters most chemotherapy out of the blood and is a repeatable procedure. Most CS-HDS benefits are demonstrated in liver-predominant diseases, like liver metastasis from uveal melanoma (UM), hepatocarcinoma (HCC) and CCA. More than 650 procedures have been performed in Europe to date, mostly to treat liver metastases from UM. In CCA, experience is still limited, but retrospective analyses have been reported, while phase II and III studies are closed, waiting for results or ongoing.

Background: 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/K -mutated 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., Competing Interests: Competing interests: PFF has received personal fees from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, New Jersey, USA (MSD). AMDG reports other from MSD during the conduct of the study; reports other from Incyte, GlaxoSmithKline, Pierre Fabre, and Sanofi outside the submitted work; and has served as an advisor and consultant for MSD, Incyte, GlaxoSmithKline, Pierre Fabre, and Sanofi. MDV has received personal fees from Novartis, MSD, and BMS outside the submitted work and has served as an advisor and consultant for MSD, BMS, Novartis, Pierre Fabre and Sanofi. VA has received personal fees and travel support from Bristol-Myers Squibb; personal fees from MSD, Merck Serono, Novartis, Pierre Fabre, Roche and Nektar; and travel support from OncoSec Medical, during the conduct of the study. HS received a research grant and personal fees from MSD and has received personal fees from Bristol-Myers Squibb, Incyte, Novartis, and Pierre Fabre outside the submitted work. PQ has received personal fees from Roche, Novartis, Bristol-Myers Squibb, MSD, Sanofi, and Pierre Fabre. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., MSD, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDx B.V. RS reports personal fees from MSD New Zealand, outside the submitted work. IMS reports other (trial expenses) from MSD. IMS has received other funds from MSD during the conduct of the study. EG is an employee and stockholder of Novartis. RG is an employee of MSD. SJD is an employee and stockholder of MSD. ESC was an employee of MSD at the time of this study. AR has received personal fees from Amgen, Chugai, Novartis, Genentech-Roche, Sanofi, and Merck and serves as an advisor for, holds stock in, and has received personal fees from Arcus, Bioncotech, Compugen, CytomX, Five Prime, RAPT Therapeutics, Merus, Rgenix, PACT Pharma, and Tango Therapeutics outside the submitted work. PAA has received grants and personal fees from Bristol-Myers Squib, Roche-Genentech, and Array BioPharma; personal fees and other from MSD; and personal fees from Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, and Boehringer Ingelheim. JS, ML, and MA-A report no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells' invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients.

Background: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma., Patients and Methods: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs., Results: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT., Conclusion: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation., (Copyright © 2020 Mannavola, Mandala, Todisco, Sileni, Palla, Minisini, Pala, Morgese, Di Guardo, Stucci, Guida, Indini, Quaglino, Ferraresi, Marconcini, Tronconi, Rossi, Nigro, Occelli, Cortellini, Quadrini, Palmieri, Pigozzo, Ascierto, Vitale, Strippoli, Ferrucci, Berardi, Randon, Cardone, Schinzari, Silvestris and Tucci.)