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Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials., (©2024 The Authors; Published by the American Association for Cancer Research.)

The management of brain metastases, a potentially devastating complication of advanced cancers, has become increasingly complex with advancements in local and systemic therapies. Improved outcomes and extended survival for patients with metastatic solid tumors have led to a surge in the prevalence and possibly incidence of brain metastases, affecting up to 40% of individuals with solid tumors. Enhanced imaging technologies contribute to more accurate and early detection, shaping the understanding of the intricate landscape of this condition. Traditionally, surgery and radiation stood as the mainstays of treatment because of the limited efficacy of systemic therapies within the brain. However, emerging clinical data, particularly in melanoma, lung, and breast cancers, reveal promising results with novel systemic treatments such as immunotherapy and targeted therapies. Despite the historical exclusion of patients with active brain metastases from clinical trials, a shift is occurring toward a more inclusive approach. This chapter delves into the multifaceted challenges associated with managing brain metastases, with a focus on the evolving landscape of systemic approaches as well as the intricacies of shared decision making, providing a comprehensive overview of the current state and future directions in navigating the complexities of brain metastases management.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: Development of brain metastasis is one of the most serious complications of advanced melanoma, carrying a significant burden of morbidity and mortality. Although advances in local treatment modalities such as stereotactic radiosurgery and breakthrough systemic therapies including immunotherapy and targeted therapies have improved the outcomes of patients with metastatic melanoma, management of patients with melanoma brain metastases (MBMs) remains challenging. Notably, patients with MBMs have historically been excluded from clinical trials, limiting insights into their specific treatment responses. Encouragingly, a growing body of evidence shows the potential of systemic therapies to yield durable intracranial responses in these patients, highlighting the need for inclusion of patients with MBMs in future clinical trials. This is pivotal for expediting the advancement of novel therapies tailored to this distinct patient population. In this review, we will highlight the evolving landscape of MBM management, focusing on local and systemic treatment strategies., Competing Interests: Conflicts of Interest and Sources of Funding: A.A. has no conflicts of interest to report. H.A.T. reports consulting or advisory roles for Bristol Myers Squibb, Merck, Novartis, Medicenna, Iovance, Eisai, Pfizer, Karyopharm and Roche; and research funding from Bristol Myers Squibb, Novartis, Dragonfly Therapeutics, GlaxoSmithKline, Merck, and Roche., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAF V600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others., Competing Interests: Competing interests: CA—Other: Stock Pfizer, Advisory Board: Iovance and Merck, Memorial Sloan Kettering Cancer Center. EIB—Consulting Fees: Nektar, Instilbio, Novartis, Xilio, Sanofi, Merck, and Iovance. DD—IP Rights: US Patent 63/124,231, Compositions and Methods for Treating Cancer, December 11, 2020, US Patent 63/208,719, Compositions and Methods For Determining Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer, June 9, 2021; Consulting Fees: Checkmate Pharmaceuticals, Finch, Shionogi, Vedanta Biosciences; Fees for Non CE Services: Medical Learning Group (MLG), Clinical Care Options (CCO); Contracted Research: Arcus, Checkmate Pharmaceuticals, CellSight Technologies, Immunocore, Merck, Tesaro/GSK. GTG—Consulting Fees: Bristol Myers Squibb, Regeneron, Genentech, Novartis, Merck, Sapience Therapeutics, Exicure, Eisai, Iovance Biotherapeutics, Lyell Immunopharma, and HUYABIO International; Contracted Research: Exelixis (institutional support), Lucerno Dynamics. OH—Researcher: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, Cytomx, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Regeneron, Seattle Gen, Torque, Zelluna; Consultant Advisor Speaker: Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche Genentech, Georiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Gen, Tempus, Vial Health Tech, Zelluna; Independent Contractor: Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche Genentech, Georiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Gen, Tempus, Vial Health Tech, Zelluna; Publically Traded Stocks: Bactonix. TJH—Contracted Research: Genentech, SkylineDX. BI—Consulting Fees: Johnson & Johnson, Volastra Therapeutics, Merck, AstraZeneca, Eisai and Janssen Pharmaceuticals; research funding to Columbia University from Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, and Synthekine. DBJ—IP Rights: MHC-II for use as immunotherapy biomarker, Abatacept as treatment for irAEs; Consulting Fees: BMS, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoIngineering, Novartis, Oncosec, Pfizer, Targovax; Contracted Research: BMS, Incyte. RPK—Consulting Fees: Regeneron. JJL—Researcher: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Consultant Advisor Speaker: AbbVie, Agenus, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine 7 Hills, Affivant, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest, AbbVie, Agenus, Amgen, Immutep, Evaxion. TCM—Consulting Fees: Merck, BMS, GigaGen, OncoSec; Pfizer – Scientific Advisory Board. MJM—Consulting Fees: AstraZeneca, Nektar Therapeutics, Istari Oncology, Immunai, Xilio Therapeutics; Fees for Non CE Services: Bristol Myers Squibb (served as a speaker). ACP—Consulting Fees: Regeneron, BMS, Merck; Fees for Non CE Services: BMS; Contracted Research: Merck, BMS, Iovance, Regeneron, Takeda, Ideaya, Replimune: All payments to institution. KMR—Consulting Fees: BMS, Merck, Eisai, Immunocore. AKSS—Consulting Fees: Novartis, Pfizer, Regeneron, Iovance. Contracted Research: Ascentage, Ideaya, Regeneron, Bristol Myers Squibb, Immunocore, Merck, Nektar, Olatec, Replimune, Seagen. KS—Contracted Research: Trials at Norris Cotton Cancer Center, Syndax, Provectus, OmniSeq, BrightPath Biotherapeutics, Ludwig Institute of Cancer Research, Hlsinn, AbbVie, BMS, OncoSec, Ultimovacs, Altellas, AstraZeneca, Xencor, Exicure, Numab, Checkmate Pharmaceuticals, Natera. RJS—Reseracher: Merck (research funding); Consultant Advisor Speaker: BMS, Merck, Novartis, Pfizer; Other: Faculty for SCION Workshop. JT—Consulting Fees: GSK, Genentech, BMS, Akoya Biosciences, Merck, AstraZeneca, Compugen, Lunaphore; Contracted Research: BMS, Akoya Biosciences; Other: Akoya Biosciences; Other Details: Patent pending for multiplexing imaging strategy; Ownership Interest Less Than 5 Per Cent: Akoya Biosciences. HAT—Consulting Fees: Genentech, BMS, Novartis, Merck, Eisai, Karyopharm, Boxer Capital, Iovance, Jazz Pharmaceuticals, Medicenna; Contracted Research: Genentech, BMS, Novartis, Merck, GSK, EMD Serono, Eisai, Dragonfly Therapeutics, RAPT Therapeutics. JKT—Nothing to Disclose. CV—Nothing to Disclose. SAW—Consulting Fees: Lyell; Contracted Research: research funds to institution from BMS and Apexigen. MKW—Consulting Fees: Merck, Pfizer, Bristol Myers Squibb, Regeneron, EMD-Serono, ExiCure, Castle Biosciences, Adagene. SITC Staff—CG, AK, NL, SM-W—Nothing to Disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression., Objective: To characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma., Design, Setting, and Participants: This single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment-naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021., Main Outcomes and Measures: Fecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups., Results: A total of 228 participants were enrolled (126 men [55.3%]; median age, 59 [range, 21-90] years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P < .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 [IQR, 9.8-23.0] vs 10.8 [IQR, 7.2-16.8]; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P < .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy., Conclusions and Relevance: The findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention.

For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes., Methods: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME)., Results: A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important., Discussion: The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI., Competing Interests: IA, BM, PS, IV, BS, HF, RS, and TC were employed by the company NEC OncoImmunity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Anzar, Malone, Samarakoon, Vardaxis, Simovski, Fontenelle, Meza-Zepeda, Stratford, Keung, Burgess, Tawbi, Myklebost and Clancy.)

Introduction: Data are scarce regarding the virologic impact and safety of immune checkpoint inhibitors (ICI) in patients with chronic hepatitis C virus (HCV) infection. We examined the virologic impact of ICI in HCV-infected patients with solid tumors and their safety., Methods: HCV-infected patients with solid tumor treated with ICI at our institution between April 26, 2016, and January 5, 2022, were enrolled in a prospective observational study. The primary outcomes were ICI-induced changes in HCV viremia (HCV inhibition and HCV reactivation) and safety of ICI., Results: We enrolled 52 consecutive patients with solid tumors treated with ICI. Most were men (41; 79%), White (31; 59%), without cirrhosis (34; 65%), and with HCV genotype 1 (40; 77%). Four patients (7.7%) experienced HCV inhibition while receiving ICI including 1 patient who developed undetectable viremia for 6 months in the absence of direct-acting antivirals (DAA). Two patients (4%) developed HCV reactivation, both while receiving immunosuppressive therapy for ICI-related toxic effects. Adverse events occurred in 36 patients (69%), and 39 of the 47 adverse events (83%) were grade 1-2. Grade 3-4 adverse events occurred in 8 patients (15%), and in all cases, they were related to ICI, not to HCV. No HCV-associated liver failure or death occurred., Discussion: Inhibition of HCV replication with virologic cure can develop in patients receiving ICI without DAA. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICI are safe in HCV-infected patients with solid tumors. Chronic HCV infection should not be considered a contraindication for ICI therapy., (Copyright © 2023 by The American College of Gastroenterology.)

Despite major advances with immunotherapy and targeted therapy in the past decade, metastatic melanoma continues to be a deadly disease for close to half of all patients. Over the past decade, advancement in immune profiling and a deeper understanding of the immune tumor microenvironment (TME) have enabled the development of novel approaches targeting and a multitude of targets being investigated for the immunotherapy of melanoma. However, to date, immune checkpoint blockade has remained the most successful with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, alone or in combination, yielding the most robust and durable clinical outcome in patients with metastatic melanoma. The highest rate of durable responses is achieved with the combination with PD-1 and CTLA-4 inhibition, and is effective in a variety of settings including brain metastases; however, it comes at the expense of a multitude of life-threatening toxicities occurring in up to 60% of patients. This has also established melanoma as the forefront of immuno-oncology (IO) drug development, and the search for novel checkpoints has been ongoing with multiple relevant targets including T-cell immunoglobulin and mucinodomain containing-3 (TIM-3), LAG-3, V-domain immunoglobulin suppressor T-cell activation (VISTA), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), among others. Lymphocyte activation gene-3 (LAG-3), which is a co-inhibitory receptor on T cells that suppress their activation, has revolutionized immunomodulation in melanoma. The 'game changing' results from the RELATIVITY-047 trial validated LAG-3 blockade as a relevant biological target and established it as the third clinically relevant immune checkpoint. Importantly, LAG-3 inhibition in combination with PD-1 inhibition offered impressive efficacy with modest increases in toxicity over single agent PD-1 inhibitor and has been U.S. Food and Drug Administration approved for the first-line therapy of patients with metastatic melanoma. The efficacy of this combination in patients with untreated brain or leptomeningeal metastases or with rare melanoma types, such as uveal melanoma, remains to be established. The challenge remains to elucidate specific mechanisms of response and resistance to LAG-3 blockade and to extend its benefits to other malignancies. Ongoing trials are studying the combination of LAG-3 antibodies with PD-1 inhibitors in multiple cancers and settings. The low toxicity of the combination may also allow for further layering of additional therapeutic approaches such as chemotherapy, oncolytic viruses, cellular therapies, and possibly novel cytokines, among others., Competing Interests: Dr. Kreidieh has no conflicts of interest to disclose. Dr. Tawbi has received grants or research support from Bristol Myers Squibb, Novartis, Merck, Genentech, GlaxoSmithKline, EMD Serono, Eisai, Dragonfly Therapeutics, and RAPT Therapeutics, and has served as a paid consultant to Bristol Myers Squibb, Genentech, Novartis, Merck, Boxer Capital, Karyopharm, Iovance, Eisai, Jazz Pharmaceuticals, and Medicenna., (© The Author(s), 2023.)

Background: Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients., Methods: Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA)., Results: A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9-12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P < .001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients., Conclusions: OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Over the past decade, the advent of molecular techniques and deeper understanding of the tumor microenvironment (TME) have enabled the development of a multitude of immunotherapy targets and approaches. Despite the revolutionary advancement in immunotherapy, treatment resistance remains a challenge leading to decreased response rate in a significant proportion of patients. As such, there has recently been an evolving focus to enhance efficacy, durability, and toxicity profiles of immunotherapy. Although immune checkpoint inhibitors have revolutionized cancer treatment with many already-approved antibodies and several others in the pipeline, bispecific antibodies build on their success in an attempt to deliver an even more potent immune response against tumor cells. On the other hand, vaccines comprise the oldest and most versatile form of immunotherapy. Peptide and nucleic acid vaccines are relatively simple to manufacture compared with oncolytic virus-based vaccines, whereas the dendritic cell vaccines are the most complex, requiring autologous cell culture. Nevertheless, a crucial question in the development of cancer vaccines is the choice of antigen whereby shared and patient-private antigen approaches are currently being pursued. There is hope that cancer vaccines will join the repertoire of successful novel immunotherapeutics in the market. Better insights into the impact of immunotherapy on effector T cells and other immune cell populations in the TME shall be a major priority across the immune-oncology discipline and can help identify predictive biomarkers to evaluate response to treatment and identify patients who would most likely benefit from immunotherapy.

Purpose: Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti-programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma., Methods: The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti-PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed., Results: Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D., Conclusion: Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti-PD-(L)1-containing regimens., [Media: see text].

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate., (© 2023. The Author(s).)

BACKGROUND: A phase 2/3 trial — A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047) — evaluated nivolumab + relatlimab as a fixed-dose combination and found a significant progression-free survival (PFS) benefit over nivolumab monotherapy in previously untreated unresectable or metastatic melanoma. We now report updated PFS and safety data and the first results for overall survival (OS) and objective response rate (ORR). METHODS: Patients were randomly assigned 1:1 to receive nivolumab 480 mg and relatlimab 160 mg fixed-dose combination or nivolumab 480 mg alone, given intravenously every 4 weeks. PFS (primary end point) according to the Response Evaluation Criteria in Solid Tumors, version 1.1, was assessed by blinded independent central review (BICR). Secondary end points, tested hierarchically, were OS and then ORR per Response Evaluation Criteria in Solid Tumors, version 1.1, per BICR. RESULTS: At a median follow-up of 19.3 months, median PFS according to BICR was 10.2 months (95% confidence interval [CI], 6.5 to 14.8) with nivolumab + relatlimab versus 4.6 months (95% CI, 3.5 to 6.4) with nivolumab (hazard ratio, 0.78; 95% CI, 0.64 to 0.94). Median OS was not reached (NR) (95% CI, 34.2 to NR) with nivolumab + relatlimab versus 34.1 months (95% CI, 25.2 to NR) with nivolumab (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P=0.059) (prespecified value for statistical significance, P≤0.043). ORRs per BICR were 43.1% (95% CI, 37.9 to 48.4) versus 32.6% (95% CI, 27.8 to 37.7), respectively. Grade 3/4 treatment-related adverse events were observed in 21.1% of patients treated with nivolumab + relatlimab versus 11.1% treated with nivolumab. CONCLUSIONS: The fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up. The combination treatment did not reach the preplanned statistical threshold for OS, with a 10.3 percentage-point difference in ORR. Grade 3/4 treatment-related adverse events were more frequent with nivolumab + relatlimab versus nivolumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03470922.)

Background: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC)., Methods: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m 2 ) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1., Results: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%., Conclusion: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials., Competing Interests: Declaration of interests RR has received research support from Project Data Sphere and personal fees from St Lucia Consulting, outside the submitted work;and has been supported by the Joint Center for Radiation Therapy Foundation Grant. CKA has received research support from Puma Biotechnology, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, Zion Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, AstraZeneca, and Elucida; served as consultant for Genentech, Eisai, IPSEN, Seattle Genetics, AstraZeneca, Novartis Pharmaceuticals, Immunomedics, Elucida, and Athenex; and received royalties from UpToDate, Jones & Bartlett. HAT received personal fees from Novartis Pharmaceuticals; grants and personal fees from Bristol Myers Squibb, Roche, and Genentech; and grants from Merck and Celegene, outside the submitted work. MM reports personal fees from KaryoPharm, Mevio, Zapprx, Sapience, and Xoft outside the submitted work. He reports participation in the board of directors for Oncoceutics and stock ownership in Chimerix. PYW has received research support from AstraZeneca, BeiGene, Celgene, Chimerix, Eli Lily, Genentech, Roche, Kazia, MediciNova, Merck, Novartis Pharmaceuticals, Nuvation Bio, Puma, Servier, Vascular Biogenics, and Variation Biotechnologies Vaccines; and is on advisory boards for AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Boston Pharmaceuticals, Celularity, Chimerix, Day One Bio, Genenta, GlaxoSmithKline, Karyopharm, Merck, Mundipharma, Novartis Pharmaceuticals, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. JdG reports grant or research support from Sanofi-Aventis, AstraZeneca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmaceuticals, and Mundipharma; paid consultancies from Celldex, Deciphera Pharmaceuticals, AbbVie, FivePrime Therapeutics, GW Pharmaceuticals, Carthera, Eli Lilly, Kadmon, Boston Biomedical, Taiho Pharmaceuticals, Kairos Venture Investments, Syneos Health, Monteris, Agios, Mundipharma Research, GenomiCare, Blue Earth Diagnostics, Del Mar Pharmaceuticals, Insightec, Voyager Therapeutics, Merck, Tocagen, Bioasis Technologies, and ResTORbio; advisory board membership for Genentech, Celldex, Foundation Medicine, Novogen, Deciphera, AstraZeneca, Insys Therapeutics, Merck, Eli Lilly, Novella Clinical, Karyopharm Therapeutics, Blue Earth Diagnostics, Kiyatec, Vanquish Oncology, Orsenix, Insightec, Prelude Therapeutics, Debiopharm Therapeutics, and Janssen Global Services; data safety monitoring board membership for VBL Therapeutics (VB111; glioblastoma), Novella (ICT-107; glioblastoma), and VBI Vaccines (VBI-1901; glioblastoma); stock ownership in Ziopharm Oncology and Gilead; and company employment (spouse) in Ziopharm Oncology. EG has received honoraria for advisory board participation from Kiyatec (personal compensation), and Karyopharm Therapetuics for data safety and monitoring board participation (compensation to employer). Her institution has received grant funding from Servier Pharmaceuticals, Celgene, MedImmune, and Tracon Pharmaceuticals; and she has been supported by the National Cancer Institute of the National Institutes of Health (NIH) under award numbers UG1CA189823 (Alliance for Clinical Trials in Oncology), R01 CA258239, U19 CA264362, and The Ben and Catherine Ivy Foundation. MK reports research funding paid to their institution from BMS, AbbVie, Biontech, Astellas, Celldex, Daiichi Sankyo, and CNS pharmaceuticals; and honoraria from George Clinical, Voyager Therapeutics, Johnson & Johnson, and the Jax lab for genomic research; and is supported by NIH grants (U01-NS090284-05, U19-CA264385-01, P50CA190991-08, P01-CA225622-04, and R01-CA235612-03). M-YCP has been supported by the National Cancer Institute of the NIH under award number U10 CA180822 (NRG Oncology—Statistics and Data Management Center). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 ., (© 2023. The Author(s).)

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1 [S1] or GNA11/Q [S2]) altered tumors., Methods: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss., Results: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common., Conclusion: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Objectives: Cancer patients have worse outcomes from the COVID-19 infection and greater need for ventilator support and elevated mortality rates than the general population. However, previous artificial intelligence (AI) studies focused on patients without cancer to develop diagnosis and severity prediction models. Little is known about how the AI models perform in cancer patients. In this study, we aim to develop a computational framework for COVID-19 diagnosis and severity prediction particularly in a cancer population and further compare it head-to-head to a general population., Methods: We have enrolled multi-center international cohorts with 531 CT scans from 502 general patients and 420 CT scans from 414 cancer patients. In particular, the habitat imaging pipeline was developed to quantify the complex infection patterns by partitioning the whole lung regions into phenotypically different subregions. Subsequently, various machine learning models nested with feature selection were built for COVID-19 detection and severity prediction., Results: These models showed almost perfect performance in COVID-19 infection diagnosis and predicting its severity during cross validation. Our analysis revealed that models built separately on the cancer population performed significantly better than those built on the general population and locked to test on the cancer population. This may be because of the significant difference among the habitat features across the two different cohorts., Conclusions: Taken together, our habitat imaging analysis as a proof-of-concept study has highlighted the unique radiologic features of cancer patients and demonstrated effectiveness of CT-based machine learning model in informing COVID-19 management in the cancer population.

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes., (© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma 1 . We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate 2 . The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial 1 , provide further confirmation of the efficacy and safety of this new immunotherapy regimen., (© 2022. The Author(s).)

Melanoma is the most aggressive skin cancer, with a high incidence of metastatic spread and a predilection for metastases to the brain. It represents the third most common origin of brain metastases after breast and lung cancer. With the advent of targeted therapy and immunotherapy in melanoma, along with improved local therapy options such as stereotactic radiosurgery (SRS), the treatment of melanoma brain metastases (MBM) has led to significant improvements in outcome. In this review, we provide an overview of management options for patients with MBM while highlighting emerging treatment options. Surgery may be considered for patients with symptomatic MBM, whereas SRS is considered standard for patients with 1 to 4 brain lesions. Combination immunotherapy has led to durable intracranial responses and improved long-term outcomes for patients with asymptomatic MBM. The data available to date have shown that patients with MBM can have a durable response and overall response that are similar to those of patients without brain metastases, and additional trials are ongoing. Mounting evidence suggests that patients with MBM should be considered for inclusion in clinical trials, which range from early-phase trials to phase 3 studies, to accelerate much-needed drug development in this population.

Background: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram., Methods: In COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4 + /CD8 + T-cell ratio via immunophenotyping., Results: Extensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4 + /CD8 + ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4 + /CD8 + ratio was strongly predictive (interaction p=0.0131)., Conclusions: These results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4 + /CD8 + T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted., Trial Registration Number: NCT02967692., Competing Interests: Competing interests: HAT reports personal consulting fees and institutional research support from Novartis; institutional research support and personal consulting fees from Merck, Bristol Myers Squibb, and Genentech; institutional research support from GSK and Celgene; and consulting fees from Eisai and Iovance. CR reports consulting fees from and advisory board participation with Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Amgen, Sanofi, Merck, Merck Sharp & Dohme, and AstraZeneca. JCB reports stock ownership of and employment with Novartis; also, he is a coinventor on a patent application related to reported biomarker subgroups of interest. DG reports employment with Novartis and that they are a coinventor on a patent application related to reported biomarker subgroups of interest. EG reports stock ownership of and employment with Novartis. JG, AS, and GG report employment with Novartis. KTF reports grants or contracts from Novartis and Sanofi; consulting fees from, advisory board participation with, stock ownership of, and a leadership or fiduciary role with Clovis Oncology and Strata Oncology; consulting fees from and a leadership or fiduciary role with Vivid Biosciences and Checkmate Pharmaceuticals; consulting fees from, advisory board participation with, and stock ownership of X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, FogPharma, Neon, Tvardi, xCures, Monopteros, and Vibliome; stock ownership of and a leadership or fiduciary role with Loxo Oncology; and consulting fees from Lilly, Novartis, Genentech, Bristol Myers Squibb, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, and Debiopharm. AR reports clinical trial funding and consulting fees from and advisory board participation with Novartis; consulting fees from Amgen, Bristol Myers Squibb, Chugai, Genentech, Merck, Roche, Sanofi, and Vedanta; advisory board participation with and stock ownership of Advaxis, Apricity, Arcus, Compugen, CytomX, Five Prime, Highlight Therapeutics, ImaginAb, IsoPlexis, Kalthera, Kite-Gilead, Merus, PACT Pharma, RAPT, Rgenix, and Tango; and research funding from Agilent and Bristol Myers Squibb through Stand Up To Cancer (SU2C). RD reports intermittent, project-focused consulting fees from and advisory relationships with Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator, MaxiVAX SA, and touchlME. DS reports clinical trial funding to their institution from Novartis; institutional research grants and personal consulting fees, payments or honoraria, and support for attending meetings/travel from and advisory board participation with Novartis and Bristol Myers Squibb; institutional research grants and personal consulting fees and support for attending meetings/travel from and advisory board participation with Amgen; consulting fees, payments or honoraria, and support for attending meetings/travel from and advisory board participation with Pierre Fabre, Sanofi-Genzyme, and Merck Serono; consulting fees and support for attending meetings/travel from and advisory board participation with Merck Sharp & Dohme, Roche, Incyte, Array BioPharma, Pfizer, Regeneron, 4SC, InflaRx, NeraCare, Ultimovacs, Sun Pharma, Philogen, Immunocore, and Sandoz-Hexal; and leadership or fiduciary roles in the Dermatologic Cooperative Oncology Group, German Cancer Society, Hilfe-Stiftung, Deutsche Hautkrebsstiftung, NVKH eV, and EUMelaReg. GVL reports consulting fees from and advisory board participation with Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics, Merck Sharp & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group, Regeneron, SkylineDx BV, and Specialised Therapeutics Australia Pty Ltd; and personal payments or honoraria from Bristol Myers Squibb and Pierre Fabre. PDN reports consulting fees from AstraZeneca, Bristol Myers Squibb, Immunocore, Ipsen, Merck Sharp & Dohme, Merck, Novartis, Pfizer, and 4SC; personal payments or honoraria from Novartis, Merck, and Pfizer; and support for meeting attendance/travel from Bristol Myers Squibb. PAA reports research funding from, consulting fees from, and advisory board participation with Bristol Myers Squibb, Roche Genentech, Array BioPharma, and Sanofi; consulting fees from and advisory board participation with Novartis, Merck Serono, MedImmune, Sun Pharma, Idera, Sandoz, and 4SC; consulting fees from Italfarmaco, Pfizer, OncoSec, Takis, and Lunaphore; advisory board participation with Pierre Fabre, Incyte, AstraZeneca, Syndax, Ultimovacs, Immunocore, Alkermes, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Nouscom, and Seagen; consulting fees from, advisory board participation with, and support for meeting attendance/travel from Merck Sharp & Dohme; and leadership or fiduciary roles with the Society for Immunotherapy of Cancer, Society for Melanoma Research, Melanoma Foundation, and the Campania Society of Immunotherapy of Cancer. All authors acknowledge funding for medical writing support by ArticulateScience from Novartis, related to the present study., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed 1,2 . Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts 2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate., (© 2022. The Author(s).)

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.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8 + T cell axis in both blood and inflamed joints. CX3CR1 hi CD8 + T cells in blood and CXCR3 hi CD8 + T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1 hi CD8 + T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE., (© 2022. The Author(s).)

Background: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response., Methods: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT., Results: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039)., Conclusions: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit., (© 2021 American Cancer Society.)

Background: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation., Methods: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review., Results: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group., Conclusions: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.)., (Copyright © 2022 Massachusetts Medical Society.)

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial., Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058., Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A)., Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests HAT worked in a consulting/advisory role for Array BioPharma, Bristol Myers Squibb (BMS), Genentech/Roche, Merck, and Novartis; participated in a scientific advisory board for Kayopharm; received research/grant support from BMS, Celgene, Genentech/Roche, GlaxoSmithKline (GSK), and Merck; and received honoraria from Eisai. PAF worked in a consulting role for AbbVie, Boehringer Ingelheim, NCI Neuro-Oncology Branch Peer Review, Novellus, Physical Sciences Oncology Network, Tocagen, and Ziopharm; received honoraria from BTG, NCRI, Tocagen, and Ziopharm; worked in an advisory role for Bayer, Inovio, Novocure, and BTG; and received research/grant support from CDMRP, NIH/NCI, Department of Defense, Pfizer, State of Florida Bankhead Coley, and Moffitt Center of Excellence Celgene Project. FSH worked in a consulting role for BMS, Corner Therapeutics, Eisai, EMD Serono, Genentech/Roche, Gossamer, Idera, Kairos, Merck, Novartis, Psioxus Therapeutics, Pieris Pharmaceutical, Takeda, and Sanofi; worked in an advisory role for 7 Hills Pharma, Aduro, Apricity, Bicara, Checkpoint Therapeutics, Pionyr, and Torque; received research/grant support from BMS and Novartis; received royalties from BMS and Novartis; and holds equity in Apricity. APA worked in an advisory role for Array BioPharma, OncoSec Medical, and Regeneron; received research/grant support from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, OncoSec Medical, Regeneron, Sensei, and Tessa; received travel/accommodations/expenses support from OncoSec Medical; and holds stock in OncoSec Medical and Valitor Biosciences. OH worked in a consulting role for and received research/grant support from Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus, and Zelluna; received research/grant support from BMS; and served as a speaker for BMS, Novartis, Pfizer, and Sanofi Regeneron. CDL received research/grant support from Novartis and Merck; worked in an advisory role for BMS and Immunocore; and received travel/accommodations/expenses support from BMS and Immunocore. SJM received research/grant support from Amgen, Merck, and Syndax Pharmaceuticals; worked in a consulting role for iTeos Therapeutics and EMD Serono; and participated in a Data Safety Monitoring board for IQVIA. MBA worked in a consulting role for Adagene, Agenus, AstraZeneca, Calithera, Exelixis, Idera, Immunocore, Iovance, Neoleukin, Sanofi, SeaGen, and Takeda; and worked in an advisory role for Apexigen, Aveo, BMS, Eisai, Elpis, Genentech/Roche, Leads Biopharma, Merck, Novartis, Pfizer, PACT, Pyxis Oncology, and Werewolf Therapeutics. KL received research/grant support from BMS, Merck, Roche/Genentech, Pfizer, and Regeneron; and worked in a consulting role for Merck, Roche/Genentech, and Pfizer. MAP worked in a consulting/advisory role for Aduro, BMS, Eisai, Incyte, Merck, NewLink Genetics, Novartis, and Pfizer; received research/grant support from Array BioPharma, AstraZeneca, BMS, Infinity, Merck, Novartis, and RGenix; and received honoraria from BMS and Merck. SJ worked in a consulting/advisory role for Array Biopharma, BMS, EMD Sorono, Genentech, Novartis, Sanofi, Sun Biopharma, and Pfizer. NIK worked in an advisory role for Array BioPharma, BMS, EMD Serono, Genentech, HUYA Bioscience International, Immunocore, Merck, Regeneron, and Jounce; received research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience International, Merck, Novartis, Replimmune, and Regeneron; received honoraria from BMS and Sanofi; holds stock in Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, and Asensus Surgical (formerly TransEnterix); participated in a Data Safety Monitoring board for AstraZeneca and Incyte; and participated in the Scientific Review Committee for NCCN (from Pfizer) and study steering committees for BMS, Regeneron, and Nektar. ACP worked in a consulting/advisory role for BMS, Merck, Regeneron, and Sanofi/Regeneron; received research/grant support from BMS, Merck, Regeneron, and Replimune; and worked on a speaker's bureau for BMS. MSE participated in a Data Safety Monitoring board for BMS; and holds stock or stock options in BMS. DAR worked in a consulting/advisory role for AbbVie, Advantagene, Agenus, Amgen, Bayer, BMS, Boston Biomedical, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Medicenna, Merck, Merck KGaA, Monteris, Oncorus, Oxigene, Novocure, Regeneron, Stemline, and Taiho; and received research/grant support from Tragara, Acerta Pharmaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, and Omniox. RK worked in a consulting/advisory role for Array BioPharma, BMS, Immunocore, Merck, Novartis, Pfizer, and Regeneron; received research/grant support from BMS, Merck, and Regeneron; received honoraria from Array BioPharma and BMS; and received travel/accommodations/expenses support from BMS. AT worked in a consulting/advisory role for Array Biopharma, BioNTech, BMS, Clinigen, EMD Serono, Genentech/Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron; and received research/grant support from BMS, Genentech/Roche, OncoSec Medical, Merck, Sanjofi-Genzyme, Regeneron, Clinigen, and CheckMate. CC received research/grant support from Siemens Healthineers and Raysearch Laboratories; and received honorarium from Elekta. CR and PD are employees of BMS and hold BMS stock or stock options. MA is an employee of BMS. IP worked in a consulting role for Amgen, Merck, and Nouscom. KAM worked in a consulting/advisory role for ImaginAb, Oncosec, Werewolf, Xilio, and Tentarix; participated in a Data Safety Monitoring board for CheckMate Pharmaceuticals; and received research/grant support from ImaginAb. RPT and JG report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients' overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%-20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients., Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months)., Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed., Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.

Background: Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials., Methods: Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively)., Results: Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy., Conclusions: Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption., Trial Registration: ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908)., Competing Interests: Conflict of interest statement DS has received research grants from Novartis, Bristol Myers Squibb, and Amgen; received consulting fees from, travel support from, and had advisory relationships with Novartis, Bristol Myers Squibb, MSD, Roche, Incyte, Array, Pierre Fabre, Pfizer, Sanofi-Genzyme, Regeneron, 4SC, InFlarX, Neracare, Ultimovacs, Sun Pharma, Philogen, Amgen, Merck-Serono, Immunocore, Sandoz-Hexal; received honoraria from Novartis, Bristol Myers Squibb, Pierre Fabre, Sanofi-Genzyme and Merck-Serono; and held leadership or fiduciary roles with Dermatologic Cooperative Oncology Group (DeCOG), German Cancer Society, Hilfe-Stiftung, Deutsche Hautkrebsstiftung, NVKH eV and EuMelaReg. CR has received consulting fees from and had advisory relationships with Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Amgen, Sanofi, Merck, MS and AstraZeneca. RD has had intermittent, project-focused consulting and/or advisory relationships with and received honoraria from Novartis, MSD, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalyn, Second Genome, Regeneron, Alligator, MaxiVAX SAand touchIME outside the submitted work. KTF has received grants from Novartis and Sanofi; received consulting fees from Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals and X4 Pharmaceuticals; has served on scientific advisory boards for PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, Lilly, Novartis, Genentech, Bristol Myers Squibb, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm; had advisory relationships with Clovis Oncology, Strata Oncology, X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros and Vibliome; held leadership or fiduciary roles with Loxo Oncology, Clovis Oncology, Strata Oncology, Vivid Biosciences and Checkmate Pharmaceuticals; and holds stock or stock options with Loxo Oncology, Clovis Oncology, Strata Oncology, X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros and Vibliome. HAT has received institutional research support from Merck, Bristol Myers Squibb, Genentech, GlaxoSmithKline and Celgene and received consulting fees from Merck, Bristol Myers Squibb, Genentech, Eisai and Iovance. AMM has received consulting fees from Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre and QBiotics. HB holds stock or stock options with Bristol Myers Squibb and is employed with Novartis. ML is employed with Novartis. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array BioPharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics S.L., MSD, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. and Specialised Therapeutics Australia Pty Ltd and has received honoraria from Bristol Myers Squibb and Pierre Fabre., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies., (©2021 American Association for Cancer Research.)

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward., (©2021 American Association for Cancer Research.)