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Background: The combination of ipilimumab and nivolumab is a highly effective treatment for metastatic cutaneous melanoma. However, immune-related adverse events (irAEs) are common, often necessitating treatment interruption and the use of immunosuppressive agents. There is no data on the impact of resuming nivolumab on survival following recovery from the irAE and completion of immunosuppressive treatment., Patients and Methods: In this retrospective analysis, we examined a cohort of patients treated with ipilimumab/nivolumab who developed irAEs requiring treatment interruption and immunosuppressive therapy. The differences in physician practice patterns at our institution allowed us to examine the survival effect of restarting single-agent nivolumab. A multivariate analysis of clinical factors associated with improved survival was performed., Results: We identified 165 patients who were treated with ipilimumab/nivolumab and developed irAEs requiring treatment interruption and immunosuppressive therapy. Patients with the best overall response of progressive disease were excluded. Of the remaining 122 patients, 46 resumed single-agent nivolumab. When stratified by age and adjusted for sex, M-stage, lactate dehydrogenase (LDH), therapy duration, and irAE type, the effect of resumption of nivolumab on survival was highly significant (p=0.02). Patients who resumed nivolumab had a 68% reduction in the hazard of death compared with patients who had not yet or never resumed nivolumab (HR: 0.32, 95% CI: 0.12 to 0.84). Of the patients who resumed nivolumab, 12 (26%) patients had subsequent irAEs, with five patients having grade 3 irAEs. No grade 4 or 5 irAEs were noted., Conclusions: Resuming single-agent nivolumab following a treatment interruption for ipilimumab/nivolumab-associated irAE and completion of immunosuppressive therapy increased overall survival compared with discontinuing nivolumab permanently in patients with metastatic melanoma. Toxicity observed post-resumption of single-agent nivolumab was manageable with no severe irAEs observed., Competing Interests: Competing interests: EB consults as an advisory board member for Werewolf pharma, Merck, Iovance, Sanofi, Xilio, Novartis and Instilbio, receives clinical trial support from Lilly, Novartis, Partners therapeutics, Genentech and BVD. FSH reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from 7 Hills Pharma, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Catalym, personal fees from Immunocore, personal fees from Kairos, personal fees from Rheos, personal fees from Zumutor, personal fees from Corner Therapeutics, personal fees from Puretech, personal fees from Curis, personal fees from AstraZeneca, personal fees from Solu Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent THERAPEUTIC PEPTIDES Therapeutic Peptides- Patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, a patent ÚNTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES Deduplication number: 20170343552 pending, and a patent Antibodies against EDIL3 and methods of use thereof pending., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small-molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases., Materials and Methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients and an initial evaluation of efficacy after 13 patients., Results: From April 2018 to April 2019, 13 patients were enrolled. Patients were predominantly female (69%) with a median age of 64 years (34-76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months., Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition., Significance: Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Abstract: Immune checkpoint inhibition and targeted therapies have revolutionized the treatment of melanoma. However, chemotherapy and interleukin 2 (IL-2) therapy may still have a role in the later-line treatment of patients who do not have durable responses to other treatments. Chemotherapy can work transiently in patients whose disease has progressed on immune checkpoint inhibitors and for whom there are no appropriate targeted therapy options. High-dose IL-2 therapy can still be effective for a very small number of patients following progression on other therapies. In addition, modified IL-2 agents and IL-2 in combination with tumor-infiltrating lymphocyte therapy may play a role in future treatments for melanoma., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma., Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881., Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups., Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting., Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests JSW has been a consultant for AstraZeneca, Bristol Myers Squibb, Merck, and Regeneron; has received research grants (to institution) from Merck and Moderna; has received travel support from Moderna; and is named on a PD-1 patent with Biodesix (not related to this trial). MSC has been a consultant for Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck Sharp & Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck Serono, and Sanofi; and has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Sanofi. AK has received honoraria from Merck Sharp & Dohme. TaM has received research grants (to institution) from Moderna; has been a consultant or served on a data safety monitoring–advisory board for AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; has received payment or honoraria from AstraZeneca; and has received travel support from AstraZeneca and Bristol Myers Squibb. MHT has received research grants from Bristol Myers Squibb, Exelixis, and Merck; has been a consultant for Cascade Prodrug, Incyte, and Immune-Onc; has received payment or honoraria from Array Biopharma, Bayer, Blueprint Medicines, Bristol Myers Squibb, Eisai, Merck, Novartis, and Sanofi/Regeneron; and has served on a data safety monitoring or advisory board for Oncosec. KBK has received research grants from Merck and Moderna. MMc has received research grants (to institution) from Aadi Biosciences, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, ASCO, Astellas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, G1 Therapeutics, Genentech–Roche, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Merck, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, OncoC4, Oncorus, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, and Xilio; and has been a consultant (payment to institution) for Castle Biosciences, Eisai, IQVIA, Merck, Moderna, and Pfizer. GVL has been a consultant for Agenus, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA, Merck Sharp & Dohme, Novartis, OncoSec, PHMR, Pierre Fabre, Provectus, Qbiotics, and Regeneron; has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; and has served on an advisory board for Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, and Regeneron. RJS has received research grants from Merck; has royalties or licences from Up-to-Date; has been a consultant for Marengo, Merck, Novartis, Pfizer, and Replimune; and has served on a data safety monitoring or advisory board for Duke University and Yale University. MF has received research grants from Moderna; and has served on an advisory board for Bristol Myers Squibb, Instil Bio, Merck, Novartis, and Regeneron. CLC has been a consultant for and has served on an advisory board for EMD Serono, Eisai, Iovance, Merck, Regeneron, and Replimune. AP has had a leadership position in Cota Healthcare and OMI; and holds stock options in Celularity and OMI. ThM has received research grants from Agenus, Anaveon, Bioatla, Bristol Myers Squibb, Day One, Genentech, InflaRx, Iovance, Merck, Regeneron, Replimune, Trisalus, and Ultimovacs; has received payment or honoraria from Honor Health; and has served on a data safety monitoring or advisory board for University of Colorado Cancer Center. VA has received speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; has received travel support from Bristol Myers Squibb and Pierre Fabre; and has served on an advisory board for Bristol Myers Squibb, Immunocore, Limbic, Merck Sharp & Dohme, Novartis, and QBiotics. GTG has received research grants (to institution) from Exelixis and Lucerno Dynamics; has been a consultant for Bristol Myers Squibb, Eisai, Exicure, Genentech, Immunocore, Incyte, Iovance, Lyell Immunopharma, Merck, Novartis, Regeneron, and Sapience Therapeutics; has received payment or honoraria from Immunocore; and has served on a data safety monitoring or advisory board for Huyabio. JJL has received research support (all to institution for clinical trials) from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck Sharp & Dohme, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; has been a consultant for 7 Hills, AbbVie, Actym, Alnylam, Alphamab Oncology, Arch Oncology, Atomwise, Bayer, Bright Peak, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Duke Street Bio, Eisai, EMD Serono, Endeavor, Exo, Flame, Fstar, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, Kanaph, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, Inzen, IO Biotech, Macrogenics, Mavu, Merck Sharp & Dohme, Mersana, Nektar, NeoTx, Novartis, Onc.AI, OncoNano, Partner, Pfizer, Pioneering Medicines, PsiOxus, Pyxis, RefleXion, Regeneron, Ribon, Roivant, Saros, Servier, STINGthera, Stipe, Synlogic, Synthekine, Tempest, and Xilio; has served on an advisory board for AbbVie, Evaxion, and Immutep; is a board member of the Society for Immunotherapy of Cancer; holds stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest; and has applied for patents (both provisional) for Serial 15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: diagnostic, prognostic and therapeutic uses thereof). ST has received speaker fees from Bristol Myers Squibb and honoraria from Pfizer; and has served as a paid expert witness for malpractice cases. EIB has received research grants (to institution) from Genentech; has been a consultant for Instilbio, Iovance, Merck, Nektar, Novartis, Sanofi, and Xilio; and has served on a data safety monitoring–advisory board for Asher. JAH is an employee of and holds stock options in Merck & Co, Rahway, NJ, USA. MH is an employee of Merck &Co, Rahway, NJ, USA. MaM, LZ, CR-T, PH, and PA are employees of and hold stock options in Moderna. IF is an employee of and holds stock options in Moderna; and was a co-inventor on the individualised neoantigen therapy Moderna patent. VS is an employee of Moderna; and holds stock options in AbbVie and Moderna. MB is an employee of Moderna; and holds stock options in Bristol Myers Squibb, Moderna, and Novartis. RSM is an employee of and holds stock and options in Moderna; and was a co-inventor on the individualised neoantigen therapy patent and other seminal Moderna patents. TZ is an employee of and holds stock options in Moderna; was a co-inventor on some seminal Moderna patents; and has served as a paid board member for Adaptimmune and Teva Pharmaceuticals. GA, TTT, MS, and JS declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate immunomodulator use, risk factors and management for rheumatoid arthritis (RA) flares, and mortality for patients with pre-existing RA initiating immune checkpoint inhibitors (ICI) for cancer., Methods: We performed a retrospective cohort study of all patients with RA meeting 2010 ACR/EULAR criteria that initiated ICI for cancer at Mass General Brigham or Dana-Farber Cancer Institute in Boston, MA (2011-2022). We described immunomodulator use and changes at baseline of ICI initiation. We identified RA flares after baseline, categorized the severity, and described the management. Baseline factors were examined for RA flare risk using Fine and Gray competing risk models. We performed a landmark analysis to limit the potential for immortal time bias, where the analysis started 3 months after ICI initiation. Among those who survived at least 3 months, we examined whether RA flare within 3 months after ICI initiation was associated with mortality using Cox regression., Results: Among 11,901 patients who initiated ICI for cancer treatment, we analyzed 100 pre-existing RA patients (mean age 70.3 years, 63 % female, 89 % on PD-1 monotherapy, 50 % lung cancer). At ICI initiation, 71 % were seropositive, 82 % had remission/low RA disease activity, 24 % were on glucocorticoids, 35 % were on conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and 10 % were on biologic or targeted synthetic DMARDs. None discontinued glucocorticoids and 3/35 (9 %) discontinued DMARDs in anticipation of starting ICI. RA flares occurred in 46 % (incidence rate 1.84 per 1000 person-months, 95 % CI 1.30, 2.37); 31/100 flared within 3 months of baseline. RA flares were grade 1 in 16/46 (35 %), grade 2 in 25/46 (54 %), and grade 3 in 5/46 (11 %); 2/46 (4 %) required hospitalization for RA flare. Concomitant immune-related adverse events occurred in 15/46 (33 %) that flared. A total of 72/100 died during follow-up; 21 died within 3 months of baseline. Seropositivity had an age-adjusted sdHR of 1.95 (95 % CI 1.02, 3.71) for RA flare compared to seronegativity, accounting for competing risk of death. Otherwise, no baseline factors were associated with RA flare, including cancer type, disease activity, RA duration, and deformities. 9/46 (20 %) patients had their ICI discontinued/paused due to RA flares. In the landmark analysis among 79 patients who survived at least 3 months, RA flare in the first 3 months was not associated with lower mortality (adjusted HR 1.24, 95 % CI 0.71, 2.16) compared to no RA flare., Conclusion: Among patients with pre-existing RA, few changed immunomodulator medications in anticipation of starting ICI, but RA flares occurred in nearly half. RA flares were mostly mild and treated with typical therapies. Seropositivity was associated with RA flare risk. A minority had severe RA flares requiring disruption of ICI, and RA flares were not associated with mortality., Competing Interests: Declaration of Competing Interest Dr. Yoshida has performed consultancy for OM1, Inc. Dr. LeBoeuf has performed consultancy for Bayer, Seattle Genetics, Sanofi, Silverback, and Synox Therapeutics. Dr. Buchbinder serves on an advisory board for Merck, BMS, and Novartis. Dr. Gedmintas has received payment for lectures for Harvard CME of Intensive Review of Internal Medicine and Innovations and New Practices in Internal Medicine. Dr. Rao has received research support from Bristol Myers Squibb, Janssen, and Merck, and performed consultancy for AstraZeneca, Pfizer, GlaxoSmithKine, Aditum, HiFiBio Therapeutics, and Scipher Medicine unrelated to this work. Dr. Gravallese has received grants from the NIH and Rheumatology Research Foundation. Dr. Gravallese has received royalties from Up to Date and textbook “Rheumatology.” Dr. Gravallese has received payment for speaking at IFRA meeting China, Advances in Targeted Therapies Meeting, University of NC, MUSC, and ACR. Dr. Gravallese has received support for attending meeting with Advances in Targeted Therapies and the NIH. Dr. Gravallese serves in a leadership role for the NIH and NIAMs Council member. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.

Background: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy., Methods: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively., Results: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients., Conclusions: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma., Trial Registration Number: NCT02298959., (© 2024. The Author(s).)

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.)

BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600 E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM., Methods and Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020. Recurrence rates were estimated using cumulative incidence in the presence of the competing risk of death., Results: Mucosal sites were head/neck (n = 29, 78%), vaginal (n = 7, 19%), and anorectal (n = 1, 3%). Patients received ICI prior to or concurrent with RT (n = 14, 38%), following RT (n = 5, 14%), or at recurrence (n = 18, 49%). The objective response rate for evaluable patients was 31% for ICI as initial treatment (95% CI, 11%-59%) and 19% for ICI at recurrence (95% CI, 4%-46%). Median follow-up was 26 months for living patients; median overall survival (OS) was 54 months (95% CI, 31 months-not reached). Two-year OS was 85%; distant metastasis-free survival 44%. The 2-year cumulative incidence of local recurrence (LR) was 26% (95% CI, 13%-41%). For 9 patients with unresectable disease, 2-year OS was 88% (95% CI, 35%-98%); LR was 25% (95% CI, 3%-58%). For 5 patients with positive nodes at diagnosis, 2-year OS was 100%; LR was 0%., Conclusions: High rates of local control were achieved with RT with or without oncologic resection and ICI for localized and locally advanced MM. In particular, favorable local control was possible even for patients with unresectable or node-positive disease. Although risk of distant failure remains high, patients with MM may benefit from aggressive local therapy including RT in the setting of immunotherapy treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines., Methods: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones., Results: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m 2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer., Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach., (© 2023 American Cancer Society.)

Despite the wide use of immune checkpoint inhibition for the treatment of melanoma, the mechanisms leading to long-term stable disease are incompletely understood. Patients with metastatic melanoma who had received ipilimumab alone or ipilimumab plus nivolumab 2+years prior and attained at least 6 months of stable disease were identified. Positron emission tomography/computed tomography (PET/CT) was performed. Pretreatment and posttreatment biopsies of areas of stable disease were assessed for tumor, fibrosis, and inflammation. Seven patients underwent PET/CT and tissue biopsy. Fluorodeoxyglucose avid lesions on PET/CT ranged from no activity to an SUV of 22. In 6 patients, the residual stable lesions were composed of necrosis and fibrosis with a prominent pigment containing macrophages and no residual melanoma. In 1 patient, a nodal lesion demonstrated melanoma with active inflammation. In most patients with durable stable disease after treatment with ipilimumab or ipilimumab/nivolumab, residual lesions demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest ongoing immune surveillance. One patient did demonstrate residual melanoma, indicating the need for ongoing monitoring of this patient population., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy., Methods: We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110., Results: Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached)., Conclusion: MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors for cancer might be at risk of increased mortality, rheumatoid arthritis flares, and other immune-related adverse events (AEs). We aimed to determine whether pre-existing rheumatoid arthritis was associated with higher mortality and immune-related AE risk in patients treated with immune checkpoint inhibitors., Methods: This retrospective, comparative cohort study was conducted at the Mass General Brigham Integrated Health Care System and the Dana-Farber Cancer Institute in Boston (MA, USA). We searched data repositories to identify all individuals who initiated immune checkpoint inhibitors from April 1, 2011, to April 21, 2021. Patients with pre-existing rheumatoid arthritis had to meet the 2010 American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) criteria. For each pre-existing rheumatoid arthritis case, we matched up to three non-rheumatoid arthritis comparators at the index date of immune checkpoint inhibitor initiation by sex (recorded as male or female), calendar year, immune checkpoint inhibitor target, and cancer type and stage. The coprimary outcomes were time from index date to death and time to the first immune-related AE, measured using an adjusted Cox proportional hazards model. Deaths were identified by medical record and obituary review. Rheumatoid arthritis flares and immune-related AE presence, type, and severity were determined by medical record review., Findings: We identified 11 901 patients who initiated immune checkpoint inhibitors for cancer treatment between April 1, 2011, and April 21, 2021; of those, 101 met the 2010 ACR-EULAR criteria for rheumatoid arthritis. We successfully matched 87 patients with pre-existing rheumatoid arthritis to 203 non-rheumatoid arthritis comparators. The median age was 71·2 years (IQR 63·2-77·1). 178 (61%) of 290 participants were female, 112 (39%) were male and 268 (92%) participants were White. PD-1 was the most common immune checkpoint inhibitor target (80 [92%] of 87 patients with rheumatoid arthritis vs 188 [93%] of 203 comparators). Lung cancer was the most common cancer type (43 [49%] vs 114 [56%]), followed by melanoma (21 [24%] vs 50 [25%]). 60 (69%) patients with rheumatoid arthritis versus 127 (63%) comparators died (adjusted hazard ratio [HR] of 1·16 [95% CI 0·86-1·57]; p=0·34). 53 (61%) patients with rheumatoid arthritis versus 99 (49%) comparators had any all-grade immune-related AE (adjusted HR 1·72 [95% CI 1·20-2·47]; p=0·0032). There were two (1%) grade 5 immune-related AEs (deaths) due to myocarditis, both in the comparator group. Rheumatoid arthritis flares occurred in 42 (48%) patients with rheumatoid arthritis, and inflammatory arthritis occurred in 14 (7%) comparators (p<0·0001). Those with rheumatoid arthritis were less likely to have rash or dermatitis (five [6%] vs 28 [14%]; p=0·048), endocrinopathy (two [2%] vs 22 [11%]; p=0·0078), colitis or enteritis (six [7%] vs 28 [14%] comparators; p=0·094), and hepatitis (three [3%] vs 19 [9%]; p=0·043)., Interpretation: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors had similar risk of mortality and severe immune-related AEs as matched comparators. Although patients with pre-existing rheumatoid arthritis were more likely to have immune-related AEs, this finding was mostly due to mild rheumatoid arthritis flares. These results suggest that this patient population can safely receive immune checkpoint inhibitors for cancer treatment., Funding: None., Competing Interests: Declaration of interests: Dr. Yoshida has received consulting fees from OM1, Inc. at the time of this work and is now employed by and owns stock options from OM1, Inc unrelated to this work. Dr. Shadick is supported by Mallinckrodt, Lilly, BMS, Amgen, Abbvie, and Aqtual unrelated to this work. Dr. LeBoeuf receives consulting fees from Bayer, Seattle Genetics, Sanofi, Silverback, and Synox Therapeutics unrelated to this work. Dr. Buchbinder has received a research grant from Genentech and has participated on advisory boards for Merck, Bristol Myers Squibb, and Novartis unrelated to this work. Dr. Gedmintas has received honoraria for invited lectures for the Harvard Continuing Medical Education programs Intensive Review of Internal Medicine and Innovations and New Practices in Internal Medicine (not sponsored by for-profit institutions). Dr. Gravallese receives royalties from UpToDate and the Rheumatology textbook (published by Elsevier), has received honoraria for scientific lectures at academic institutions/meetings (none for industry or for-profit institutions) and the American College of Rheumatology (serving on task forces for COVID treatment and vaccine guidelines), has received reimbursement for travel to academic institutions and meetings hosted by the American College of Rheumatology, and has received partial salary support serving as president-elect and president of the American College of Rheumatology and as an Associate Editor for the New England Journal of Medicine. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. All other authors report no conflicts of interest.

Background: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown., Methods: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated., Results: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group., Conclusions: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised., Methods: We performed a multi-institutional, retrospective study of patients with advanced melanoma treated with anti-PD-1 monotherapy or ICI combination (ipilimumab and anti-PD-1). Response rates, survival, and toxicities were examined based on age comparing those under 40 years of age with older patients (age 41-70 and ≥ 71 years)., Results: A total of 676 patients were included: 190 patients (28%) aged ≤40 years, 313 (46%) between ages 41-70, and 173 patients (26%) aged ≥71. Patients ≤40 years had higher response rates (53% vs 38%, p = 0.035) and improved progression-free survival (median 13.7 vs 4.0 months, p = 0.032) with combination ICI compared to monotherapy. Progression-free survival was similar among groups while overall survival was inferior in patients >70 years, who had low response rates to combination therapy (28%). ICIs had a similar incidence of severe toxicities, though hepatotoxicity was particularly common in younger patients vs. patients >40 with monotherapy (9% vs. 2%, p = 0.007) or combination ICI (37% vs. 10%, p < 0.001)., Conclusions: ICIs had comparable efficacy between younger and older patients, although outcomes were superior with combination ICI compared to monotherapy in patients aged ≤40 years. Toxicity incidence was similar across age groups, though organs affected were substantially different., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, and Targovax, and has received research funding from BMS and Incyte. RJS has served on advisory boards or as a consultant for BMS, Eisai, Iovance, Merck, Novartis, Oncosec, and Pfizer, and has received research funding from Merck. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion, Hexal AG, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, and Regeneron. MSC is a consultant advisor for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, and Roche; honoraria: Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics. IMR has served on advisory boards or as a consultant for Amgen, BMS, GSK, Novartis, MSD, Roche, Celegene, Pierre Fabre, Highlight Therapeutics (formerly Bioncotech), Regeneron, Sanofi, Merck Serono, Astra Zeneca, BiolineRx, and Sun Pharma. EMC has served on advisory boards or as a consultant for Amgen, BMS, GSK, Novartis, MSD, Roche, Celegene, Pierre Fabre, Regeneron, Sanofi, Merck Serono, Astra Zeneca, and Sun Pharma. LZ (MGH) has served on advisory boards or as a consultant for Merck. SU declares research support from Bristol Myers Squibb, and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; outside the submitted work. LZ (Essen) reports personal fees and other (advisory board participation, travel grants) from Bristol-Meyers-Squibb, MSD, Pierre Fabre, Roche, and Novartis; other (advisory board participation and/or travel grants) from Sanofi and Amgen; all outside the submitted work. EL reports personal fees and other (advisory board participation and/or travel grants) from Amgen, BMS, MSD, Novartis, Roche, and medac; personal fees from Janssen; other fees from Actelion and Pierre-Fabre; all outside the submitted work. DS reports research finding to the institution for clinical studies or research from BMS, MSD, Novartis, Amgen, Array; patient fees to the institution from BMS, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, SunPharma, Sandoz, and UltimoVacs; reimbursement for travel from BMS, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; non-financial support from BMS, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, SunPharma, and Sandoz; all outside the submitted work. SMB has served as a consultant for Two River Consulting and Third Rock Ventures and reports equity holdings in Kronos Bio and 76Bio. All remaining authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL)., Objective: To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI)., Design, Setting, and Participants: The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QOL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QOL end point., Interventions: Patients were randomized (1:1) to treatment with adjuvant pembrolizumab vs standard of care with ipilimumab/HDI., Main Outcomes and Measures: Quality of life was assessed for patients at baseline and cycles 1, 3, 5, 7, and 9 after randomization using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy-Diarrhea, and European QOL 5-Dimension 3-Level scales. The primary end point was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate QOL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and programmed cell death ligand 1 status. A clinically meaningful difference of 5 points was targeted., Results: Among 1303 eligible patients (median [range] age, 56.7 [18.3-86.0] years; 524 women [40.2%]; 779 men [59.8%]; 10 Asian [0.8%], 7 Black [0.5%], 44 Hispanic [3.4%], and 1243 White [95.4%] individuals), 1188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3 (ipilimumab/HDI = 267 [32.1%]; pembrolizumab = 565 [67.9%]). Evaluable patients were predominantly younger than 65 years (623 [74.9%]) and male (779 [58.9%]). Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% CI, 7.9-11.3; P < .001) higher (better QOL) for pembrolizumab compared with ipilimumab/HDI, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favor of pembrolizumab through cycle 7. In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8; P < .001) or HDI (difference, 17.0 points; 95% CI, 14.6-19.4; P < .001)., Conclusions and Relevance: This secondary analysis of a phase 3 randomized clinical trial found that adjuvant pembrolizumab improved QOL vs treatment with adjuvant ipilimumab or HDI in patients with high-risk resected melanoma., Trial Registration: ClinicalTrials.gov identifier: NCT02506153.

Background: Gastrointestinal immune-related adverse events are frequently caused by immune checkpoint inhibitors (ICIs) and often require interruption of cancer treatment. Compared with ICI colitis and enteritis, limited information exists about ICI gastritis. This study characterized clinical features and treatment outcomes of ICI gastritis., Methods: Consecutive cancer patients who received ICIs and underwent endoscopy with gastric biopsies while on ICIs from 2011 to 2021 were retrospectively assessed. Specific histopathologic features identified ICI gastritis., Results: Of 6450 ICI-treated patients, 162 (2.5%) underwent endoscopy with gastric biopsies. ICI gastritis was identified in 54 (33%) biopsied patients; 38 (70%) had concurrent ICI enteritis/colitis and 16 (30%) had isolated ICI gastritis. Dyspepsia (38%) and bloating (25%) were the most frequent symptoms of isolated ICI gastritis. Compared with patients with concomitant enteritis/colitis, patients with isolated gastritis were less likely to have diarrhea (13% vs 68%; p < .001) or abdominal pain (19% vs 47%; p = .07). Patients with isolated ICI gastritis less frequently required glucocorticoids (69% vs 92%; p = .04) and had lower incidence of ICI hold/withdrawal (13% vs 42%; p = .06). There was no association between severity or extent of luminal inflammation and antitumor response (p = .85 and p = .44, respectively). Endoscopically, gastric mucosa appeared normal in 11 (20%) patients with biopsy-proven ICI gastritis., Conclusion: ICI gastritis may present alone or more commonly with concurrent enteritis/colitis, which may differentiate its clinical course. Gastric biopsies are required to diagnose a substantial minority of endoscopically normal, clinically significant cases. Most patients with isolated gastritis can continue ICI therapy uninterrupted, but a notable proportion require glucocorticoids., Plain Language Summary: Immune checkpoint inhibitors are effective anticancer treatments, but can cause inflammatory toxicities, including of the stomach (gastritis), intestine, and colon. Limited information is available on gastritis triggered by these agents. Adult patients with cancer who were treated with immune checkpoint inhibitors and had an upper gastrointestinal endoscopy with biopsies of the stomach were examined. More than two-thirds (70%) of people with checkpoint inhibitor gastritis also had inflammatory changes of the small intestine and/or colon. Compared with patients with isolated checkpoint gastritis, the subgroup with concomitant enteritis/colitis more frequently had abdominal pain, diarrhea, needed steroids, and/or needed to pause or stop antitumor therapy., (© 2022 American Cancer Society.)

Abstract: Cancer treatment has dramatically changed over the last decade with the development of immunotherapy. Therapies including immune cytokines, immune checkpoint inhibition, intratumoral therapies, and cellular therapies are already widely used in the oncology clinic. Active development continues in these areas and in the development of vaccines, bispecific therapies, and more refined cellular therapies. In this review, we will examine the role that immune therapy has in cancer treatment and explore areas of future development., Competing Interests: Conflicts of Interest and Source of Funding: E.I.B. has served on advisory boards for Nektar, Novartis, Apexigen, Shionogi, and BMS and received research funding from Lilly, Novartis, Partners therapeutics, Genentech, BMS, and BVD. F.S.H. serves as an advisor or consultant for BMS, Merck, EMD Serono, Novartis, Surface Oncology, Compass Therapeutics, Apricity, Sanofi, Pionyr, Bicara, Checkpoint, Genentech/Roche, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, Kairos, Eisai, Rheos, Zumutor, and Corner Therapeutics., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race., Patients and Methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted., Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01)., Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival., Competing Interests: Disclosure FD: receives/received honoraria and travel support from Merck Sharp & Dohme Bristol-Myers Squibb and Sun Pharma. KN: honoraria from Ono Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb and MSD. EIB: has received consulting fees from BMS and Novartis; has research funding paid to the institution from BMS, Merck, Novartis and Genentech. JAS: conference support from MSD. AZ: received travel support from Novartis, Sanofi Grenzyme and Bristol-Myers Squibb, outside the submitted work. MJM: served as a consultant for AstraZeneca, immunai, nektar therapeutics, catalyst pharmaceuticals and istari oncology. YN: consultant/advisory board—MSD, Novartis. Institutional research funding—Kaken, Ono pharma, Pola Pharma, Torii. Honoraria—BMS, Maruho, MSD, Novartis, Ono Pharma, Taisho Toyama, Taiho Pharma. XB: merit award supported by BMS.CA: Travel accommodations—meetings: Roche, BMS, AMGEN. AI: advisory board: Novartis. Honoraria for lectures: BMS, MSD, Novartis, Sanofi, Pierre-Fabre. MF: advisory board—Bayer. KCK: has served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. VA: personal fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec. OK: personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. AH: has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre and Q Biotic. RDC: consultant/advisory board—Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, Trisalus. OH: speaker’s bureau honoraria from BMS, Novartis, Pfizer and Sanofi Regeneron, and is an advisory board member/consultant for Aduro, Akeso Bio, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus and Zelluna. AH: received grants and personal fees from Amgen, BMS, Immunocore, Novartis, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and Sun Pharma, outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD and Novartis. MM: received honoraria for participation at advisory boards from Novartis, BMS, MSD, Pierre Fabre, Sanofi, reports lecture from Novartis, BMS, MSD, Pierre Fabre, Sanofi and reports grants from Roche, Novartis. CR: advisor for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Merck, Roche, AstraZeneca and is scientific founder of Aglaia therapeutics. CL: BMS: research grant, honoraria, consultancy, speaker’s bureau, travel accommodations—meetings, advisory role, serving on an advisory board; MSD: honoraria, consultancy, advisory role, serving on an advisory board, travel accommodations—meetings; Novartis: honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Amgen: honoraria, consultancy, speaker’s bureau, serving on an advisory board; Roche: research grant, honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Avantis Medical Systems: board; Pierre-Fabre/Pfizer/Incyte: honoraria. JG: consultant/advisory boards for MSD, Roche, Pfizer, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences and Oriengene. DBJ: advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance Biotherapeutics, Janssen, Merck, Novartis and OncoSec. Research support from Bristol Myers Squibb and Incyte. PAA: has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. ANS: advisory board/personal fees: Bristol-Myers Squibb, Immunocore, Novartis, Castle Biosciences. Institutional trial support: Bristol-Myers Squibb, Immunocore, Novartis, Xcovery, Polaris, Pfizer, Checkmate Pharmaceuticals, Forghorn Therapeutics. RJS: advisory board—BMS, Merck, Novartis, Pfizer; research support from Merck. LZ: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis. SS: grants from Novartis, AstraZeneca, Merck Sharp & Dohme and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme and Bristol Myers Squibb, outside the submitted work. CUB: personal fees from BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, grants from BMS, Novartis, NanoString, other from Uniti Cars, Forty Seven, Neon Therapeutics, Verastem, other from Immagene B.V. RD: intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work. BCS: speaker’s bureau honoraria and personal fees from BMS, Novartis, MDS, Pierre Fabre. AMM: advisory board—BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. GVL: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. All other authors have declared no conflicts of interest. Data sharing Availability of data and material: patients’ medical records. All data were anonymized immediately after collection., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of interest Dr LeBoeuf is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, and Synox Therapeutics outside the submitted work. Drs Bougrine, Bui, Buchbinder, and Giobbie-Hurder have no conflicts of interest to declare.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma., Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

Introduction: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown., Methods: Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined., Results: In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed., Conclusion: Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SMG has past advisory board relationships and travel grant support from MSD, BMS, Novartis and Roche. She received research time support from the University of Zurich and medAlumni. KBB received travel grant support from Novartis and honoraria from MSD. SL has no conflicts of interest to declare. AF has occasional advisory board relationships with Novartis, Roche, MSD and receives travel grant support from Novartis, Roche, BMS. MM has no conflicts of interest to declare. LZ served as a consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sun Pharma, Sanofi and Novartis, outside the submitted work. CK declares travel support from Roche. RD has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Takeda, Pierre Fabre and Sun Pharma. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. ZE on prior advisory boards for Pfizer, Novartis, Genentech, Regeneron, Array, Eisai, OncoSec, Signatura, Sun Pharma; Research funding from Novartis and Pfizer. EB: Consulting as an advisory board member for Nektar and BMS. Clinical trial support from Lilly, Novartis, Partners therapeutics, Genentech and BVD. PA has advisory board relationships with BMS, Roche-Genentech, MSD, Array, Novartis, Amgen, Merck Serono, Pierre-Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, Sindax, Astra Zeneca and receives research funding from BMS, Roche, Genentech, Array. RG: Research support (to institution): Pfizer, Johnson & Johnson, Novartis, SUN, Amgen, Sanofi, Merck-Serono. Honoraria for lectures (personally): Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Merck-Serono and Sanofi. EAR has no conflicts of interest to declare. CH has no conflicts of interest to declare. DBJ has advisory board relationships with Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis and Oncosec and receives research funding from BMS and Incyte. AG: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. PK has occasional advisory board relationships with BMS, Roche, Amgen, Novartis, MSD and receives travel grant support from BMS and MSD. NB has no conflicts of interest to declare. JVC has no conflicts of interest to declare. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. MAW has an advisory role for Array Biopharma. JC has served as a consultant and has received honoraria from Sanofi-Genzyme and Bristol-Myers Squibb. VA has advisory board role for BMS, MSD, Novartis, Roche, Pierre Fabre, Nektar, Q Biotics; speakers fees from BMS, MSD, Novartis, Pierre Fabre, Limbic and travel support from BMS. JLS: honoraria from Bristol-Myers Squibb, MSD and Pierre Fabre. OM has intermittent advisory board relationships and receives honoraria from Roche, Novartis, BMS, MSD, Amgen, Pierre Fabre. He receives research funding from Roche, BMS, Novartis, MSD and Amgen. 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., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. JCH has research support from BMS, advisory board relationship with Pierre Fabre, Sanofi, Sun Pharma and MSD; receives speakers honoraria from BMS, MSD, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. BW receives research funding from BMS und MSD. LEH has no COI nor funding to disclose. DS: Dr. Schadendorf reports grants, personal fees and other from BMS, during the conduct of the study; personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from Novartis, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees from Sanofi/Regeneron, non-financial support from Merck, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, outside the submitted work. GM receives reimbursement of clinical trial costs to his institution from Roche-Genentech and Array Biopharma/Pfizer. PAO reports research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus and Roche/Genentech. CB has advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; has research funding (incl IIS funding) from BMS, MSD, 4SC, Novartis, NanoString; and has stock ownership from Uniti Cars, co-founder Immagene BV. CR has occasional advisory board relationships and receives honoraria from BMS, MSD, GSK, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi. RJS reports grant support from Merck and Amgen, as well as personal fees for consulting/advisory board membership for AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune. AH reports grant support and personal fees from Amgen, BMS, Eisai, Immunocore, MerckPfizer, MSD/Merck, Novartis Pharma, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and from SeaGen outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, OncoSec, Pierre-Fabre, QBiotics, Regeneron, Roche, Merck and Sanofi and received honoraria from BMS, MSD and Novartis. CG: Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. MAD: is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. He has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. AMM: Advisory board fees from BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In the past decade, the field of cancer immunotherapy has rapidly advanced, establishing a crucial role for immune checkpoint blockers in the treatment of a variety of cancer types. In parallel with these remarkable clinical developments, further efforts have focused on ways of unleashing adaptive immune responses against cancer. CD47, a cell surface molecule overexpressed by several cancer types that facilitates immune escape from macrophages, dendritic cells and natural killer cells, and its ligand SIRPα, have emerged as potential therapeutic targets. A number of agents directed to CD47/SIRPα have been developed and demonstrated preclinical activity. Early phase clinical trials are investigating CD47/SIRPα directed agents with available data, suggesting safety and preliminary activity. Herein, we provide an overview of the mechanistic rationale of targeting CD47/SIRPα axis and associated clinical evidence.

Background: Angiogenic factors promote the growth of tumor vasculature, modulate lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein- (CTLA-4), is safe in patients with advanced melanoma., Methods: In a phase I, 3+3 dose escalation trial, patients with metastatic or unresectable melanoma received treme in combination with MEDI3617. The primary objectives of the study were safety and determination of recommended phase II dose (RP2D). The secondary objectives included determination of 6-month and 1-year overall survival and best overall response rate. Immune cell populations and soluble factors were assessed in peripheral blood and metastatic tumors using Fluorescence activated cell sorting (FACS), Luminex, and multiplexed immunofluorescence., Results: Fifteen patients (median age: 62) were enrolled in the study (3 patients in cohort 1: treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related adverse events were rash, pruritus, fatigue, and extremity edema. No dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. There were no patients with confirmed immune-related complete response or immune-related partial response. Six of 15 patients had immune-related stable disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An increase in frequencies of circulating inducible T-cell costimulator (ICOS) + and human leukocyte antigen (HLA)-DR + CD4 + and CD8 + T cells and production of Interleukin-2 and Interleukin-10 was observed post therapy., Conclusions: Tremelimumab in combination with MEDI3617 is safe in patients with advanced melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint inhibition warrants further exploration., Trial Registration Number: NCT02141542., Competing Interests: Competing interests: PO reports research funding from and has advised Neon Therapeutics, Bristol Myers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus, and Roche/Genentech. RH reports research grant support from Novartis and consulting for Tango Therapeutics. EB reports consulting as an advisory board member for Novartis, Apexigen, Shionogi, and BMS, and clinical trial support from Lilly, Novartis, Partner Therapeutics, Genentech, and BVD. SR reports research support from Bristol Myers Squibb, Merck, Affimed, and KITE/Gilead, and scientific advisory board membership for Immunitas. RS reports grant funding as well as personal fees from Merck. He has received personal fees from Array Biopharma, Asana Biosciences, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, and Replimune. DM reports grant funding from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, and personal fees for consulting from Bristol Myers Squibb, Merck, Pfizer, Alkermes, EMD Serono, Eli Lilly, Iovance, Eisai, Werewolf Therapeutics, and Calithera Biosciences. FSH reports grants, personal fees, and other from Bristol Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees, and other from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Sanofi, personal fees from Pionyr, personal fees from Torque, personal fees from Rheos, personal fees from Bicara, other from Pieris Pharmaceuticals, personal fees from Eisai, personal fees from Checkpoint Therapeutics, personal fees from Idera, personal fees from Takeda, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Trillium, and personal fees from Catalym, outside the submitted work. In addition, FSH has a patent method for treating MICA-related disorders (#20100111973) with royalties paid, a patent tumor antigen and uses thereof (#7250291) issued, a patent angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (#20170248603) pending, a patent for compositions and methods for identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (#20160340407) pending, a patent therapeutic peptides (#20160046716, #20140004112, #20170022275, #20170008962) pending, a patent therapeutic peptides (#9402905) issued, a patent method of using pembrolizumab and trebananib pending, a patent vaccine compositions and methods for restoring NKG2D pathway function against cancers (patent number: 10279021) issued, a patent antibody that binds to MHC class I polypeptide-related sequence A (patent number: 10106611), and a patent antigalectin antibody biomarker predictive of anti-immune checkpoint and antiangiogenesis responses (publication number: 20170343552) pending., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti-programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma-molecular graded prognostic assessment (molGPA) prognostic risk groups. Baseline clinical covariates were used to identify predictors of OS in univariate/multivariable Cox proportional-hazards models. A total of 84 patients (58 monotherapy, 26 combination) were included with a median duration of follow-up of 43.4 months (maximum: 5.1 y). The median OS [95% confidence interval (CI)] was 3.1 months (1.8, 7) for ds-GPA 0-1, 22.1 months [5.4, not reached (NR)] for ds-GPA 2 and NR (24.9, NR) for ds-GPA 3-4 in the monotherapy cohort [hazard ratio (HR) for ds-GPA 3-4 vs. 0-1: 0.13 (95% CI: 0.052, 0.32); 0.29 (95% CI: 0.12, 0.63) for ds-GPA 2 vs. 0-1]. The median OS was 1.1 months (95% CI: 0.3, NR) for ds-GPA 0-1, 11.8 months (95% CI: 2.9, 23.3) for ds-GPA 2 and 24.4 months (95% CI: 3.4, NR) for ds-GPA 3-4 in the combination cohort [HR for 3-4 vs. 0-1: 0.013 (95% CI: 0.0012, 0.14); HR for ds-GPA 2 vs. 0-1: 0.033 (0.0035, 0.31)]. Predictors associated with longer survival included ds-GPA or molGPA>1 (among prognostic indices), neutrophil-to-lymphocyte ratio (<4 vs. ≥4), while high lactate dehydrogenase, neurological symptoms, and leptomeningeal metastases were associated with shorter survival. Baseline ds-GPA/molGPA>1 and neutrophil-to-lymphocyte ratio <4 were strong predictors of long-term survival to anti-PD-1-based immune checkpoint inhibitors in melanoma brain metastases patients previously naive to anti-PD-1 therapy in a real-world clinical setting treated at independent centers., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels., Methods: We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log 2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment., Results: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%)., Conclusions: Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.

Immunotherapy with immune checkpoint inhibition has dramatically changed the treatment of melanoma. Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 are approved for the treatment of advanced melanoma alone and in combination. In addition, these agents are approved for use in high-risk resected stage III melanoma in the adjuvant setting. Clinical trials testing the combination of immune checkpoint inhibition with other therapies and novel immunotherapies continue. This article reviews the current literature on approved uses of immune checkpoint inhibition in melanoma and discusses ongoing trials and future directions., Competing Interests: Disclosure Dr E.I. Buchbinder received compensation for consulting from BMS, Trieza, Novartis, and Partner Therapeutics. She receives clinical trial support form Eli Lilly, Novartis, BMS, Genentech, and BVD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care., Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies., Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed., Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility., Conclusions and Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Purpose: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn's disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis., Methods: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis., Results: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti-tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare., Conclusion: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7 , whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7 -deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations. This article is highlighted in the In This Issue feature, p. 1241 ., (©2020 American Association for Cancer Research.)

Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis., Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital., Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort., Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies., (© 2020 American Cancer Society.)

Aim: Talimogene laherparepvec (T-VEC) is an intralesional therapy for unresectable, metastatic melanoma. T-VEC real-world use in the context of anti-PD1-based therapy requires further characterization., Materials & Methods: A retrospective review of T-VEC use from 1 January 2017 and 31 March 2018 for melanoma patients was conducted at seven US institutions., Results: Among 83 patients, three categories of T-VEC and anti-PD-1 therapy were identified: T-VEC used without anti-PD-1 (n = 29, 35%), T-VEC after anti-PD-1-based therapy (n = 22, 27%) and concurrent T-VEC and anti-PD-1-based therapy (n = 32, 39%). 25% of patients discontinued T-VEC therapy due to no remaining injectable lesions, 37% discontinued T-VEC due to progressive disease. Discontinuation of T-VEC did not differ by anti-PD-1-based therapy use or timing., Conclusion: In real-world settings, T-VEC may be used concurrently with or after anti-PD-1-based therapy., Competing Interests: Financial & competing interests disclosure This study was funded by Amgen. J Sun received research funding from Amgen. JS Zager has received research funding from Novartis, Philogen, Delcath Systems, Amgen, Provectus, and served on Advisory Boards for Merck, Sanofi/ Regeneron, Novartis and Array BioPharma and Speakers Bureau for Array BioPharma, Castle Biosceicnes and Sun Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 The Authors.)

Purpose of Review: The past decade has been a time of remarkable advancement in the field of adjuvant therapy for patients with resected high-risk melanoma. Here, we review the data for adjuvant melanoma and raise questions about the best choice of therapy for an individual patient., Recent Findings: There have been several new adjuvant approvals including immunotherapy and targeted therapy approaches. Nivolumab is approved for patients with nodal involvement or metastatic disease after resection. Pembrolizumab is approved for patients with nodal involvement after resection. In addition, the combination of dabrafenib and trametinib is approved in patients' nodal involvement after resection whose tumors harbor BRAF V600E/K mutations. New therapeutic opportunities have provided promising options for patients with high-risk disease. These advances have significantly challenged the previous standard-of-care for this population of patients. Data is still forthcoming regarding durability of benefit and safety of these new treatments.

Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 + T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO + GZMB + Ki67 + ) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV + lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 + and CD8 + T cells as culprits of checkpoint inhibitor-associated immune encephalitis.

The development of immunotherapy to target cancer has led to improved treatment of many types of malignancy. The immune checkpoint inhibitors are a class of medications that block cell signaling and allow the immune system to recognize and attack cancer cells. CTLA-4, PD-1, and PD-L1 inhibitors have been approved as treatment options in many different types of localized and advanced malignancies. Immune checkpoint inhibitors can be associated with unique side effects known as immune-related adverse events. Side effects most commonly occur in the skin, gastrointestinal tract, lung, and endocrine glands but can affect other organ systems as well., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting., Methods: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models., Results: Overweight/Class-I (25- < 35 kg/m 2 ) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m 2 ). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HR males :0.11; 95%CI:0.03-0.4; adjusted-HR females : 0.56; 95%CI:0.16-1.89 ; p-value interaction :0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-value interaction :0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts., Conclusions: The findings support the existence of an "obesity paradox" restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).

Background: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored., Methods: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIM SM database. Patient characteristics, toxicity and efficacy were analyzed., Results: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy., Conclusion: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.

Under current AJCC staging criteria, stage IIC patients paradoxically have worse outcomes than IIIA patients despite the lack of nodal metastatic disease. This study sought to identify additional clinicopathologic characteristics correlated with worse patient outcomes. Retrospective chart review of stage IIC and IIIA melanoma patients were evaluated between 1995 and 2011 with clinical follow-up through 2015. Records were reviewed for demographics, clinical characteristics, and tumor pathology. Fisher's exact test and Wilcoxon's rank-sum test were used to assess group differences. Clinicopathologic features were evaluated relative to overall survival (OS), time to distant metastases, and local/regional recurrence. Overall, 128 patients were included (45 stage IIC and 83 stage IIIA) with a median follow-up time of 5.7 years. Compared with stage IIIA patients, stage IIC patients were older, and their melanomas were more likely to be nodular, amelanotic, thicker, have higher mitotic rate, tumor lymphocytic infiltrate, no radial growth phase, and less likely to have associated precursor lesions. Stage IIC patients had shorter OS and time to distant metastases; multivariate regression revealed that older age (>55 years) and mitotic rate (>5 mitoses/mm) were independent predictors of OS. Melanomas in stage IIC disease may be biologically distinct from those that are seen in stage IIIA. While sentinel node biopsies remain the standard-of-care, these results suggest that clinicians may want to assess the clinicopathologic characteristics described above to aggressively counsel, screen for distant disease, and consider adjuvant therapy, in particular for older patients and higher mitotic rates in thicker primary tumors, regardless of nodal status.

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/nature22991.

Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups ( P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti-PD-1 or combination anti-PD-1 and anti-CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133-40. ©2017 AACR ., (©2017 American Association for Cancer Research.)