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The article discusses the effectiveness of cemiplimab in the treatment of patients with advanced cutaneous squamous cell carcinoma. The study presents findings of the phase 1 study of cemiplimab for patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, and the pivotal phase 2 study for patients with metastatic disease. It implies that cemiplimab was linked to adverse events in patients with advanced cutaneous squamous-cell carcinoma.

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14-20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets.

Background: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM., Patients and Methods: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed., Results: 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing., Conclusions: This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp., Competing Interests: Competing interests: JJS discloses PI on clinical trial: Amgen, AstraZeneca, Bristol-Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; Research Grant/Contract: AstraZeneca, Bristol-Myers Squibb, Immunocore; Consultant/Advisory Board: Bristol-Myers Squibb, Delcath Systems, Immunocore, Merck; Congress attendance: Bristol-Myers Squibb, Merck. RDC discloses Consultant: Aura Biosciences, Castle Biosciences, Chimeron, Immunocore, InxMed, Iovance, Merck, Oncosec, Pierre Fabre Pharmaceuticals Inc., PureTech Health, Regeneron Pharmaceuticals, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, TriSalus; Stock Option: Aura Biosciences, Chimeron, Rgenix. MOB discloses Consultant/Advisory Board: Adaptimmune, Bristol-Myers Squibb Canada, GlaxoSmithKline, Immunocore, Instil Bio, Iovance Biotherapeutics, Merck, Novartis, Pfizer, Sanofi Pasteur Inc., Sun Pharma, IDEAYA Bio, Medison, Regeneron and Iovance.; Safety Review Committee: GlaxoSmithKline, Adaptimmune; Research Funding: Merck, Takara Bio, Novartis. ANS discloses Grant/Contract: Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Pfizer, Alkermes, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Bristol-Myers Squibb, Immunocore, Novartis, Pfizer, Polaris, Xcovery. JCH discloses Speaker: Amgen, Bristol-Myers Squibb, GSK, Immunocore, Merck Sharp and Dohme, Novartis Pharma, Pierre Fabre, Sanofi-Aventis U.S. LLC; Sunpharma; Research grant/contract: Bristol-Myers Squibb, Sanofi, Sunpharma; Consultant/Advisory Board: Bristol-Myers Squibb, GSK, Immunocore, Merck Sharp and Dohme, Novartis Pharma, Pierre Fabre Pharmaceuticals Inc., Philogen, Onkowissen, Sanofi-Aventis U.S. LLC, Sun Pharmaeutical Industries Inc. AI discloses Research Funding to Institution: Dynavax, GSK/Sarah Cannon, Immunocore, Merck, Neon Therapeutics/Sarah Cannon, Checkmate Pharmaceuticals. LH-A discloses Advisory/Consulting: BMS, Castle Bioscience; Research Funding to Institution: BMS, AstraZeneca, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, Genentech, Foghorn. PN discloses Data and Safety Monitoring: 4SC, Achilles; Consultant/Advisory Board: 4SC, Bristol-Myers Squibb, Immunocore, Merck, Merck Sharp and Dohme, Novartis, Pfizer; Research Grant/Contract: Immunocore. OH discloses Contract: Aduro biotech, Akeso biotech, Amgen Inc., Beigene Ltd, Bioatla, Bristol-Myers Squibb, Genentech USA, Inc., GlaxoSmithKline, Idera Pharmaceuticals, Immunocore, Incyte Corporation, Janssen Global Services, LLC, Merck, Next Cure Inc., Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, Seattle Genetics, Tempus, Zelluna Immunotherapy; Contracted Research for Institution: Aduro biotech, Akeso biotech, Amgen Inc., Arcus Biosciences, Bioatla, Bristol-Myers Squibb, CytomX Therapeutics, Exelixis Inc., Genentech, GlaxoSmithKline, Idera Pharmaceuticals, Immunocore, Incyte Corporation, Iovance Biotherapeutics, Merck, Merck Serono, Moderna, NextCure Inc., Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Seattle Genetics, Torque Pharma, Zelluna Immunotherapy; Speakers Bureau: Bristol-Myers Squibb, Novartis, Pfizer. MR discloses employment and stock ownership in Syapse Inc. DBJ discloses Advisory Boards/Consultant: Bristol-Myers Squibb, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko; Research Funding: Bristol-Myers Squibb, Incyte. JJL discloses DSMB: AbbVie, Agenus, Amgen, Immutep, Evaxion; Scientific Advisory Board: (no stock) 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; Consultancy with compensation: 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; Research Support: (all to institution for clinical trials unless noted) 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; Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). EE discloses Advisory Boards/Consultant: Immunocore. SL discloses Consulting: Bayer, Immunocore; Expenses: Bayer. LC discloses Employment and Stock: Immunocore. CH discloses Stock: Amgen Inc., Macrogenics; Employment: Immunocore. TS discloses advisory/consulting: Immunocore, Castle Biosciences; research funding to institution (clinical trials): Immunocore, Verastem, IDEAYA, TriSalus, and BMS., (© 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.)

Background: Recent studies evaluating patients with a positive sentinel lymph node biopsy (SLNB+) show no melanoma-specific survival difference between patients undergoing lymph node basin surveillance and completion lymph node dissection (CLND). This has been broadly applied, despite underrepresentation of head and neck (HN) cutaneous melanoma patients. We evaluated whether this was upheld in the HN melanoma cohort., Methods: Patients with HN melanoma with a SLNB+ were selected from the National Cancer Database (NCDB) from 2012 to 2019. Overall survival (OS) of patients who underwent SLNB only versus SLNB + CLND were compared. Subgroup analyses were performed based on pathologic N (pN) and receipt of immunotherapy. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were calculated., Results: Analysis of 634 patients with multivariable Cox regression showed no difference in OS in SLNB only versus SLNB + CLND cohorts (hazard ratio [HR] 1.13; 95% confidence interval [CI] 0.71-1.81; p = 0.610). Charlson-Deyo score (CDS) 1 versus 0 (HR 1.70; 95% CI 1.10-2.63; p = 0.016), pN2+ versus pN1 (HR 1.74; 95% CI 1.23-2.45; p = 0.002), and lymphovascular invasion (LVI) versus no (HR 2.07; 95% CI 1.34-3.19; p = 0.001) were associated with worse prognosis. Subgroup analysis by pN showed no OS benefit for CLND in either pN1 (HR 1.04; 95% CI 0.51-2.10; p = 0.922) or pN2+ (HR 1.31; 95% CI 0.67-2.57; p = 0.427) patients or in patients who received immunotherapy (HR 1.32; 95% CI 0.54-3.22; p = 0.549)., Conclusions: This study of SLNB + HN melanoma patients showed no OS difference in SLNB only versus SLNB + CLND. Further studies need to be performed to better define the role of CLND., (© 2023. Society of Surgical Oncology.)

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Competing Interests: None disclosed.

Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial., Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS., Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among β-blocker users and 0.59 (95% CI 0.48-0.71) among those not using β-blockers., Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Competing Interests: Conflict of interest statement Alexander Eggermont Consulting fees: Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck/MSD, Nektar, Novartis, Pfizer, SAiRoPA, Sellas, SkylineDx, TigaTx, TTxDiscovery. Payment or honoraria: Biocad, BMS, Merck/MSD. Participation on a Data Safety Monitoring Board or Advisory Board: GSK, Novartis and Pfizer. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences German Cancer Aid. Stock or stock options: SkylineDx and SAiRoPA. Rutger Koornstra Grants or contracts from any entity: Roche. Leonel Hernandez-Aya Grants or contracts from any entity: Bristol Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck, Polynoma, Corvus Pharmaceuticals, Roche, Genentech, Merck Serono, Amgen, MedImmune, Takeda Pharmaceuticals, Moderna Therapeutics. Consulting fees: Massive Bio, Bristol Myers Squibb - Advisory Board. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi, Regeneron Pharmaceuticals - Speakers bureau. Support for attending meetings and/or travel: Sanofi, Regeneron Pharmaceuticals, Bristol Myers Squibb. Anna Maria di Giacomo Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb. Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob Consulting fees: Bristol Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis - Speakers bureau. Support for attending meetings and/or travel: BMS, MSD Oncology, Novartis, Pierre Fabre. Ralf Gutzmer Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb. Caroline Robert Consulting fees: ROCHE, NOVARTIS, PIERRE FABRE, MSD, BMS, SANOFI, PFIZER, AstraZeneca. Oliver John Kennedy None declared. Paul Lorigan Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: BMS, Merck, GSK. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pierre Fabre, Novartis, MSD, BMS. Support for attending meetings and/or travel: BMS, Support to attend ASCO, MSD - Support to attend ASCO. Mario Mandalà Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, NOVARTIS, PIERRE FABRE, SANOFI. Participation on a Data. Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre - Advisory Boards. Michal Kicinski All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: Pierre Fabre - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution), BMS - Sponsor and provider of an academic grant for different melanoma studies (money paid to my institution). Stefan Suciu All support for the present manuscript: Merck - Merck is the sponsor of the study (money paid to my institution). Grants or contracts from any entity: BMS, Pierre-Fabre - Sponsor and provider of academic grants to other EORTC melanoma studies; payments were made to my institution. Sara Valpione None declared. Sara Gandini None declared. Christian Blank Grants or contracts from any entity: BMS, Novartis, NanoString, and 4SC. Consulting fees: BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre - Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Unity Cars – Stocks, Immagene BV – Co-founder. Alexander C.J. van Akkooi Grants or contracts from any entity: Amgen, Merck-Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC. Georgina V Long Consulting fees: 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, Specialised Therapeutics Australia Pty Ltd. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Participation on a Data: Safety Monitoring Board or Advisory Board: See consulting fees, All for advisory boards. Victoria Atkinson Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp & Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Merck - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Pierre Fabre, Merck Sharp & Dohme - Advisory Boards. Andrey Meshcheryakov Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino Payment or honoraria for lectures, presentations, speakers bureauads, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis - Honoraria for lectures, presentations, speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron Pharmaceuticals, QBiotics, Nektar, Eisai - Advisory Board. Shahneen Sandhu Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Merck Serono, Genentech, AstraZeneca - Funding to the institution. Consulting fees: Amgen, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Bristol Myer Squibb - Funding to the institution. James Larkin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare research, Royal College of General Practitioners, VJOncology, Agence Unik, Bristol Myers Squibb - Honoraria for lectures, presentations. Participation on a Data Safety Monitoring Board or Advisory Board: Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, MCA, Inselgruppe, Pfizer, Goldman Sachs, MSD - Advisory Board. Susana Puig Grants or contracts from any entity: Almirall - To My Institution, ISDIN - To My Institution, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Rohe Posay - To Me, Sanofy, Sunpharma - To Me, Pfizer, Roche, Regeneron - To Me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay - To Me, Pfizer, Roche, Regeneron - To Me, BMS, Sunpharma - TO ME. Support for attending meetings and/or travel: Almirall - TO ME. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofy - To Me, Sunpharma, Almirall - To Me, ISDIN, Pfzer, Novartis - TO ME. Paolo A. Ascierto Grants or contracts from any entity: Bristol Myers Squibb, Roche, Genentech, Array BioPharma - To my institution. Consulting fees: Bristol Myers Squibb, Roche, Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche, Genentech, Merck - Advisory Board. Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma Industries, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron Pharmaceuticals - To me. Piotr Rutkowski Grants or contracts from any entity: Novartis, Roche, Bristol Myers Squibb - My institution. Consulting fees: Bristol Myers Squibb, MSD, Novartis, Roche, Eli Lilly, Pfizer, Pierre. Fabre - Advisory Role - Personal fees. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen - Advisory boards, To me, Pfizer, Novartis, Eli Lilly - speakers bureaus. Participation on a Data Safety Monitoring Board or Advisory Board: See above - Advisory Board. Dirk Schadendorf Grants or contracts from any entit: Bristol Myers Squibb, Novartis, Roche, MSD Oncology, Array BioPharma/Pfizer. Consulting fees: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharna, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Sandoz. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA - speakers bureaus. Support for attending meetings and/or travel: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron. Participation on a Data Safety Monitoring Board or Advisory Board: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar - Advisory Board., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Anti-PD-1-based therapies prolong survival in advanced melanoma, but disease progression is common. This study evaluated treatment patterns and overall survival (OS) after anti-PD-1 progression. Methods: Retrospective data from patients with advanced melanoma and progression on anti-PD-1 treatment between 2014 and 2019 were taken from Flatiron Health, which reflects largely community practice. Treatment patterns and OS were analyzed for BRAF mutant (mt) and wild-type (wt) subgroups; OS was also examined across all patients. Results: Progression following anti-PD-1 was recorded for 679 patients. Median OS ranged from 5.0 to 11.3 months. Of 275 BRAF mt and 374 BRAF wt patients, 113 (41.1%) and 228 (61.0%) received no subsequent therapy, respectively. However, 48.4% of BRAF mt and 57.8% of BRAF wt patients continued anti-PD-1 treatment beyond progression. Conclusion: This real-world study underscores the need for effective treatments for advanced melanoma post-progression on anti-PD-1 therapy.

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10 -4 , 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10 -7 ), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979., (© 2022. The Author(s).)

Background: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here., Methods: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients., Results: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952))., Conclusions: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas., Trial Registration Number: NCT01546571., Competing Interests: Competing interests: CLS discloses research funding to his University from Merck, Celldex, and GlaxoSmithKline; research support in kind to his University from Theraclion, 3M, Merck, and Celldex; Scientific Advisory Board role with Immatics (prior), and Curevac; principal investigator role for Polynoma with compensation to his university, related to this manuscript; and patent royalties as co-inventor of peptides for use in cancer vaccines (patents held by the UVA Licensing and Ventures Group). KDL received research funding from Polynoma. JH served on an advisory board for Nektar and BMS in 2020. SNM has received research grants from BMS and from Sorrento Pharma. TB is receiving time and effort support from Genentech for a melanoma prevention study and is the principal investigator for melanoma clinical studies sponsored by Genentech, Amgen, and Replimune. JC serves as consultant/speaker for Amgen, BMS, Merck, Novartis, Pfizer, Roche. SGH serves as an advisor to Incyte. BC has received honoraria from Merck (DSMB member), Clinigen (Ad board), Nektar (Ad Board), research support from Galectin Therapeutics, Clinigen. BMS (to Institution) and AstraZeneca (to Institution). MOB discloses roles on Advisory boards (Merck, BMS, Novartis, EMD Serono, Sanofi, Pfizer, Immunocore, GSK); safety Review Committees (GSK, Adaptimmune), and research funding from Merck and Takara Bio. JL has received research funding to his institution from BMS, Immunocore, Polynoma, Iovance and has participated in advisory boards from Regeneron and Array. DM directly is on speaker’s bureaus for Pfizer, Merck, Astellas, and SeaGen. TS serves on Advisory boards for Immunocore and Castle Biosciences. EH is on the speakers’ bureaus for Amgen and Castle Biosciences. SK is on the speakers’ bureau for Janssen, Pfizer, Roche/Genentech, AstraZeneca. RW is on a Speaker’s bureau for AstraZeneca. ABe has served as an advisor to Cardinal Health and Castle Biosciences. ABa is a consultant/speaker for Regeneron, Castle Biosciences, and receives research funding to her institution from Polynoma, Castle Biosciences, Pellepharm. CM has received grants, ad board and speaker fees from Novartis, BMS, Merck and Pfizer. VG is an investor in Medocity. DB: Research support- Natera; served on advisory boards for Merck, AstraZeneca, Novartis, Eli Lilly, Janssen, Oncocyte; speaker’s bureau-Janssen, Guardant. JJP is a paid consultant for Polynoma., (© 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.)

Background: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL)., Methods: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks)., Results: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001)., Conclusions: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement., Trial Registration Number: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498., Competing Interests: Competing interests: DR—institutional research grant and funding from Regeneron Pharmaceuticals, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, GlaxoSmithKline, and Sanofi; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; and travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. NIK—grants from Regeneron Pharmaceuticals; grants and advisory board fees from Bristol-Myers Squibb and HUYA Bioscience International; advisory board fees from EMD Serono, Regeneron Pharmaceuticals, Genentech, AstraZeneca (data safety monitoring committee), Incyte (data safety monitoring committee), Iovance, Merck, ARRAY Biopharma, Jounce Therapeutics, and Immunocore; grants from Merck, Novartis, GlaxoSmithKline, Celgene, and Amgen; honorarium from Sanofi; and common stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, Amarin, and Transenetrix. CDS—steering committee member for Castle Biosciences; steering committee member and consultant for Regeneron Pharmaceuticals; consultant for Sanofi; received research funding from Castle Biosciences, Regeneron Pharmaceuticals, Novartis, Genentech, and Merck; and is a chair for the National Comprehensive Cancer Network. AG—personal fees and non-financial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Merck KGaA, Eisai, and Pfizer; non-financial (travel) support from Astellas; and clinical trial unit support from PPD Australia. ALSC—consulting and advisory roles at Regeneron Pharmaceuticals and Merck; and research funding from Regeneron Pharmaceuticals, Novartis, Galderma, Jounce Therapeutics, and Merck. KDL—grants and personal fees from Regeneron Pharmaceuticals during the conduct of the study. AML—uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. LH-A—performed consulting and advisory roles at Massive Bio; speakers’ bureau roles at Sanofi and Regeneron Pharmaceuticals; received travel, accommodations, and expenses from Regeneron Pharmaceuticals, Sanofi, and Bristol-Myers Squibb; and research funding from Bristol-Myers Squibb, Regeneron Pharmaceuticals, Immunocore, Merck Sharp & Dohme, Polynoma, Corvus Pharmaceuticals, Roche, Merck Serono, Amgen, MedImmune, and Takeda. BGMH—consulting or advisory roles at Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Pfizer, Roche, Eisai, and Merck; and institutional research funding from Amgen. DS—institutional patients’ fees from Regeneron Pharmaceuticals; advisory board honorarium fees from Amgen and Leo Pharma; speaker fee from Boehringer Ingelheim; advisory board, speaker honorarium, and patients’ fees from Roche, Novartis, Bristol-Myers Squibb, and Merck-EMD; advisory board and speaker honorarium fees from Incyte and Pierre Fabre; advisory board honorarium and patients’ fees from MSD; steering committee honorarium fees from 4SC; advisory board fees from AstraZeneca, Pfizer, and Array; and advisory board and patients’ fees from Philogen. AH—institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals; and consultancy fees from OncoSec. ES, JB, S-YY, SL, ZC, EO, C-IC, VM, IL, MGF—employees of and shareholders in Regeneron Pharmaceuticals. MS—employee and shareholder in Sanofi. MRM—honoraria and travel expenses from Regeneron Pharmaceuticals, Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Novartis, Genentech, and Eli Lilly., (© 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.)

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results., Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37., Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73])., Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AMME reports being the study chair of the EORTC 18071/CA-029 phase 3 clinical trial (Bristol Myers Squibb [BMS]) and of the EORTC 1325/KEYNOTE-054 phase 3 trial (Merck Sharp & Dohme), and has worked in a consulting or advisory role and received honoraria from Biocad, Biotech, BioInvent, BMS, CatalYm, GlaxoSmithKline (GSK), IO Biotech, ISA Pharmaceuticals, Merck, Novartis, Regeneron Pharmaceuticals, Sellas, and SkylineDx. CUB reports receiving grants from BMS, NanoString Technologies, Novartis, and Third Rock Ventures and personal fees from AstraZeneca, BMS, GenMab, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, and Roche during the conduct of the study; he owns stocks in Unity Cars, and is co-founder of Immagene BV. MM reports receiving grants from BMS, MSD, and Roche Novartis and has worked in a consulting or advisory role for BMS, MSD, and Pierre Fabre. GVL has worked in a consulting or advisory role and received honoraria from Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim, BMS, Highlight Therapeutics, MSD, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and SkylineDX. VGA has worked in a consulting or advisory role and received speaking fees or travel support, or both, from BMS, Merck, MSD, Nektar, Novartis, OncoSec, Pierre Fabre, and Roche. SD reports receiving grants from BMS and MSD. AMH reports receiving personal fees from BMS, MSD, and Novartis. AM has worked in a consulting or advisory role and received honoraria from Amgen, AstraZeneca, Aventis, Bayer, BIOCAD, BMS, Eisai, Eli Lilly, Merck, Sanofi, SERVIER, and Takeda Pharmaceuticals. AK reports grants and personal fees from MSD. MSC has worked in a consulting role and received honoraria from BMS, Eisia, IDEAYA Biosciences, Merck Serano, MSD, Novartis, Oncosec, Pierre Fabre, Q biotics, Roche, and Sanofi. SSa reports receiving grants from Amgen, AstraZeneca, BMS, Endocyte, and MSD. JL reports receiving grants from Achilles Therapeutics, AVEO Pharmaceuticals, BMS, Covance, Genentech/Roche, Immunocore, MSD, Nektar, Novartis, Pharmacyclics, and Pfizer and has worked in a consulting role and received honoraria from Achilles Therapeutics, AstraZeneca, Boston Biomedical, BMS, Covance, Eisai, EUSA Pharma, Genentech/Roche, GSK, Immunocore, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Secarna Pharmaceuticals, and Vitaccess. SP received grants from Abbie, Almirall, AMLO Biosciences, Castle Biosciences, La Roche Posay, Leo Pharma, Melagenix, and Sun Pharma, has worked in a consulting role and received honoraria from Almirall, ISDIN, La Roche-Posay, Leo Pharma, Regeneron, Sanofi, and Sun Pharma, and speaker's bureau from Bioderma, BMS, La Roche Posay, Pierre Fabre, Roche, and Sanofi. PAA received grants and research funds from Array BioPharma, BMS, and Genentech/Roche and has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, BMS, Genentech/Roche Genmab, Idera Pharmaceutials, Immunocore, Incyte, MedImmune, Merck Serono, MSD, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax Pharmaceuticals, and Ultimovacs. PR has worked in a consulting or advisory role and received honoraria from Blueprint Medicines, BMS, MSD, Novartis, Pfizer, and Pierre Fabre. DS has worked in a consulting role and received honoraria from 4SC, Array BioPharma, AstraZeneca, Incyte, Pierre Fabre, and Pfizer. RK has worked in a consulting role and received honoraria from BMS, MSD, Novartis, Pierre Fabre, and Roche. LH-A reports that his institution received fees to conduct clinical trials from Merck, Amgen, BMS, Corvus, Genentech, Immunocore, Merck-EMD, Novartis, Polynoma, Regeneron, and Roche. AMDG has worked in a consulting or advisory role and received fees from BMS, GSK, Pierre Fabre, and Sanofi. AJMvdE has worked in a consulting or advisory role and received fees from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre and grants from BMS, Sanofi, and Roche. J-JG has worked in a consulting or advisory role or received speaker fees, and received fees from Amgen, BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. RG has worked in an advisory role and received fees from 4SC, Almirall, Amgen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and Sun Pharma and received grants from Amgen, Johnson & Johnson, Novartis, and Pfizer. RJ reports receiving grants and patient fees from MSD during the conduct of the study and receiving grants from BMS and Iovance and fees to conduct clinical trials for his institutions from Roche, GSK, AstraZeneca, and Novartis. PCL has worked in a consulting or advisory role and his institution received honoraria and grants from 4SC, Amgen, BMS, Merck, and Novartis. ACJvA reports receiving grants from 4SC, Amgen, BMS, Merck, MSD, Novartis, Pfizer, and Sanofi. CK and NI are employees and shareholders of Merck. MK and SSu report receiving grants from Merck during the conduct of the study. CR has worked in a consulting or advisory role and received honoraria from Amgen, Biothera, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. SM declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Little is known regarding the mutation profiles of ctDNA in the older adult breast cancer population. The objective of this study is to assess differences in mutation profiles in the older adult breast cancer population using a ctDNA assay as well as assess utilization of testing results., Methods: Patients with advanced breast cancer underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360) between 5/2015 and 10/2019 at Siteman Cancer Center. The profiling results of a multi-institutional database of patients with advanced breast cancer who had undergone molecular profiling were obtained. Associations between mutations and age group (≥ 65 vs. < 65) were examined using a Fisher's exact test., Results: In the single-institutional cohort, 148 patients (69.2%) were < 65 years old and 66 patients (30.8%) ≥ 65 years old. ATM, BRAF, and PIK3CA mutations were found more frequently in older patients with ER + HER2- breast cancers (p < 0.01). In the multi-institutional cohort, 5367 (61.1%) were < 65 years old and 3417 (38.9%) ≥ 65 years old. ATM, PIK3CA, and TP53 mutations were more common in the older cohort (p < 0.0001) and MYC and GATA3 mutations were less common in the older cohort (p < 0.0001). CtDNA testing influenced next-line treatment management in 40 (19.8%) patients in the single-institutional cohort., Conclusion: When controlling for subtype, results from a single institution were similar to the multi-institutional cohort showing that ATM and PIK3CA were more common in older adults. These data suggest there may be additional molecular differences in older adults with advanced breast cancers.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD 50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11., Competing Interests: Conflict of interest K. J. B. and M. D. O. are listed as coinventors on a provisional patent application on Targeted Pharmacological Therapeutics In Uveal Melanoma that is owned by Washington University in St. Louis. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up., Patients and Methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors., Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600 E/K v wild type)., Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5-5.6), and the median overall survival was 11.9 months (95% CI 9.0-16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

Background: Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498)., Methods: The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability., Results: For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan-Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%)., Conclusion: In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses., Trial Registration Number: Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498., Competing Interests: Competing interests: DR: institutional research grant and funding from Regeneron Pharmaceuticals, Inc., Sanofi, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, and GlaxoSmithKline; uncompensated scientific committee and advisory board from Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, and Bristol-Myers Squibb; travel and accommodation from Merck Sharp & Dohme and GlaxoSmithKline. MRM: honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., Sanofi, Novartis, Genentech, Eli Lilly, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., Novartis, Genentech, and Eli Lilly. AML: uncompensated advisory board from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses. CDS: steering committee member for Castle Biosciences; a steering committee member and consultant for Regeneron Pharmaceuticals, Inc.; a consultant for Sanofi; has received research funding from Castle Biosciences, Regeneron Pharmaceuticals, Inc., Novartis, Genentech, and Merck, and is a chair for the National Comprehensive Cancer Network. NIK: grants from Regeneron Pharmaceuticals, Inc.; grants and advisory board fees from Bristol-Myers Squibb and HUYA Bioscience International; advisory board fees from EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array BioPharma, and Immunocore; grants from Merck, Novartis, GlaxoSmithKline, Celgene, and Amgen; honorarium from Sanofi; and common stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, Amarin, and TransEnterix. BGMH: consulting or advisory roles at Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Pfizer, Roche, Eisai, Merck, and institutional research funding from Amgen. DS: institutional patients’ fees from Regeneron Pharmaceuticals, Inc.; advisory board honorarium fees from Amgen and Leo Pharma; speaker fee from Boehringer Ingelheim; advisory board, speaker honorarium and patients’ fees from Roche, Novartis, Bristol-Myers Squibb, and Merck-EMD; advisory board and speaker honorarium fees from Incyte and Pierre Fabre; advisory board honorarium and patients’ fees from Merck Sharp & Dohme, steering committee honorarium fees from 4SC, advisory board fees from AstraZeneca, Pfizer, and Array; and advisory board and patients’ fees from Philiogen. LAD: advisory role at Regeneron Pharmaceuticals, Inc., and research funding from Eisai, Pfizer, Regeneron Pharmaceuticals, Inc. LH-A: performed consulting and advisory roles at Massive Bio; speakers’ bureau roles at Sanofi and Regeneron Pharmaceuticals, Inc., and received travel, accommodations, and expenses from Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol-Myers Squibb, and research funding from Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., Immunocore, Merck Sharp & Dohme, Polynoma, Corvus Pharmaceuticals, Roche, Merck Serono, Amgen, MedImmune, and Takeda. ALSC: consulting and advisory roles at Regeneron Pharmaceuticals, Inc., Merck; research funding from Regeneron Pharmaceuticals, Inc., Novartis, Galderma, and Merck. BM: speaker’s honoraria, travel, accommodations and expenses from Regeneron Pharmaceuticals, Inc. and Sanofi. AH: institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme/Merck, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. CU: honoraria, consulting, or advisory roles, speaker’s bureau role, research funding and travel, accommodation, and expenses from Novartis, Sanofi, Galderma, and Almirall. TE: consulting or advisory roles at Sanofi Genzyme, Bristol-Myers Squibb, Roche, Novartis and Merck Sharp & Dohme; speakers’ bureau role at Roche and Merck Sharp & Dohme and research funding from Novartis and Bristol-Myers Squibb. BS: consulting or advisory roles at Merck Sharp & Dohme and Merck KGaA Australia. ACP: honoraria and consulting or advisory roles at Bristol-Myers Squibb, Merck, Regeneron Pharmaceuticals, Inc., Array, Novartis, Seattle Genetics, Amgen; research funding from Bristol-Myers Squibb, Merck, Regeneron Pharmaceuticals, Inc., Celldex, and Forance and travel, accommodation, expenses from Regeneron Pharmaceuticals, Inc., Array, and Seattle Genetics. JLG: research institution support for the study from and advisory board for Regeneron Pharmaceuticals, Inc. RG: honoraria from Almirall Hermal GmbH, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Sun Pharma; consulting or advisory role for 4SC, Almirall Hermal GmbH, Amgen, Bristol-Myers Squibb, Incyte, LEO Pharma, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche/Genentech, Sun Pharma, and Takeda; research funding from Amgen, Johnson & Johnson, Novartis, and Pfizer; travel, accommodations, expenses from Bristol-Myers Squibb, Merck Sorono, Pierre Fabre, and Roche. MA: consulting or advisory roles for Pulse Biosciences and Revance Therapeutics. EO, MM, VJ, ES, JB, SL, IL, MGF: employees and shareholders of Regeneron Pharmaceuticals, Inc. AG: personal fees and non-financial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Merck KGaA, Eisai, and Pfizer; non-financial (travel) support from Astellas; and clinical trial unit support from PPD Australia., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown., Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma., Design, Setting, and Participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017., Interventions: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent., Main Outcomes and Measures: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset., Results: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03)., Conclusions and Relevance: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm., Trial Registrations: ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

Background: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma., Methods: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498., Findings: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia., Interpretation: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care., Funding: Regeneron Pharmaceuticals and Sanofi., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, p. 16 . This article is highlighted in the In This Issue feature, p. 1 ., (©2019 American Association for Cancer Research.)

Background: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy., Patients, Methods and Results: Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00])., Conclusions: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. Methods: A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. Results: A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months ( P =.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively ( P <.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively ( P =.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively ( P =.56). Conclusions: Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression., (Copyright © 2019 by the National Comprehensive Cancer Network.)

Background: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma., Methods: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated., Results: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group., Conclusions: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

Influenza morbidity and mortality can be severe and costly. Vaccination rates remain suboptimal in cancer patients due to provider- and patient-related factors. The objective of this study was to evaluate whether low-cost provider- and patient-focused interventions would increase influenza vaccination rates at the University of Michigan Comprehensive Cancer Center (UMCCC). This quality improvement project included all patients without documentation of influenza vaccination prior to their first outpatient appointment during the 2011-2012 and 2012-2013 influenza seasons. The multi-stepped intervention included provider and patient reminders. Influenza vaccination rates were compiled using CPT-4 codes. Same-day (with appointment) vaccination rates during the intervention seasons were compared to historical (2005-2011 seasons) controls; vaccination rates were also compared to contemporary control population at the University of Michigan Health System (UMHS). Reasons for non-adherence with vaccination were explored. The cumulative same-day vaccination rate in eligible adults was 10.1 % (2011-2012) and 9.4 % (2012-2013) compared to an average 6.9 % during influenza seasons 2005-2011. Based on logistic regression analysis, there was a 37.6 % (95 % CI 35-40.3 %) and 56.1 % (95 % CI 40.9-73 %) relative increase in the adult vaccination rate associated with the intervention, with 399 and 697 additional vaccinations, respectively, for each season. During the 2012-2013 season, the UMCCC adult vaccination rate was higher compared to the remainder of that of the UMHS. The intervention was well accepted by providers. Reasons for no vaccination were provider- and patient-related. Increasing provider and patient awareness with a simple, inexpensive intervention was associated with higher influenza vaccination rates at a large academic cancer center. The intervention is permanently implemented during influenza seasons.