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Background: In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119., Methods: Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline., Results: HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, -1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points., Conclusions: HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Schmid: Consultant/Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Puma, and Roche; grant funding to institution: Astellas, AstraZeneca, Genentech, Medivation, Novartis, Oncogenex, and Roche. Oleg Lipatov: Nothing to disclose. Seock-Ah Im: consulting/advisory role: AstraZeneca, Novartis, Roche/Genentech, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daiichi Sankyo, Idience Co. Ltd., and Bertis; research funding to institution: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Korea, and Boryung Pharm. Anthony Goncalves: Nonfinancial support/consultant (compensated to hospital): AstraZeneca, Novartis, Astellas, Pfizer, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Lilly, Mylan, Parexel, and Roche. Eva Muñoz-Couselo: Nothing to disclose. Keun Seok Lee: Consultant: Lilly, Novartis, Pfizer, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Bixink, Everest Medicine, Daiichi Sankyo, and Roche; drug supplies: Dong-A Pharm. Kenji Tamura: Nothing to disclose. Laura Testa: Funding for the current trial conduct, provision of study materials, medical writing, and article processing charges: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; research grant: Novartis; payment or honoraria for medical education: Lilly, Novartis, Pfizer, AstraZeneca, Daiichi-Sankyo, and Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; support for attending meetings and/or travel: Roche, Gilead, and AstraZeneca; Data Safety Monitoring/Advisory board: AstraZeneca, Lilly, Novartis, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daichi-Sankyo, and Pfizer; steering committee for trials: AstraZeneca and Lilly. Isabell Witzel: Research funding to institution: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; personal fees: Daiichi Sankyo, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, and Roche. Shoichiro Ohtani: Lecture fees: AstraZeneca, Chugai, Lilly, and Pfizer. Nicholas Turner: Advisory board honoraria: AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Zentalis, Gilead, Inivata, Guardant, and Exact Sciences; research funding: AstraZeneca, Pfizer, Roche/Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Guardant Health, Invitae, Inivata, Personalis, and Natera. Stefania Zambelli: Nothing to disclose. Nadia Harbeck: Consulting/Lecture fees: AstraZeneca, Daiichi Sankyo, Lilly, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, and Seattle Genetics. Fabrice Andre: Research grants to institution: AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche; Advisory board or speaker (compensation to institution): AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, and Guardant Health; and personal fees (advisory board): Lilly. Rebecca Dent: Advisory board: AstraZeneca, Eisai, Eli Lilly and Company, Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, and Pfizer; Consultant: Genentech; Travel: Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer. Jaime A. Mejia: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Xuan Zhou: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Amin Haiderali: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Allison Martin Nguyen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Javier Cortes: Consulting fees: AstraZeneca, Athenex, Bioasis, BioInvent, Boehringer Ingelheim, Celgene, Cellestia, Clovis Oncology, Daiichi Sankyo, Ellipses, Erytech, Gemoab, Gilead, GSK, Hibercell, Leuko, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Polyphor, Roche, and Seattle Genetics; fees for non-CME services received directly from commercial interest or their agents (e.g., speakers' bureaus): Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Roche, and Samsung Bioepis; contracted research: Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Piqur Therapeutics, Puma, Queen Mary University of London, and Roche; Ownership interest (stock, stock options, or other ownership interest excluding diversified mutual funds): MedSIR; Travel/Accommodation: Daiichi Sankyo, Eisai, Novartis, Pfizer, and Roche; Patent: HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Eric P. Winer: Advisory board member: LEAP; Consultant: G1 Therapeutics, Garrick Therapeutics, Genomic Health, GlaxoSmithKline, Jounce, Lilly, Novartis, Roche Genentech, Seattle Genetics, and Syros., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Purpose: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline., Methods: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application., Results: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%)., Conclusions: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: IM reports receiving an ESMO Research Fellowship sponsored by Roche and honoraria for serving as a speaker bureau for MSD. CH reports a grant from Bayer and Merck., personal fees from MSD, Merck and Amgen. JML reports receiving a grant from Sanofi, honoraria for consultancy from Novartis, Roche, BMS, Pierre Fabre, Sanofi, Highlight Therapeutics and personal fees from Novartis, Roche, MSD, Pfizer, BMS, Astellas Pharma, Pierre Fabre and Sanofi. IB reports honoraria for consultancy from Orion Pharma, BMS, Astrazeneca, Merck Serono, Rakutan Pharma, Roche, Sanofi, MSD eTheRNA Immunotherapies and Achilles Therapeutics Limited. AA reports honoraria for consultancy from AMCURE and research funding from AMCURE. OM reports personal fees from MSD and Janssen. IG reports fees for a speaker for MSD and Roche. AH reports travel grants from Kyowa & Kirin, MSD and Merck and funding from Hold’em for Life Oncology Fellowship, TTCC and SEOM and CRIS Foundations. GA reports no conflict of interest. VG reports no conflict of interest. MO reports fees for consultancy from MSD. JR reports receiving fees for a speaker for Sanofi. EMC reports receiving fees for serving as a member of scientific advisory boards from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and participation as principal investigator in clinical trials from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi. EE reports research funding from Array Biopharma, MSD, Abbvie, Amgen, GlaxoSmithKline, Astrazeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche and honoraria for consulting from Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi. Dr Rodon reports non financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAXOSMITHKLINE,; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, iOnctura and Molecular Partners (including serving on the scientific advisory board from 2015 to the present), receiving research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millennium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. CS reports receiving fees for serving as a member of scientific advisory boards or receiving travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann - La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon and Sanofi Aventis and paid directly to her Institution: AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon and Zenith Pharma. TM reports receiving fees for consulting Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutic, GSK and Deciphera Pharmaceutical and received support for travel or accommodation from Roche, AstraZeneca, and PharmaMar and institutional personal interest paid directly to her institution: Agios, Aslan, AstraZecena, Bayer, Celgene, Genentech, Hallozyme, Immunomedics, Lilly, Merimarck, Millenim, Novartis, Pfizer, Pharmacyclics and Roche. AO reports receiving fees for consulting from Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutic, GSK and Deciphera Pharmaceutical and received support for travel or accommodation from Roche, AstraZeneca, and PharmaMar, and institutional financial interest paid directly to her institution: Abbvie Deutschland, Ability Pharmaceuticals, Advaxis Inc., Aeterna Zentaris, AMGEM, SA, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann – La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc., Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., Pharma Mar SA, Tesaro Inc., BMS, Bristol Meyers Squibb. JC reports receiving fees for advisory board from Bayer, Johnson & Johnson,Bristol-Myers Squibb, Astellas Pharma, Pfizer, Sanofi, MSD Oncology, Roche, AstraZéneca and for speakers bureau from Bayer, Johnson & Johnson, Asofarma, Astellas Pharma, travel from BMS, Ipsen, Roche, AstraZéneca, and research grants from AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., Astrazeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb International Corporation (BMS), Clovis Oncology, INC, Cougar Biotechnology INC, Deciphera Pharmaceuticals LLC, Exelixis INC, F. Hoffmann-La Roche LTD, Genentech INC, Glaxosmithkline, SA, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics INC., Laboratoires Leurquin Mediolanum SAS, Lilly, S.A., Medimmune, Millennium Pharmaceuticals, INC., Nanobiotix SA, Novartis Farmacéutica, S.A., Pfizer, S.L.U, Puma Biotechnology, INC, Sanofi-Aventis, S.A., SFJ Pharma LTD. II, Teva Pharma S.L.U. EF reports research funding from Fundacion Merck Salud, personal fees for consulting from ABBVIE, Astrazeneca, Blueprint Medicines, Boehringer Ingelheim, BMS, ELI Lilly, Guardant Health, Jansenn, Merck, Novartis, Pfizer, Roche, Samsung, Takeda, GSK and Bayer, personal fees for speakers bureao from Astrazeoncology, Roche, Takeda, Boehringer Ingelheim, BMS, ELI Lilly, Medsxape, Merck, Novartis, Pfizer, Prime Oncology, Roche, Takeda, Touchime and in Grifols independent member of the board. Josep Tabernero reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. RD declares advisory role for Roche, Boehringer Ingelheim, received a speaker’s fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme, and research grants from Merck and Pierre Fabre. EG reportspersonal financial interest in the form of scientific consultancy role for Roche/Genentech - F.Hoffmann/La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, TFS, Alkermes, Thermo Fisher, Bristol-Mayers Squibb, MabDiscovery, Anaveon; fees for speakers bureau from Merck Sharp & Dohme, Roche, Thermo Fisher, Roche, Lilly; travel grants from Bristol-Mayers Squibb, Merck Sharp & Dohme, Menarini, Glycotope; research grants from Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, BeiGene.The remaining authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical needs. Several studies have proved that high levels of tumor infiltrating lymphocytes (TILs) at diagnosis of TNBC confer better prognosis and patients respond better to specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC patients have very high levels of TILs, and another 15% lacks TILs. One possible reason to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated by an immune checkpoint in local lymph nodes, provoking their retention in there as they are unresponsive to other immune stimuli. We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints in lymph nodes. We have also performed a customised 50-immune gene NanoString expression panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation and neoantigen load analyses. In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could explain why lymphocytes get retained in there and do not migrate to tumour. These patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4 in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded humoral response. These results could provide a strategy to revert low tumour immune infiltration at diagnosis of TNBC, improving their prognosis., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: A.Q. received transportation and accommodation fees from MSD outside the submitted work. V.P. has received fees as consultant, participated in advisory boards or received travel grants from Sysmex, Roche, MSD, AstraZeneca and Genomic Health. A.P. has received personal fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; fees as a consultant from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD and Lilly; grants from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, MedSIR, Celgene, Astellas and Pzifer; is a member of the executive board of Reveal Genomics, SL, Beast International Group (BIG) and SOLTI cooperative group; and in the patronage committee of SOLTI Foundation and Actitud Frente al Cáncer Foundation. R.D. has declared advisory role for Roche, Boehringer Ingelheim, has received a speaker's fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme, and research grants from Merck and Pierre Fabre. P.S. has received personal fees and fees as a consultant from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma and Roche; grants from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex and Roche. C.G. reports grants from Roche and Pfizer; and received personal fees from Daichii Sankyo, MSD, Astra Zeneca, outside the submitted work. J.P-G. has received fees as a consultant from Roche and Eli Lilly; and travel and accommodation expenses from Roche. E.M-C. has received travel and accommodation fees from BMS and MSD; personal fees and fees as a consultant from Novartis, Roche, BMS, MSD, Pier Fabre and Sanofi. L.M-A. has received consultancy from Roche; received an educational grant and travel from BMS; holds a research collaboration with NanoString Technologies; and received grants to the Institution from Grifols, Gilead, MSD, Jansen and AbbVie. J.C. has received fees as a consultant from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko; personal fees from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, Daiichi Sankyo; research funding from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London, Seagen; and owns stock, patents and intellectual property from MedSIR. T.M., G.V., L.P., P.G., M.M., J.B.-H., C.A. and M.V. declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Limited data are available on nivolumab in challenging subgroups with advanced melanoma. We report outcomes of nivolumab after prior ipilimumab in patients who are typically excluded from clinical trials., Patients and Methods: In this phase II, single-arm, open-label, multicentre study (CheckMate 172), patients with advanced melanoma who progressed on or after ipilimumab received nivolumab 3 mg/kg, every 2 weeks for up to 2 years. The primary objective was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: At a minimum follow-up of 18 months, grade ≥3 treatment-related select AEs with the most variation across subgroups were diarrhoea and colitis (1.1% [n = 11] and 0.3% [n = 3] for the total population [n = 1008]; 0.6% [n = 1] and 0.6% [n = 1] for patients with an asymptomatic central nervous system [CNS] metastasis [n = 165; 16.4%]; 4.5% [n = 3] and 3.0% [n = 2] for patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 2 [n = 66; 6.5%]; 2.4% [n = 2] and 0% for those who experienced a grade 3/4 immune-related AE [irAE] with prior ipilimumab [n = 84; 8.3%]; and 0% and 0% for autoimmune disease [n = 25; 2.5%], respectively). Median overall survival was 21.4 months in the total population and was 11.6, 2.4, 21.5, and 18.6 months in patients with a CNS metastasis, ECOG PS 2, a grade 3/4 irAE with prior ipilimumab, and autoimmune disease, respectively., Conclusions: In this large, phase II clinical trial of patients with advanced melanoma who progressed on or after ipilimumab, nivolumab demonstrated a safety profile consistent with that of prior clinical trials. ClinicalTrials.gov ID: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab., Patients and Methods: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ≥3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively., Conclusions: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS., Gov Id: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)