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Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care., (©2024 American Association for Cancer Research.)

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jean-Marie Michot (JMM) declare conflict of interest outside of the considered work, as being principal/sub-Investigator of clinical trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Regeneron, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor. JMM declare conflict of interest outside of the considered work, research grants from Astex pharmaceuticals. JMM declare conflict of interest outside of the considered work, personal fees (fees paid for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.) from: Ideogen, Glaxosmithkline, MSD, Therakos/Mallinckrodt, Regeneron. Thomas Hueso (TH) declare conflict of interest outside of the considered work, as being principal/sub-Investigator of clinical trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Regeneron, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor. Arthur Geraud (AG) declare conflict of interest outside of the considered work, as being principal/sub-Investigator of clinical trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Regeneron, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions., Competing Interests: Declaration of interests L. Zitvogel is founder of everImmune and its SAB President. L.D. is an everImmune SAB member. R.D. is a scientific co-founder of everImmune. L. Zitvogel received a research contract from Kaleido, 9 meters/Innovate Pharma, and is currently sponsored by Pileje. G.Z. received a research grant from Fondation Roche; received fees from Roche, MSD, BMS, and Astra Zeneca; and is a consultant for Da Volterra & Inventiva. E.D. reports grants and personal fees from Roche Genentech, grants from Boehringer, grants from AstraZeneca, grants and personal fees from Merck Serono, grants from BMS, and grants from MSD. E.D. is founder of Graegis/Alys. M.L.I., L.B., and A.F. are employees and shareholders of Bio-Me. P.D. had consulting and advisory roles for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, and Samsung, as well as honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, and Samsung. P.D. ran clinical trials as principal or co-investigator for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo and received travel, accommodation, and expenses from AstraZeneca, Roche, Novartis, prIME Oncology, and Pfizer. M.F. and R.K.W. were supported by the Seerave Foundation. R.K.W. received unrestricted research grants from Takeda, J&J, Ferring, and Tramedico; speaker’s fee from AbbVie, MSD., and Boston Scientific; and has acted as consultant for Takeda Pharmaceuticals. C.C. reported personal fees from Amgen, Bayer, Merck Serono, MSD, Nordic Pharma, Roche, Pierre Fabre, Servier, and Takeda and research grants from Bayer, Merck Serono, Pierre Fabre, Seagen, Servier, and Tempus. F.G. received honoraria from Amgen, Sanofi, Merk Serono, MSD, BMS, and Astra Zeneca; had a consultancy or advisory role for Roche and Enterome; and received direct research fundings from Roche, Enterome, Astra Zeneca, and Servier and traveling supports from Servier, Amgen, and Roche. L. Zaho is cofounder of Notitia Biotechnologies. F.B. institutional interest AbbVie, ACEA, Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, EISAI, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda.art, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis., Methods: We developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands., Results: Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA +/+ ) and a KI mouse model expressing both huBTLA +/+ /huHVEM +/+ (double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM + tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8 + T cells and regulatory T cells and an increase of effector memory CD4 + T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect., Conclusions: Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4))., Competing Interests: Competing interests: DO is a cofounder and shareholder of Imcheck Therapeutics, Alderaan Biotechnology, Emergence Therapeutics, and Stealth IO. HL is a co-founder and scientific advisor of JC discovery. FB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F Hoffmann-La Roche, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. The other authors do not declare any conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET)., Methods: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O 2 ) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort., Results: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation., Conclusion: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer., Competing Interests: Rebecca J. LeeSpeakers' Bureau: AstraZenecaResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst) Rohan ShottonHonoraria: ServierTravel, Accommodations, Expenses: Servier Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Therapeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Dirk ArnoldEmployment: Asklepios KlinikenHonoraria: Bayer, Merck Serono, Roche/Genentech, Servier, Bristol Myers Squibb, Merck Sharp and Dome, AstraZeneca, Amgen, Boston Scientific, Pierre Fabre, IpsenConsulting or Advisory Role: Bayer, Merck Serono, Biocompatibles, Terumo, Bristol Myers Squibb, MSD Oncology, AstraZenecaResearch Funding: Roche/Genentech (Inst), Sanofi (Inst), Oncolytics (Inst)Travel, Accommodations, Expenses: Boston ScientificUncompensated Relationships: ESMO Council, ESMO Journals (Ann Oncol, ESMO Open), German Society for Hematology and Medical Oncology, German Cancer Society, European Organisation for Research and Treatment of Cancer (EORTC) Kathryn BanfillStock and Other Ownership Interests: Roche (I)Honoraria: AstraZeneca Mark BaxterHonoraria: IpsenTravel, Accommodations, Expenses: Ipsen Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Merck Serono, MSD Oncology, Takeda, Bayer, Seattle Genetics, Mirati TherapeuticsConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Mirati TherapeuticsResearch Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, AstraZeneca/MedImmune, MSD Oncology Benjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Lilly (Inst), Onxeo (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Sanofi (Inst), Takeda (Inst), Cristal Therapeutics (Inst), Daiichi Sankyo (Inst), Janssen Oncology (Inst), OSE Immunotherapeutics (Inst), BeiGene (Inst), Boehringer Ingelheim (Inst), Roche/Genentech (Inst), Tolero Pharmaceuticals (Inst), 4D Pharma (Inst), Aptitude Health (Inst), Cergentis (Inst), Chugai Pharma (Inst), Genzyme (Inst), Ipsen (Inst), Turning Point Therapeutics (Inst), Eisai (Inst) Antonio CallesHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Lilly, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Bayer, Takeda, Sanofi/RegeneronConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Igen Biotech, Sanofi/RegeneronResearch Funding: MSD Oncology Ellen CopsonHonoraria: Roche, Pfizer, AstraZeneca, Lilly, NovartisConsulting or Advisory Role: Lilly, NanoString Technologies, Pfizer, Sanofi/Aventis, RocheSpeakers' Bureau: Roche, Pfizer, AstraZeneca, Sanofi/AventisResearch Funding: SECA, AstraZeneca (Inst)Travel, Accommodations, Expenses: Roche, AstraZeneca Adina E. CroitoruConsulting or Advisory Role: Ipsen, Pfizer, MSD OncologyResearch Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Astellas Pharma (Inst), Exelixis (Inst), Merck (Inst), Merck KGaA (Inst)Travel, Accommodations, Expenses: Merck, ServierUncompensated Relationships: Lilly, Roche, Bayer, Pfizer, Sanofi Leonie EastlakeTravel, Accommodations, Expenses: Servier Paul FitzpatrickStock and Other Ownership Interests: AstraZeneca/MedImmuneResearch Funding: AstraZeneca/MedImmune (Inst)Other Relationship: Pistoia Alliance, EHDEN IMI project Henrik FrederiksenResearch Funding: AbbVie (Inst), Gilead Sciences (Inst), Sanofi (Inst) Hannah FrostResearch Funding: AstraZeneca (Inst) Sarju GanatraExpert Testimony: Haymarket Medical EducationTravel, Accommodations, Expenses: Haymarket Medical Education Andreas GlenthøjHonoraria: Novo NordiskConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Bluebird Bio, Sanofi, Novo Nordisk, AgiosResearch Funding: Sanofi, Saniona A/STravel, Accommodations, Expenses: Agios Fabio GomesHonoraria: AstraZeneca, Merck Serono, Roche Donna M. GrahamConsulting or Advisory Role: Clinigen GroupSpeakers' Bureau: Cancer Drug Development ForumResearch Funding: Pfizer (Inst) Kevin HarringtonHonoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Pfizer (Inst), Replimune (Inst), Inzen Therapeutics (Inst), Codiak Biosciences (Inst)Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst), Inzen Therapeutics (Inst)Speakers' Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst)Research Funding: AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst), Boehringer Ingelheim (Inst) Lasse H. JakobsenHonoraria: Takeda, Roche Khurum KhanHonoraria: ServierConsulting or Advisory Role: Bayer Health Christophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, ORION, Taiho Pharmaceutical, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals Olivier MichielinConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre FabreResearch Funding: MSD, Bristol Myers Squibb, NeraCare GmbHExpert Testimony: Bristol Myers SquibbTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD Anne C. MosenthalHonoraria: Springer Nature Berta ObispoHonoraria: Sanofi, Lilly, Angelini, LEO Pharma, RoviConsulting or Advisory Role: Rovi George PentheroudakisHonoraria: Roche, Amgen, Bristol Myers Squibb, MSD, MerckConsulting or Advisory Role: Roche, AmgenResearch Funding: Roche (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Sanofi, MSD, Roche, Amgen, BMS Solange PetersHonoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), Medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), ecancer (Inst)Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seattle Genetics (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst)Research Funding: Roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology (I) Kimberly Rieger-ChristResearch Funding: Veracyte, Ravel, Grail, Exact Sciences, Nucleix Timothy RobinsonTravel, Accommodations, Expenses: Daiichi Sankyo/Lilly Emanuela RomanoConsulting or Advisory Role: AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Roche/Genentech (Inst)Research Funding: Bristol Myers Squibb, AmgenTravel, Accommodations, Expenses: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche Michael RoweHonoraria: MSDSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Astellas Pharma Anne ThomasConsulting or Advisory Role: BMSSpeakers' Bureau: Bristol Myers SquibbExpert Testimony: BMS Lance TurtleSpeakers' Bureau: Eisai (Inst) David ViñalSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Merck Caroline WilsonConsulting or Advisory Role: Roche, Pfizer Carlo PalmieriHonoraria: PfizerConsulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle GeneticsResearch Funding: Pfizer, Daiichi-SankyoTravel, Accommodations, Expenses: Roche Donal LandersEmployment: AstraZeneca, AthenexLeadership: DeLondra OncologyStock and Other Ownership Interests: DeLondra OncologyResearch Funding: AstraZeneca (Inst) Timothy CooksleyHonoraria: Bristol Myers Squibb Foundation Caroline DiveConsulting or Advisory Role: Biocartis, Merck, AstraZeneca, GRAIL, Boehringer IngelheimResearch Funding: AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck, Taiho Oncology, GlaxoSmithKline, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics, Angle, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, NeoMed André FreitasResearch Funding: AstraZeneca (Inst) Anne C. ArmstrongStock and Other Ownership Interests: AstraZeneca (I)Consulting or Advisory Role: Gilead Sciences, MSDResearch Funding: AstraZeneca/MedImmune (Inst)Travel, Accommodations, Expenses: Gilead Sciences, MSD OncologyNo other potential conflicts of interest were reported.

Background: Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice., Results: In vitro , local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. In vivo , locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics., Conclusion: Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells., Competing Interests: Competing interests: GK and OK are cofounders of Samsara Therapeutics. JP is the inventor of patents for cancer vaccination licensed to Turnstone Biologics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants., Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Functional Status (FS) is an important domain in Comprehensive Geriatric Assessment (CGA) and is most often evaluated using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales separately., Method and Objectives: This secondary analysis of a previous prospective cohort study was conducted between September 2015 and May 2018 at Marseille University Hospital, France, on 613 cancer outpatients aged ≥70 years. The first objective of this study was to determine the prevalence of FS impairment in older outpatients with cancer using a combination of the information collected with the ADL and short IADL scales. Our second objective was to describe the potential impact of this combined FS on three-month unplanned hospitalizations and three-month mortality in this population., Results: The median age was 81 years and 61.2% were men. The most common types of tumours were lung and thoracic (22.3%). Concerning FS, 255 patients (41.6%) had unimpaired ADL-IADL, 131 patients (21.4%) had IADL impairment, 38 patients (6.2%) had ADL impairment, and 189 patients (30.8%) had impaired ADL-IADL. In the multivariate Cox analysis, metastatic stage (adjusted Hazard Ratio (aHR) = 1.79; 95% CI [1.14-2.80]) and impaired ADL-IADL (aHR = 3.46; 95% CI [1.89-6.33]) were independently associated with three-month mortality. In the logistic regression model, impaired ADL-IADL (adjusted Odd ratio (aOR) = 3.64; 95% CI [1.84-7.20]) was the only factor independently associated with three-month unplanned hospitalizations., Interpretation: The combined use of the ADL and IADL scales to evaluate functional status in older patients with cancer is of significant prognostic value regarding the risks of three-month unplanned hospitalizations and mortality., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B + FasL + , Eomes high TCF-1 high , PD-1 + CD8 + Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death., (© 2021. The Author(s).)

Background: Changes in the management of patients with cancer and delays in treatment delivery during the COVID-19 pandemic may impact the use of hospital resources and cancer mortality., Patients and Methods: Patient flows, patient pathways and use of hospital resources during the pandemic were simulated using a discrete event simulation model and patient-level data from a large French comprehensive cancer centre's discharge database, considering two scenarios of delays: massive return of patients from November 2020 (early-return) or March 2021 (late-return). Expected additional cancer deaths at 5 years and mortality rate were estimated using individual hazard ratios based on literature., Results: The number of patients requiring hospital care during the simulation period was 13,000. In both scenarios, 6-8% of patients were estimated to present a delay of >2 months. The overall additional cancer deaths at 5 years were estimated at 88 in early-return and 145 in late-return scenario, with increased additional deaths estimated for sarcomas, gynaecological, liver, head and neck, breast cancer and acute leukaemia. This represents a relative additional cancer mortality rate at 5 years of 4.4 and 6.8% for patients expected in year 2020, 0.5 and 1.3% in 2021 and 0.5 and 0.5% in 2022 for each scenario, respectively., Conclusions: Pandemic-related diagnostic and treatment delays in patients with cancer are expected to impact patient survival. In the perspective of recurrent pandemics or alternative events requiring an intensive use of limited hospital resources, patients should be informed not to postpone care, and medical resources for patients with cancer should be sanctuarised., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: No author reported potential conflict of interest in link with the submitted work. A.B. reports personal fees from Roche SAS. I.B. reports personal fees from Roche, Novartis, CSL Behring and Takeda. M.F. reports fees from HRA Pharma (participation to board) and travel grants from Ipsen, Pfizer and Novartis. S.D. reports grants and non-financial support from Pfizer, grants from Novartis, grants and non-financial support from AstraZeneca, grants and non-financial support from Roche Genentech, grants from Lilly, grants from Puma, grants from Myriad, grants from Orion, grants from Amgen, grants from Sanofi, grants from Genomic Health, grants from GE, grants from Servier, grants from MSD, grants from BMS, grants from Pierre Fabre, grants from Seagen and grants from Exact Sciences. L.A. reports a consulting/advisory role for Novartis (Institution), Amgen (Institution), Bristol Myers Squibb (Institution), Ipsen (Institution), Roche (Institution), Pfizer (Institution), Astellas Pharma (Institution), Merck (Institution), MSD (Institution), AstraZeneca (Institution), Exelixis (Institution), Corvus Pharmaceuticals (Institution) and Peloton Therapeutics (Institution) and research Funding from Bristol Myers Squibb (Institution). D.P. reports a consulting, advisory role or lectures for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche and Samsung; honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche and Samsung; institutional financial interests (clinical trials research as the principal or co-investigator) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure and Daiichi Sankyo and travel and accommodation expenses from AstraZeneca, Roche, Novartis, prIME Oncology and Pfizer. M.D. reports honoraria for advisory boards or as a presenter in symposium from Merck Serono, MSD, AMGEN, Roche, Bayer, Ipsen, Pfizer, Servier, Pierre Fabre, HalioDx, Lilly and Sanofi. E.C. reports consulting advisory board activity for BMS, Ipsen, Sanofi, Pfizer, GSK and Merck. C.R. reports a consultant/advisory role for Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Sanofi and Pierre Fabre. C.M. reports consultant/advisory fees from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi and Orion and as acted as a principal/sub-investigator of clinical trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, GamaMabs, Genentech, Gortec, GSK, H3 Biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, MedImmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro and Xencor. J.B.M. reports personal fees from AbbVie, Jazz PHARMA and Astellas. S.M. reports personal fees from statistical advice to IDDI, Janssen Cilag and Amaris and from data and safety monitoring membership of clinical trials (Hexal, Steba, IQVIA, Roche, Sensorion, Biophytis, Servier and Yuhan). A.A. reports grant support, paid to her institution, from F. Hoffmann-La Roche. F.B. reports personal financial interests with AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Seattle Genetics and Takeda; institutional financial interests with AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis and Takeda and non-financial interests (as a principal investigator) for AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd–sponsored trials (or ISR). J.B. reports honoraria from Bristol Myers Squibb; a consulting or advisory role for Bristol Myers Squibb, MSD, PharmaMar (Inst), Bristol Myers Squibb (Inst) and Merck Serono (Inst) and travel and accommodation expenses from Bristol Myers Squibb. Other authors report no conflict of interest. Y. Takahashi declares no conflict of interest. Her editorial work for the present article has been funded by Inserm., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with cancer are presumed to be more vulnerable to COVID-19. We evaluated a screening strategy combining chest computed tomography (CT) and reverse-transcription polymerase chain reaction (RT-PCR) for patients treated with radiation therapy at our cancer center located in a COVID-19 French hotspot during the first wave of the pandemic., Methods and Materials: Chest CT images were proposed during radiation therapy CT simulation. Images were reviewed by an expert radiologist according to the COVID-19 Reporting and Data System classification. Nasal swabs with RT-PCR assay were initially proposed in cases of suspicious imaging or clinical context and were eventually integrated into the systematic screening. A dedicated radiation therapy workflow was proposed for COVID-19 patients to limit the risk of contamination., Results: From March 18, 2020 to May 1, 2020, 480 patients were screened by chest CT, and 313 patients had both chest CT and RT-PCR (65%). The cumulative incidence of COVID-19 was 5.4% (95% confidence interval [CI], 3.6-7.8; 26 of 480 patients). Diagnosis of COVID-19 was made before radiation therapy for 22 patients (84.6%) and during RT for 4 patients (15.3%). Chest CT directly aided the diagnosis of 7 cases in which the initial RT-PCR was negative or not feasible, out of a total of 480 patients (1.5%) and 517 chest CT acquisitions. Four patients with COVID-19 at the time of the chest CT screening had a false negative CT. Sensitivity and specificity of chest CT screening in patients with both RT-PCR and chest CT testing were estimated at 0.82 (95% CI, 0.60-0.95) and 0.98 (95% CI, 0.96-0.99), respectively. Adaptation of the radiation therapy treatment was made for all patients, with 7 postponed treatments (median: 5 days; interquartile range, 1.5-14.8)., Conclusions: The benefit of systematic use of chest CT screening during CT simulation for patients undergoing radiation therapy during the COVID-19 pandemic seemed limited., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience., (©2021 American Association for Cancer Research.)

The speed and spread of the COVID-19 pandemic has been affecting the entire world for the past several months. OncoAlert is a social media network made up of more than 140 oncology stakeholders: oncologists (medical, radiation, and surgical), oncology nurses, and patient advocates who share the mission of fighting cancer by means of education and dissemination of information. As a response to the COVID-19 pandemic, OncoAlert hosted The Round Table Discussions. We have documented this effort along with further discussion about the COVID-19 pandemic and the consequences on patients living with cancer to disseminate this information to our colleagues worldwide., Competing Interests: Evandro de AzambujaHonoraria: Roche/Genentech, Seattle Genetics, Zodiac PharmaConsulting or Advisory Role: Roche/Genentech, NovartisResearch Funding: Roche/Genentech, AstraZeneca, Servier/Pfizer, GlaxoSmithKline/NovartisTravel, Accommodations, Expenses: Roche/Genentech, GlaxoSmithKline Kevin PunieHonoraria: Pfizer, Lilly, Roche, Novartis, MundipharmaConsulting or Advisory Role: AstraZeneca, Lilly, Novartis, Pierre Fabre, Roche, Vifor Pharma, TevaResearch Funding: SanofiTravel, Accommodations, Expenses: Novartis, AstraZeneca, PharmaMar, Pfizer, Roche Felipe AdesHonoraria: AstraZeneca, Zodiac Pharma, Novartis, Sun PharmaConsulting or Advisory Role: biommTravel, Accommodations, Expenses: Daiichi Sankyo/Lilly Kathrin HeinrichHonoraria: Roche Pharma AGTravel, Accommodations, Expenses: Amgen, Lilly, Celgene Nicola PersoneniHonoraria: Lilly, Abbvie, Amgen, Gilead SciencesConsulting or Advisory Role: Merck SeronoSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Amgen Roberto FerraraConsulting or Advisory Role: Merck Sharp & Dohme Marina GarassinoHonoraria: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol-Myers SquibbConsulting or Advisory Role: Bristol-Myers Squibb, MSD, AstraZeneca, Novartis, Takeda, Roche, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, JanssenSpeakers' Bureau: AstraZeneca, Takeda, MSD Oncology, Celgene, Incyte, Roche, Bristol-Myers Squibb, Otsuka, LillyResearch Funding: Bristol-Myers Squibb, MSD, Roche/Genentech, AstraZeneca/MedImmune, AstraZeneca, Pfizer, GlaxoSmithKline, Novartis, Merck, Incyte, Takeda, Spectrum Pharmaceuticals, Blueprint Medicines, Lilly, AstraZeneca, Ipsen, Janssen, Exelixis, MedImmune, Sanofi, Pfizer, AmgenTravel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Michael von Bergwelt-BaildonHonoraria: Roche, Kite/Gilead, Novartis Gilberto LopesHonoraria: Boehringer IngelheimConsulting or Advisory Role: Pfizer, AstraZenecaResearch Funding: Merck Sharp & Dohme, EMD Serono, AstraZeneca, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, NOVARTIS, G1 Therapeutics, adaptimmune, Bristol-Myers Squibb, GlaxoSmithKline, Abbvie, Rgenix, Pfizer, Roche, Genentech, Lilly, JanssenTravel, Accommodations, Expenses: Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Merck Serono, MSD Oncology, Takeda, BayerConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol-Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, BayerResearch Funding: Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Pierre Fabre, Abbvie, Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, Ipsen, Innate Pharma, Novartis, Merck Serono, MSD Oncology, Pfizer, Sanofi/Aventis, TakedaTravel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb, AstraZeneca/MedImmune, MSD Oncology Toni K. Choueiri,Employment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, Heron, LillyConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOResearch Funding: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, Gateway for Cancer Research, Congressionally Directed Medical Research Programs (DOD)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, entitled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, entitled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint ResponseTravel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Howard BurrisEmployment: HCA HealthcareLeadership: HCA HealthcareStock and Other Ownership Interests: HCA HealthcareConsulting or Advisory Role: AstraZeneca, FORMA Therapeutics, Celgene, Incyte, NovartisResearch Funding: Roche/Genentech, Bristol-Myers Squibb, Incyte, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicloMed, Harpoon therapeutics, Arch, Arvinas, Revolution Medicines, Array BioPharma, Bayer, BIND Therapeutics, Kymab, miRNA Therapeutics, Pfizer, Takeda/Millennium, Foundation MedicineExpert Testimony: NovartisUncompensated Relationships: Daiichi Sankyo, Pfizer, Bayer, Grail, NovartisOpen Payments Link: https://openpaymentsdata.cms.gov/physician/201030/summary Solange PetersHonoraria: Roche, Bristol-Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Takeda, IlluminaConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol-Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen, Regeneron, Merck Serono, Boehringer Ingelheim, Takeda, Lilly, Abbvie, Bayer, Biocartis, Debiopharm Group, Illumina, PharmaMar, Sanofi, Seattle Genetics, Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent, Clovis Oncology, VaccibodyResearch Funding: Roche, Bristol-Myers Squibb, MSD, Amgen, Lilly, AstraZeneca, Pfizer, Illumina, Merck Serono, Novartis, Biodesix, Boehringer Ingelheim, Boehringer Ingelheim, Boehringer Ingelheim, Iovance BiotherapeuticsTravel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals on Oncology associate editorNo other potential conflicts of interest were reported.

Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor-host-microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development. SIGNIFICANCE: A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure., (©2021 American Association for Cancer Research.)

Background: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity., Methods: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression., Results: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population., Conclusions: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer., Trial Registration Number: NCT02955251., Competing Interests: Competing interests: JJL: Data and Safety Monitoring Board for TTC Oncology; consultancy/advisory role for 7 Hills, Abbvie, Actym, Akrevia, Algios, Alphamab Oncology, Array, Astellas, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Ideaya, Incyte, Janssen, Kanaph, Mavu (now part of AbbVie), Merck, Mersana, Novartis, Onc.AI, Pyxis, PTx, RefleXion, Regeneron, Silicon, Springbank, Tempest, Tesaro, and Vividion; research support (all to institution for clinical trials unless noted) from AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, and Xencor; patents (both provisional) with the University of Chicago: Serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); travel support from Akrevia, Bayer, Bristol-Myers Squibb, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis, Pyxis, and RefleXion. FB: consulting/advisory role for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. KC: no conflicts to disclose. AWT: Independent Data Monitoring Committee for Mirati and Genentech/Roche; consulting/advisory role (fees paid to NEXT Oncology) for AbbVie, AbGenomics, Adagene, ADC Therapeutics, Agenus, Aro Biotherapeutics, Ascentage Pharma, BioInvent, AxImmune, Bayer, BioInvent, Birdie, Cello Health, Eleven Bio, Ellipses, Elucida, EMD Serono, Five Prime, Forbius (Formation Biologics), Gilde Healthcare Partners, HBM Partners, Immunome, Immunomet, Jazz, Karma Oncology, Mekanistic, Menarini, Mersana, Nanobiotix, NBE Therapeutics, Nuvalent, Pelican, PSI Pharma Support America, Oncology International, OSI, Partner Therapeutics, Pfizer, Pieris, Pierre Fabre, Ridgeway, Ryvu Therapeutics, Scitemex, Seattle Genetics, Symphogen, Syneos, TFS Trial Form Support International, and Zymeworks. KK: consultancy/advisory role for AstraZeneca, Bristol-Myers Squibb, EMD Serono, Eli Lilly Oncology, Genentech/Roche, Inviata, Merck, Novartis, Regeneron, and Symphogen; research funding from Astellas, AbbVie, Bristol-Myers Squibb, EMD Serono, Five Prime Therapeutics, Genentech, Regeneron, Tizona, and Transgene. AH: honoraria from Amgen, Eisai, and Servier; consulting/advisory role for AstraZeneca, Incyte, and Debiopharm; travel support from Amgen, Servier, Lilly, AstraZeneca, and MedImmune; research funding from Incyte. CLT: consultancy/advisory role for MSD, Bristol-Myers Squibb, Merck Serono, Roche, AstraZeneca, GlaxoSmithKline, Rakuten, Seattle Genetics, and Nanobiotix. VS: one-time educational honoraria from Medscape; consultancy/advisory role for Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, Incyte, QED Pharma, MedImmune, and Novartis; travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, and Incyte; research funding from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals. FT: stock or other ownership in Salarius Pharmaceuticals; consultancy/advisory role for Tempus Lab; patents, royalties, or other intellectual property for clinical trial software. SK: honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; consultancy/advisory role for AstraZeneca, Boehringer, Merck Sharp & Dohme, and Pfizer; travel support from AstraZeneca, Boehringer, Bristol-Myers Squibb, and Roche. PAC: honoraria from Novartis, Roche/Genentech, Blueprint Medicines, Amgen, and Merck Serono; research funding from Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, and Merck Sharp & Dohme. MK: consultancy/advisory role for AbbVie, Ipsen, Pfizer, Roche, and Jackson Laboratory for Genomic Medicine; research funding from AbbVie, Bristol-Myers Squibb, and Specialized Therapeutics. HLK: personal fees from Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Deciphera, Inhibrx, Inventiva, Kyowa, Merck, and Paredox Therapeutics; non-financial support from AstraZeneca, Boehringer Ingelheim, Inventiva, Merck, and Paredox Therapeutics; research funding to institution from Aduro, AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Lilly, Merck, Polaris, Verastem, Blueprint, Tesaro, and Inhibrx. FF: no conflicts to disclose. KA: no conflicts to disclose. HF, MP, SY, DTC, WRH, JSH, and MAM: employment with AbbVie and may hold stock or other options. LF: research funding from AbbVie, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Janssen, Merck, and Roche/Genentech. No honoraria or payments were made for authorship., (© 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: A Comprehensive Geriatric Assessment (CGA) has been proposed to assess prognosis and to adapt oncological care in older patients with cancer. However, few biological markers are incorporated in the CGA., Methods: This comparative study on older patients with cancer was realized before final therapeutic decision and during a CGA that included biological markers. Our objective study was to know if the serum vitamin B12-C-reactive protein index (BCI) can help to estimate early death and unplanned hospitalization. Associations between BCI and unplanned hospitalization or mortality were analyzed using ordered multivariate logistic regression., Findings: We included 621 older cancer adults in outpatient care with a median age of 81 years (range, 70-98 years) from September 2015 to May 2018. In this study, 5.6% of patients died within 3 months, 8.8% had unplanned hospitalization within 1 month, and 11.4% had unplanned hospitalization within 3 months. Hypercobalaminemia was present in 83 patients (13.4%), and 34 patients (5.5%) had BCI >40,000. According to the multivariate analysis, BCI was a prognostic factor of mortality within 3 months and unplanned hospitalizations at 1 and 3 months. Impaired activities of daily living (ADL) and palliative care were also risk factors for mortality within 3 months. Impaired instrumental ADL, low albumin level, and palliative care were risk factors for unplanned hospitalization at 1 month., Interpretation: BCI could be routinely added to the CGA process, as part of a pretreatment workup, in order to assess more precisely the frailties and to adapt oncological care in older patients treated for cancer., Implications for Practice: Aging comes with an increase of frailties and comorbidities. To identify frailties in older patients with cancer, this study used a Comprehensive Geriatric Assessment, which allowed for the adaptation of each treatment plan in accordance with the individual needs of the patients. However, biological characteristics were not included in this assessment. This study showed that hypercobalaminemia and vitamin B12 -C-reactive protein index may be potential markers for cancer with poor prognosis, particularly in the older population. These biological markers can be used in geriatric oncology and general medicine., (© 2020 AlphaMed Press.)

A novel coronavirus, SARS-CoV-2, was first reported as a respiratory illness in December 2019 in Wuhan, China. Since then, the World Health Organization (WHO) Emergency Committee declared a global health. COVID-19 has now spread worldwide and is responsible of more than 472,216 persons, out of 9,100,090 officially diagnosed worldwide since 23 of June. In the context of cancer patients, COVID-19 has a severe impact, regarding pulmonary infection but also cancer treatments in this fragile and immunocompromised population, and ICU admission for cancer patients in the context of COVID-19 requires ethical and clinical consideration. In our cancer center, intensivists, oncologists, pharmacists, and hospital administrators had to prepare for a substantial increase in critical care bed capacity (from 10 ICU beds, 6 medical intensive care beds, and 12 surgical intensive care beds, bed capacity was increased to 28 medical intensive care beds with ventilating capacity) and to adapt infrastructure (i.e., ICU beds), supplies (i.e., drugs, ventilators, protective materials), and staff (i.e., nurses and medical staff). Overall, thirty-three COVID-19 patients were admitted in our ICU, 17 cancer-free and 16 with cancer, and 23 required mechanical ventilation, resulting in 4 deaths (of them two patients with cancer). We report here management of a dedicated intensive care unit of a cancer center during the COVID-19 infection pandemic, considering resource allocation and redistribution of healthcare workers.

Immunotherapy by immune check-points inhibitors (ICIs) recently improved many solid tumors survival data. ICIs target and inhibit down-regulation signals between T cells and tumor cells involved in carcinogenesis, in order to enhance anti-tumor immunity. With few years' hindsight of ICIs utilization in daily practice, we learned about their safety profile. By releasing the brakes of the host immune-system, ICIs exposure leads to on-target off-tumor immune related adverse events (IRAEs). Compared to standard chemotherapiy regimens, IRAEs remain rare, but sometimes serious and compromising treatment continuation, mostly despite objective tumor response. Several immunotherapy molecules are currently developed, with various mechanisms of action but always targeting the immune anti-tumor response. New drugs imply new safety profiles, especially since a lot of ongoing clinical trials are assessing combination of multiples drugs. Consequently, a good knowledge and management of these new toxicities will be essential to choose the new therapeutic schedules in many tumor types. Indeed, despite the actual poor prognosis of concerned tumor types, the progressive outcomes improvement implies long-term exposure to treatments. Safety and quality of life under treatment will become key endpoints for therapeutic decision., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Polymorbidity induces polypharmacy in older patients may lead to potential drug-drug interactions (DDI) which can modify the tolerance and safety of oncological treatments and alter the intended therapeutic effect. The objective of our study was to describe the decision-making process for oncological treatment and related outcomes, in a population of older adults undergoing a comprehensive geriatric assessment (CGA) associated to a comprehensive medication reconciliation (CMR) prior to initiating oncological treatment., Methods: ChimioAge is a prospective observational study conducted between 01/2017 and 07/2018 at Marseille University Hospital and approved by the French National Ethics Committee. It comprised all consecutive patients aged 70 years and over who were referred for a CGA as part of CMR, before initiating systemic treatment., Results: One hundred and seventy-one cancer patients were included. Mean age was 79.2 years, over half had metastatic cancers, 75% had an ECOG performance status zero or one, and two-thirds were independent in daily activities. Two-thirds of the patients had polypharmacy and the CMR identified potential DDI with systemic treatment in 43.3% of patients. Following the CGA, the CMR and the hospital oncologists decision, 30% of the patients received adapted systemic treatment with reduced doses at initiation. They presented fewer toxicities - irrespective of grade and type - than patients who received standard treatment (p<0.001) and had comparable overall survival (Log rank p=0.21)., Conclusion: This is one of the first studies to highlight the value in conducting CMR and a CGA simultaneously before initiating systemic treatment in older patients with cancer. These two evaluations could give oncologists decisive information to personalize cancer treatment of older patients and optimize treatment dose to offer the best efficacy and minimize toxicity., Competing Interests: Laurent Greillier reports personal fees and non-financial support from ABBVIE, ASTRA-ZENECA, BOEHRINGER INGELHEIM, BMS, MSD, and ROCHE and personal fees from TAKEDA, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2020 Couderc et al.)

The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.

Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer., Patients and Methods: The study consisted of a 3+3 dose-escalation stage ( n = 66) and a tumor-specific expansion stage ( n = 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day -1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle., Results: Patients ( n = 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, non-small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response., Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab., (©2019 American Association for Cancer Research.)

Tumor banks are asked to clinical and translationnal research project development in oncology. They strongly participate to the assessment, then to the validation of diagnostic, prognostic and predictive biomarkers. The progressive change of these structures leads to induce a professionalization of their functioning and to identify them as key actors in oncology by the stakeholders of the public and private worlds. The progresses made in biotechnologies and therapeutics are rapidly modifying the impact and the proper functioning of the biobanks. These latter are now facing different challenges, in particular for their sustainability. Among the major issues, the integration of the clinical and biological data becoming increasingly complex leads to urgently consider an optimization of the role of different biobanks in France. Their goal is to be an attractive counterpart face to the international competition. The purpose of this review is to briefly describe the current evolution of the biobanks, then their present and future challenges, and finally the role made by the pathologists in these new issues in oncology field., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: Various studies have shown that the drafting of Advance Directives (ADs) is relatively uncommon. This study was performed to explore cancer patients' attitudes toward ADs, and their reasons for completing or not completing advance directive forms., Methods: The research included interdependent steps designed to gradually collect patients' agreement and comments concerning their participation in an AD study. A thematic content analysis was performed on patients' comments. A total of 147 patients spontaneously agreed to participate before the presentation of the specific theme (AD) of the study., Results: A large majority of the sample reported having no knowledge about ADs. Of the patients who initially agreed to participate, two-thirds declined after the presentation of the theme of the study. The reasons of patients who declined to participate related to avoidance of the issue of death, a focus on present time perspective, or an ambivalence between the AD proposal and recovery plans., Conclusions: This study provides further evidence of the difficulties for patients to express their willingness to engage in AD discussions or research. The extent of the psychological issues experienced by patients and the level of avoidance they expressed raise many questions about the ethical issues and the spread of ADs used in oncology settings.

Background: Studies have suggested that clinicians do not feel comfortable with the interpretation of symptom severity, functional status, and quality of life (QoL). Implementation strategies of these types of measurements in clinical practice imply that consensual norms and guidelines regarding data interpretation are available. The aim of this study was to define subgroups of patients according to the levels of symptom severity using a method of interpretable clustering that uses unsupervised binary trees., Methods: The patients were classified using a top-down hierarchical method: Clustering using Unsupervised Binary Trees (CUBT). We considered a three-group structure: "high", "moderate", and "low" level of symptom severity. The clustering tree was based on three stages using the 9-symptom scale scores of the EORTC QLQ-C30: a maximal tree was first developed by applying a recursive partitioning algorithm; the tree was then pruned using a criterion of minimal dissimilarity; finally, the most similar clusters were joined together. Inter-cluster comparisons were performed to test the sample partition and QoL data., Results: Two hundred thirty-five patients with different types of cancer were included. The three-cluster structure classified 143 patients with "low", 46 with "moderate", and 46 with "high" levels of symptom severity. This partition was explained by cut-off values on Fatigue and Appetite Loss scores. The three clusters consistently differentiated patients based on the clinical characteristics and QoL outcomes., Conclusion: Our study suggests that CUBT is relevant to define the levels of symptom severity in cancer. This finding may have important implications for helping clinicians to interpret symptom profiles in clinical practice, to identify individuals at risk for poorer outcomes and implement targeted interventions.

Objective: Researchers are interested in studying whether the quality of life (QoL) of cancer patients and caregivers is influenced by internal psychobehavioral processes (temporality and coping strategies) and the personality traits that they or their relatives experience. We examined these associations in a sample of patient-caregiver dyads by using the actor-partner interdependence model., Methods: This cross-sectional study involved 156 cancer patient-caregiver dyads. The self-reported data included QoL (Short-Form 36), coping strategies (Brief Coping Orientation to Problems Experienced Scale), time perspectives (Zimbardo Time Perspective Inventory), and personality (Big Five Inventory). The actor-partner interdependence model was used to test the dyadic effect individualizing actor (degree to which the individual's characteristics were associated with their QoL) and partner (degree to which the individual's characteristics were associated with the QoL of the other dyad member) effects., Results: Actor effects were found for patients and caregivers: The use of positive thinking and future/present-hedonistic perspectives were associated with higher QoL; the use of avoidance and past-negative perspective were associated with lower QoL. Partner effects were also found highlighting the specific mechanisms of the interconnections in the patient-caregiver dyad. The patient's QoL was higher when the caregiver used social support and experienced openness. The caregiver's QoL was lower when the patient used social support and avoidance strategies and experienced future perspective., Conclusions: The examination of the relationships between individuals' QoL and their internal psychobehavioral processes and personality traits will have several applications in the routine clinical management. Individual-level and dyad-level interventions should be proposed: cognitive-rehabilitation, emotional and cognitive self-regulation for time perspectives, and personality constructs., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Cardiovascular toxicity has become a challenging issue during cancer therapy. Nonetheless, there is a lack of consensual guidelines for their management. We aimed to determine the current practices of oncologists regarding cardiovascular toxicity related to anthracyclines, trastuzumab and angiogenic inhibitors and to gather their opinions on the development of cardio-oncology programs., Methods: A cross-sectional declarative study was submitted to French oncologists in the form of an individual, structured questionnaire., Results: A total of 303 oncologists responded to the survey. Ninety-nine percent of oncologists prescribed cardiotoxic therapies, including anthracyclines (83%), trastuzumab (51%) and other angiogenic inhibitors (64%). The method adopted for managing cardiovascular toxicity was based on guidelines from expert oncology societies for only 35% of oncologists. None was aware of recommendations from expert cardiology societies. Prescription of pre-, peri- and post-therapy cardiovascular assessment was inconsistent and significantly less frequent for all classes of angiogenic inhibitors than for anthracyclines and trastuzumab (P<0.0001). Relative to pre-therapy assessment, post-therapy assessment was prescribed significantly less often for all cancer therapies (P<0.0001). Attitudes regarding the onset of left ventricular dysfunction were much more inconsistent when angiogenic inhibitors were involved. Additionally, the management of hypertension and QT prolongation was also inconsistent. Finally, 88% of oncologists supported projects of cardio-oncology programs development., Conclusions: Practices of oncologists are disparate in the field of cardiovascular toxicity. This finding underlines the complexity of managing many different situations and the need for distribution of formal guidelines from oncology and cardiology expert societies. The development of personalized cardio-oncology programs seems essential., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D)., Methods: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway., Results: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6)., Conclusions: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Background: The purposes of this study, performed on a large sample of cancer patient-caregiver dyads, were: i) to simultaneously investigate, using an individualized quality of life (QoL) measure (Schedule for the Evaluation of Individual QoL, SEIQoL), the QoL domains freely expressed by cancer patients and their caregivers, and ii) to explore overlapping between the SEIQoL assessment and QoL assessment using traditional instruments., Methods: The study employed a cross-sectional design including cancer patients who were going to receive chemotherapy treatment and their caregivers. Quality of life was assessed using condition-specific questionnaires (EORTC QLQ-C30 and CarGOQoL), generic health-related questionnaire (SF-36), and open individualized measure (SEIQoL)., Results: The final sample included 205 patient-caregiver dyads. From the SEIQoL, Family, Health, and Leisures were the most freely expressed QoL domains by patients and caregivers, but reported with different weights. Love life and financial issues were less spontaneously mentioned. The SEIQoL index was moderately correlated to the condition-specific QoL questionnaires (R lower than |0.40|) and to SF-36 (correlation coefficients: R ranging from 0.17 to 0.31)., Conclusion: Individualized QoL measures allow individuals to spontaneously express important, non-predefined domains. This study highlights the need to explore QoL using a combination of individualized questionnaires and standardized questionnaires, capturing complementary facets that patients consider important in their life.

Combining radiotherapy with immune checkpoint blockade may offer considerable therapeutic impact if the immunosuppressive nature of the tumor microenvironment (TME) can be relieved. In this study, we used mathematical models, which can illustrate the potential synergism between immune checkpoint inhibitors and radiotherapy. A discrete-time pharmacodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway is described. This mathematical framework describes how a growing tumor first elicits and then inhibits an antitumor immune response. This antitumor immune response is described by a primary and a secondary (or memory) response. The primary immune response appears first and is inhibited by the PD1-PDL1 axis, whereas the secondary immune response happens next and is inhibited by the CTLA4 pathway. The effects of irradiation are described by a modified version of the linear-quadratic model. This modeling offers an explanation for the reported biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal effect (an off-target immune response). Furthermore, it explains why discontinuing immunotherapy may result in either tumor recurrence or a durably sustained response. Finally, it describes how synchronizing immunotherapy and radiotherapy can produce synergies. The ability of the model to forecast pharmacodynamic endpoints was validated retrospectively by checking that it could describe data from experimental studies, which investigated the combination of radiotherapy with immune checkpoint inhibitors. In summary, a model such as this could be further used as a simulation tool to facilitate decision making about optimal scheduling of immunotherapy with radiotherapy and perhaps other types of anticancer therapies. Cancer Res; 76(17); 4931-40. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor., Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added., Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications., Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR., (©2014 American Association for Cancer Research.)

Purpose: The study objective was to validate a specific quality of life (QoL) questionnaire for caregivers of cancer patients, the CareGiver Oncology Quality of Life questionnaire (CarGOQoL), based on the exclusive points of view of the caregivers., Materials and Methods: A 75-item questionnaire generated from content analysis of interviews with caregivers was self-completed by 837 caregivers of cancer patients. In addition to sociodemographic data and patient characteristics, self-reported questionnaires assessing QoL, burden, coping and social support were collected. Psychometric properties combined methods relying on both classical test theory and item response theory., Results: The final 29 items selected assessed 10 dimensions: psychological well-being, burden, relationship with health care, administration and finances, coping, physical well-being, self-esteem, leisure time, social support and private life; they were isolated from principal component analysis explaining 73% of the total variance. The missing data and the floor effects were low. Some ceiling effects were found for B (34%). Cronbach's alpha coefficients ranged from 0.72 to 0.89, except private life (PL) (0.55). Unidimensionality of the scales was confirmed by Rasch analyses. Correlations with other instruments confirmed the isolated content and significant links were found with respect to patient's characteristics. Reproducibility and sensitivity to change were found satisfactory., Conclusion: The CarGOQoL could provide a reliable and valid measure of caregivers of cancer patients' QoL which are key-actors in the provision of health care., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).