IMC-F106C is the first TCR bispecific protein targeting CD3 and PRAME, the most broadly expressed cancer testis antigen, which is homogenously expressed in multiple tumors (eg, lung, ovarian, endometrial, melanoma, breast). ImmTAC bispecifics redirect polyclonal T cells to target intra/extracellular cancer proteins, as validated by tebentafusp (tebe; gp100×CD3 ImmTAC) with an overall survival benefit in metastatic uveal melanoma (mUM). HLA-A*02:01+ patients (pts) with selected advanced tumors are eligible. Prospective PRAME testing required in low PRAME prevalence tumors. Primary objectives: safety and recommended dose. Secondary/exploratory objectives: efficacy, biomarkers and ctDNA response. IMC-F106C is dosed weekly with extended monitoring for intra-patient dose escalation during first 3 wks until target dose (TD). As of April 2022, 42 heavily pre-treated pts, across tumor types, were treated in 9 cohorts (TD 0.3-160 mcg) during dose escalation. 86% of tumors were confirmed PRAME+, median H score = 203. Most common (>30%) related AEs were consistent with the mechanism of action: pyrexia 64%; cytokine release syndrome (CRS) 45%; hypotension, fatigue 38% each; chills 36%; and nausea 33%. These were mostly Grade (G) 1/2, occurred in first 3 wks and rapidly resolved. 31% pts had related G3/4 AEs, most commonly lymphopenia 14% and AST increase 7%. There were no G3/4 CRS, treatment related discontinuations or deaths. Confirmed PRs were seen at TD of ≥ 20 mcg, a threshold dose for consistent and robust T cell activation. 18 pts at ≥ 20mcg were confirmed PRAME+, including 5 mUM pts who progressed on prior tebe. In 13 tebe-naïve pts, 69% (9/13) had tumor shrinkage and 38% (5/13) had a partial response (PR) including 2 of 3 cutaneous melanoma (all failed prior anti-PD1 & CTLA4), 1 of 2 ovarian, 2 of 5 mUM. All PRs are confirmed, 4 PRs ongoing. ctDNA response was observed across multiple tumor types and included some pts with complete clearance. IMC-F106C, the first PRAME×CD3 ImmTAC, is well tolerated and demonstrated durable RECIST partial responses and ctDNA response in PRAME+ pts across multiple tumor types. Dose escalation and multiple expansions are ongoing.

BackgroundTCR bispecific proteins (bsp) redirect polyclonal T cells to target intra/extracellular proteins in cancer, as validated by tebentafusp (CD3×gp100 TCR) with a survival benefit in metastatic uveal melanoma (HR 0.51). IMC-C103C is a TCR bsp against MAGE-A4, a cancer-testis antigen expressed in several tumor types (eg, lung, ovarian, HNSCC, GEJ) but minimally in normal tissue.MethodsHLA-A*02:01+ pts with selected advanced tumors are eligible; prospective MAGE-A4 testing is required in indications with lower MAGE-A4 prevalence. The Ph1 primary objective is to identify the expansion dose. Other objectives: adverse events (AE), clinical activity (RECIST v1.1), biomarkers. IMC-C103C is dosed IV weekly, with step-dosing at > 15 μg (full dose at Day 15).ResultsTable: 91PImmune cell activation markers, day 15-16Day 15 Dose, μgN treated*Blood lymphocytes % decrease, medianSerum IL6 fold increase, medianDetectable IFNg (>LLOD) n/N0.5-4.57Not done1.20/715-6420-605.32/18903-78281/31406-89344/62404-93504/4*40/42 pts treated on Day 15; only 13/18 pts received ≥ 90 μg dose on day 15. Open table in a new tab ConclusionsIMC-C103C is tolerable, demonstrates pharmacodynamic activity consistent with T cell activation (initially at ≥ 15 μg, consistently and robustly at ≥ 90 μg), drives T cells into tumor, and is clinically active. Dose optimization is ongoing.Clinical trial identificationNCT03973333.Legal entity responsible for the studyImmunocore Ltd.FundingImmunocore Ltd.DisclosureD. Davar: Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Checkmate Pharmaceuticals; Financial Interests, Institutional, Research Grant: CellSight Technologies; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Tesaro/GSK; Financial Interests, Personal, Advisory Role, Consultant: Checkmate Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consultant: Shionogi; Financial Interests, Personal, Advisory Role, Consultant: Vedanta CE; Other, Personal, Other, US Patent 63/124,231, Dec 11, 2020 : US Patent; Other, Personal, Other, US Patent 63/208,719, June 9 2021: US Patent. R.F. Sweis: Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Aduro; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Astellas; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: AstraZeneca; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: EMD Serono; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Exelixis; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Eisai; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Janssen; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Mirati; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Pfizer; Financial Interests, Personal, Advisory Role, Personal fees/Consulting: Seattle Genetics; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Aduro; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Immunocore; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Moderna; Financial Interests, Institutional, Research Grant: QED therapeutics. G. Blumenschein Jr.: Financial Interests, Personal, Research Grant, Grant/Contract: Amgen; Financial Interests, Personal, Research Grant, Grant/Contract: Bayer; Financial Interests, Personal, Research Grant, Grant/Contract: Adaptimmune; Financial Interests, Personal, Research Grant, Grant/Contract: Elelixis; Financial Interests, Personal, Research Grant, Grant/Contract: Daiichi Sankyo; Financial Interests, Personal, Research Grant, Grant/Contract: GSK; Financial Interests, Personal, Research Grant, Grant/Contract: Immatics; Financial Interests, Personal, Research Grant, Grant/Contract: Immunocore; Financial Interests, Personal, Research Grant, Grant/Contract: Incyte; Financial Interests, Personal, Research Grant, Grant/Contract: Kite Pharma; Financial Interests, Personal, Research Grant, Grant/Contract: Macrogenics; Financial Interests, Personal, Research Grant, Grant/Contract: Torque; Financial Interests, Personal, Research Grant, Grant/Contract: AstraZeneca; Financial Interests, Personal, Research Grant, Grant/Contract: Bristol Myers Squibb; Financial Interests, Personal, Research Grant, Grant/Contract: Celgene; Financial Interests, Personal, Research Grant, Grant/Contract: Genentech; Financial Interests, Personal, Research Grant, Grant/Contract: MedImmune; Financial Interests, Personal, Research Grant, Grant/Contract: Merck; Financial Interests, Personal, Research Grant, Grant/Contract: Novartis; Financial Interests, Personal, Research Grant, Grant/Contract: Roche; Financial Interests, Personal, Research Grant, Grant/Contract: Xcovery; Financial Interests, Personal, Research Grant, Grant/Contract: Tmunity Therapeutics; Financial Interests, Personal, Research Grant, Grant/Contract: Regeneron; Financial Interests, Personal, Research Grant, Grant/Contract: Beigene; Financial Interests, Personal, Research Grant, Grant/Contract: Repertoire Immune Medicines; Financial Interests, Personal, Research Grant, Grant/Contract: Verastem; Financial Interests, Personal, Advisory Role, Consulting: AbbVie; Financial Interests, Personal, Advisory Role, Consulting: Adicet; Financial Interests, Personal, Advisory Role, Consulting: Amgen; Financial Interests, Personal, Advisory Role, Consulting: Ariad; Financial Interests, Personal, Advisory Role, Consulting: Bayer; Financial Interests, Personal, Advisory Role, Consulting: Clovis Oncology; Financial Interests, Personal, Advisory Role, Consulting: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting: Celgene; Financial Interests, Personal, Advisory Role, Consulting: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting: Instil Bio; Financial Interests, Personal, Advisory Role, Consulting: Genentech; Financial Interests, Personal, Advisory Role, Consulting: Gilead; Financial Interests, Personal, Advisory Role, Consulting: Lilly; Financial Interests, Personal, Advisory Role, Consulting: Janssen; Financial Interests, Personal, Advisory Role, Consulting: MedImmune; Financial Interests, Personal, Advisory Role, Consulting: Merck; Financial Interests, Personal, Advisory Role, Consulting: Novartis; Financial Interests, Personal, Advisory Role, Consulting: Roche; Financial Interests, Personal, Advisory Role, Consulting: Tyme Oncology; Financial Interests, Personal, Advisory Role, Consulting: Xcovery; Financial Interests, Personal, Advisory Role, Consulting: Virogin Biotech; Financial Interests, Personal, Advisory Role, Consulting: Maverick Therapeutics; Financial Interests, Personal, Other, Data safety board/Advisory board: Virogin Biotech; Financial Interests, Personal, Other, Data safety board/Advisory board: Maverick therapeutics; Financial Interests, Personal, Stocks/Shares: Virogin Biotech; Non-Financial Interests, Personal, Other, Immediate family member employed: Johnson & Johnson / Janssen. I. Melero: Financial Interests, Institutional, Sponsor/Funding: Immunocore. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: Achilles; Financial Interests, Personal, Advisory Board: Adicet; Financial Interests, Personal, Advisory Board, Honoraria: Bayer; Financial Interests, Personal, Advisory Board, Ad board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Ad board: Evelo Therapeutics; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board, Adboard/consultancy: Tknife; Financial Interests, Personal, Advisory Board, Ad board: Zelluna; Financial Interests, Institutional, Other, iMATCH is a 12 partner consortium funded by not for profit Innovate UK : IMATCH; Financial Interests, Institutional, Officer, Clinical lead for this 10 partner consortium of clinical academic and commercial partners: SAMPLE; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Achilles Ltd; Financial Interests, Institutional, Principal Investigator: Adaptimmune; Financial Interests, Institutional, Principal Investigator: Agalimmune Ltd; Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Aveo; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Principal Investigator: CytomX; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: GenMab; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Immunocore; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: Kymab Ltd; Financial Interests, Institutional, Principal Investigator: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Synthon; Other, Personal, Other, Panel member for a funding committee (MRC is a UK government NFP organisation): MRC DPFS panel member. 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Moore: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Aravive; Financial Interests, Personal, Advisory Board: Alkemeres; Financial Interests, Personal, Advisory Board: Blueprint; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Elevar; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: GSK/Tesaro; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: IMab; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Mereo; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board: VBL Therapeutics; Financial Interests, Institutional, Research Grant: PTC Therapeutcs; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: GSK/Tesaro. N.H. Segal: Financial Interests, Personal, Advisory Role, Consulting/ advisory board: Immunocore; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: PsiOxus; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: Roche/Genentech; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: Revitope; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: ABL Bio; Financial Interests, Personal, Advisory Role, Consulting/ advisory board: Novartis; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Immunocore; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Roche/Genentech. 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Garralda: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Thermo Fisher; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: F.Hoffmann/La Roche; Financial Interests, Personal, Advisory Role: Ellipses Pharma; Financial Interests, Personal, Advisory Role: Neomed Therapeutics1 Inc; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Janssen Global Services; Financial Interests, Personal, Advisory Role: SeaGen; Financial Interests, Personal, Advisory Role: TFS; Financial Interests, Personal, Advisory Role: Alkermes; Financial Interests, Personal, Advisory Role: Thermo Fisher; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: MabDiscovery; Financial Interests, Personal, Advisory Role: Anaveon; Financial Interests, Personal, Other, Travel Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel Grant: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel Grant: Menarini; Financial Interests, Personal, Other, Travel Grant: Glycotope; Financial Interests, Personal, Speaker's Bureau: Merck Sharp & Dohme; Financial Interests, Personal, Speaker's Bureau: Roche; Financial Interests, Personal, Speaker's Bureau: Thermo Fisher; Financial Interests, Personal, Speaker's Bureau: Lilly; Financial Interests, Institutional, Principal Investigator: Affimed Gmbh; Financial Interests, Institutional, Principal Investigator: Amgen SA; Financial Interests, Institutional, Principal Investigator: Anaveon AG; Financial Interests, Institutional, Principal Investigator: AstraZeneca AB; Financial Interests, Institutional, Principal Investigator: Biontech Gmbh; Financial Interests, Institutional, Principal Investigator: Catalym Gmbh; Financial Interests, Institutional, Principal Investigator: Cytomx; Financial Interests, Institutional, Principal Investigator: F.Hoffmann La Roche Ltd; Financial Interests, Institutional, Principal Investigator: F-Star Beta Limited; Financial Interests, Institutional, Principal Investigator: Genentech Inc; Financial Interests, Institutional, Principal Investigator: Genmab B.V.; Financial Interests, Institutional, Principal Investigator: Hutchison Medipharma Limited; Financial Interests, Institutional, Principal Investigator: Icon; Financial Interests, Institutional, Principal Investigator: Imcheck Therapeutics; Financial Interests, Institutional, Principal Investigator: Immunocore Ltd; Financial Interests, Institutional, Principal Investigator: Janssen-Cilag SA; Financial Interests, Institutional, Principal Investigator: Medimmune Llc; Financial Interests, Institutional, Principal Investigator: Merck Kgga; Financial Interests, Institutional, Principal Investigator: Novartis Farmacéutica, S.A; Financial Interests, Institutional, Principal Investigator: Peptomyc; Financial Interests, Institutional, Principal Investigator: Ribon Therapeutics; Financial Interests, Institutional, Principal Investigator: Roche Farma SA; Financial Interests, Institutional, Principal Investigator: Seattle Genetics Inc; Financial Interests, Institutional, Principal Investigator: Symphogen A/S; Financial Interests, Institutional, Principal Investigator: Taiho Pharma Usa Inc. B. Wilky: Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Springworks; Financial Interests, Personal, Advisory Role: Deciphera; Financial Interests, Personal, Advisory Role: Adaptimmune; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Epizyme; Financial Interests, Personal, Advisory Role: Adcendo; Financial Interests, Personal, Research Grant: Agenus; Financial Interests, Personal, Research Grant: Exelixis; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Deciphera; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Adaptimmune; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Daiichi Sankyo. H. Arkenau: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Bicycle; Financial Interests, Personal, Advisory Role: Bicycle; Financial Interests, Personal, Advisory Role: Engitix; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Role: ONC; Financial Interests, Personal, Advisory Role: Lab genius; Financial Interests, Personal, Advisory Role: Cell centric; Financial Interests, Personal, Advisory Role: Beigene; Financial Interests, Personal, Advisory Board: Taiko; Financial Interests, Personal, Full or part-time Employment: Sarah Cannon; Financial Interests, Institutional, Full or part-time Employment: Sarah Cannon. T.R. J. Evans: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Personal, Other, Support to attend international conferences: Bayer; Financial Interests, Institutional, Advisory Board: Bicycle Therapeutics; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb; Financial Interests, Personal, Other, Support to attend international conferences: Celgene; Financial Interests, Institutional, Advisory Board: Clovis; Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Advisory Board: Medivir; 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Non-Financial Interests, Personal, Other, Member of Clinical Experts Review Panel / Clinical Research Committee: Cancer Research; Non-Financial Interests, Personal, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Personal, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Personal, Member, Cancer Society Member: America Association for Cancer Research; Non-Financial Interests, Personal, Member, Cancer Society Member: American Society of Clinical Oncology; Non-Financial Interests, Personal, Member, Cancer Society Member: Association of Cancer Physicians (UK); Non-Financial Interests, Personal, Member, Cancer Society Member: British Association for Cancer Research; Non-Financial Interests, Personal, Member, Cancer Society Member: European Association for Cancer Research; Non-Financial Interests, Personal, Member, Cancer Society Member: International Liver Cancer Association; Other, Personal, Other, Clinical Subjects Editor: British Journal of Cancer; Other, Personal, Other, Chair of Independent Data Monitoring Committee P1trial: Genmab. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Acerta; Financial Interests, Institutional, Research Grant: Adaptimmune; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Apexigen; Financial Interests, Institutional, Research Grant: Arcus Biosciences; Financial Interests, Institutional, Research Grant: Array BioPharma; Financial Interests, Institutional, Research Grant: Artios Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Atreca; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: BerGenBio; Financial Interests, Institutional, Research Grant: BioAtla; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Calithera Biosciences; Financial Interests, Institutional, Research Grant: Checkpoint Therapeutics; 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Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: NeoImmune Tech; Financial Interests, Institutional, Research Grant: Neovia Oncology; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Numab Therapeutics; Financial Interests, Institutional, Research Grant: OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PMV Pharmaceuticals; Financial Interests, Institutional, Research Grant: RasCal Therapeutics; Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals; Financial Interests, Institutional, Research Grant: Relay Therapeutics; Financial Interests, Institutional, Research Grant: Revolution Medicines; Financial Interests, Institutional, Research Grant: Ribon Therapeutics; Financial Interests, Institutional, Research Grant: Rubius Therapeutics; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Silicon Therapeutics; Financial Interests, Institutional, Research Grant: Stem CentRx; Financial Interests, Institutional, Research Grant: Syndax Pharmaceuticals; Financial Interests, Institutional, Research Grant: Takeda Pharmaceuticals; Financial Interests, Institutional, Research Grant: Tarveda; Financial Interests, Institutional, Research Grant: TCR2 Therapeutics; Financial Interests, Institutional, Research Grant: Tempest Therapeutics; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: TMUNITY Therapeutics; Financial Interests, Institutional, Research Grant: Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: University of Michigan; Financial Interests, Institutional, Research Grant: Vyriad; Financial Interests, Institutional, Research Grant: WindMIL; Financial Interests, Institutional, Research Grant: Y-mAbs Therapeutics; Financial Interests, Institutional, Advisory Role: AbbVie; Financial Interests, Institutional, Advisory Role: Achilles Therapeutics; Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Axelia Oncology; Financial Interests, Institutional, Advisory Role: Atreca; Financial Interests, Institutional, Advisory Role: Black Diamond; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Calithera Biosciences; Financial Interests, Institutional, Advisory Role: Checkpoint Therapeutics; Financial Interests, Institutional, Advisory Role: CytomX Therapeutics; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Advisory Role: EcoR1; Financial Interests, Institutional, Advisory Role: Editas Medicine; Financial Interests, Institutional, Advisory Role: Eisai; Financial Interests, Institutional, Advisory Role: EMD Serono; Financial Interests, Institutional, Advisory Role: G1 Therapeutics; Financial Interests, Institutional, Advisory Role: Genentech / Roche; Financial Interests, Institutional, Advisory Role: Genmab; Financial Interests, Institutional, Advisory Role: GlaxoSmithKline; Financial Interests, Institutional, : Gritstone Oncology. M. Dar: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. C. Holland: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. S. Marshall: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. S. Stanhope: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. P. Kirk: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. J.S. Lopez: Financial Interests, Institutional, Research Grant: Roche-Genentech; Financial Interests, Institutional, Research Grant: Basilea; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Personal, Advisory Board: Basilea; Financial Interests, Personal, Advisory Board: Ellipses. All other authors have declared no conflicts of interest. BackgroundTCR bispecific proteins (bsp) redirect polyclonal T cells to target intra/extracellular proteins in cancer, as validated by tebentafusp (CD3×gp100 TCR) with a survival benefit in metastatic uveal melanoma (HR 0.51). IMC-C103C is a TCR bsp against MAGE-A4, a cancer-testis antigen expressed in several tumor types (eg, lung, ovarian, HNSCC, GEJ) but minimally in normal tissue. TCR bispecific proteins (bsp) redirect polyclonal T cells to target intra/extracellular proteins in cancer, as validated by tebentafusp (CD3×gp100 TCR) with a survival benefit in metastatic uveal melanoma (HR 0.51). IMC-C103C is a TCR bsp against MAGE-A4, a cancer-testis antigen expressed in several tumor types (eg, lung, ovarian, HNSCC, GEJ) but minimally in normal tissue. MethodsHLA-A*02:01+ pts with selected advanced tumors are eligible; prospective MAGE-A4 testing is required in indications with lower MAGE-A4 prevalence. The Ph1 primary objective is to identify the expansion dose. Other objectives: adverse events (AE), clinical activity (RECIST v1.1), biomarkers. IMC-C103C is dosed IV weekly, with step-dosing at > 15 μg (full dose at Day 15). HLA-A*02:01+ pts with selected advanced tumors are eligible; prospective MAGE-A4 testing is required in indications with lower MAGE-A4 prevalence. The Ph1 primary objective is to identify the expansion dose. Other objectives: adverse events (AE), clinical activity (RECIST v1.1), biomarkers. IMC-C103C is dosed IV weekly, with step-dosing at > 15 μg (full dose at Day 15). ResultsTable: 91PImmune cell activation markers, day 15-16Day 15 Dose, μgN treated*Blood lymphocytes % decrease, medianSerum IL6 fold increase, medianDetectable IFNg (>LLOD) n/N0.5-4.57Not done1.20/715-6420-605.32/18903-78281/31406-89344/62404-93504/4*40/42 pts treated on Day 15; only 13/18 pts received ≥ 90 μg dose on day 15. Open table in a new tab *40/42 pts treated on Day 15; only 13/18 pts received ≥ 90 μg dose on day 15. ConclusionsIMC-C103C is tolerable, demonstrates pharmacodynamic activity consistent with T cell activation (initially at ≥ 15 μg, consistently and robustly at ≥ 90 μg), drives T cells into tumor, and is clinically active. Dose optimization is ongoing. IMC-C103C is tolerable, demonstrates pharmacodynamic activity consistent with T cell activation (initially at ≥ 15 μg, consistently and robustly at ≥ 90 μg), drives T cells into tumor, and is clinically active. Dose optimization is ongoing.

In early clinical studies, agonistic antibodies targeting the T-cell costimulatory receptors OX40 and CD137 have shown immune-stimulatory effects. Dose-limiting hepatotoxicity significantly hindered further development of CD137 monotherapies. FS120 is a novel tetravalent bispecific antibody incorporating OX40 binding into the Fc-region (termed an Fcab) and CD137 Fabs in a natural human IgG1 antibody and with silenced FcyR activity for reduced toxicity, as shown in preclinical safety studies. FS120 crosslinks and clusters the receptors eliciting a robust immune stimulation and activity in mouse tumor models, independent of FcyR crosslinking (Gaspar et al 2020, Cancer Immunology Research doi: 10.1158/2326-6066).

Background: T-cell directed therapies (e.g. CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. Aims: To report safety results from an ongoing Phase 1/1b study (NCT02500407) of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%), with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts.Summary/Conclusion: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile.

ConclusionThe world's first clinical real-time motion-including tumor dose reconstruction during radiotherapy was demonstrated.This milestone marks a significant step towards real-time monitored radiotherapy with important potential applications for real-time QA and dose-guided treatment adaptation.

Background ImmTAC® bispecific molecules are unique TCR–anti-CD3 agents that redirect T cells against intracellular antigens, in contrast to antibody-based therapies, which are limited to extracellular antigens. The most advanced ImmTAC, tebentafusp (IMCgp100), against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma, a solid tumor. In contrast, bispecific antibodies have shown activity in hematologic cancers but appear less active in solid tumors. ImmTAC molecules recognize a specific peptide presented on a defined Class I HLA molecule via an affinity enhanced, engineered, soluble TCR. Through the addition of an anti-CD3 scFv domain fused to the TCR targeting domain, an ImmTAC can redirect T cell activity against cancer cells, regardless of the specificity of the T cell. IMCnyeso is an ImmTAC against NY-ESO-1/LAGE-1A, which are cancer testis antigens expressed in a variety of solid malignancies, but with very low or absent normal tissue expression. Trial design IMCnyeso-101 is a multi-center, open-label, first-in-human study of IMCnyeso in HLA-A*02:01-positive patients with NY-ESO-1- and/or LAGE-1A-positive advanced NSCLC, synovial sarcoma, melanoma, or urothelial carcinoma. The study includes dose escalation (Bayesian logistic regression models) and expansion for IMCnyeso monotherapy (QW), followed by expansion into indication specific arms to test for signs of efficacy in defined patient cohorts. Primary endpoints are establishing MTD/RP2D and safety and tolerability. Secondary endpoints include: characterization of PK and ADA, efficacy by RECIST v1.1 (PFS, ORR and DOR) and OS. The dose escalation portion of the study is in progress. The trial continues to enroll; NCT number NCT03515551. Clinical trial identification NCT03515551. Legal entity responsible for the study Immunocore. Funding Immunocore. Disclosure J. Lopez: Research grant / Funding (institution), During the conduct of the study: Immunocore, Roche, Genentech; Advisory / Consultancy, Outside the submitted work: Novartis (personal fees); Research grant / Funding (institution), Outside the submitted work: MSD; Research grant / Funding (institution), Outside the submitted work (grant and non-financial support): Basilea; Advisory / Consultancy, Research grant / Funding (institution), Outside the submitted work: Genmab. T. Sato: Advisory / Consultancy: Immunocore; Advisory / Consultancy: IDEAYA Biosciences; Advisory / Consultancy: Neon Therapeutics, Inc. F. Thistlethwaite: Honoraria (self), Achilles Therapeutics. B. Van Tine: Honoraria (institution), Advisory / Consultancy: Immunocore ; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Speaker Bureau / Expert testimony: Adaptimmune; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (self): Tracon. J.A. Rodon: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Orion Pharmaceuticals; Advisory / Consultancy: Servier Pharma; Honoraria (self), Advisory / Consultancy: Peptomyc; Honoraria (self): Merck Sharp; Advisory / Consultancy: Merck Sharp & Dome; Advisory / Consultancy: Kelun Pharma/Klus Pharma; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Roche Pharma; Advisory / Consultancy: Elipses Pharma; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): BioAtla; Research grant / Funding (institution): GenMab; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Kelun-Biotech; Research grant / Funding (institution): Takeda-Millenium; Research grant / Funding (institution): Glaxosmithkline; Research grant / Funding (institution): Ipsen. J. Dukes: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore Ltd. R. Easton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore. S. Marshall: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore. All other authors have declared no conflicts of interest.

BACKGROUND:Weight loss interventions based solely on text messaging (short message service [SMS]) have been shown to be modestly effective for short periods of time and in some populations, but limited evidence is available for positive longer-term outcomes and for efficacy in Hispanic populations. Also, little is known about the comparative efficacy of weight loss interventions that use SMS coupled with brief, technology-mediated contact with health coaches, an important issue when considering the scalability and cost of interventions. We examined the efficacy of a 1-year intervention designed to reduce weight among overweight and obese English- and Spanish-speaking adults via SMS alone (ConTxt) or in combination with brief, monthly health-coaching calls. ConTxt offered 2-4 SMS/day that were personalized, tailored, and interactive. Content was theory- and evidence-based and focused on reducing energy intake and increasing energy expenditure. Monthly health-coaching calls (5-10 minutes' duration) focused on goal-setting, identifying barriers to achieving goals, and self-monitoring. METHODS AND FINDINGS:English- and Spanish-speaking adults were recruited from October 2011 to March 2013. A total of 298 overweight (body mass index [BMI] 27.0 to 39.9 kg/m2) adults (aged 21-60 years; 77% female; 41% Hispanic; 21% primarily Spanish speaking; 44% college graduates or higher; 22% unemployed) were randomly assigned (1:1) to receive either ConTxt only (n = 101), ConTxt plus health-coaching calls (n = 96), or standard print materials on weight reduction (control group, n = 101). We used computer-based permuted-block randomization with block sizes of three or six, stratified by sex and Spanish-speaking status. Participants, study staff, and investigators were masked until the intervention was assigned. The primary outcome was objectively measured percent of weight loss from baseline at 12 months. Differences between groups were evaluated using linear mixed-effects regression within an intention-to-treat framework. A total of 261 (87.2%) and 253 (84.9%) participants completed 6- and 12-month visits, respectively. Loss to follow-up did not differ by study group. Mean (95% confidence intervals [CIs]) percent weight loss at 12 months was -0.61 (-1.99 to 0.77) in the control group, -1.68 (-3.08 to -0.27) in ConTxt only, and -3.63 (-5.05 to -2.81) in ConTxt plus health-coaching calls. At 12 months, mean (95% CI) percent weight loss, adjusted for baseline BMI, was significantly different between ConTxt plus health-coaching calls and the control group (-3.0 [-4.99 to -1.04], p = 0.003) but not between the ConTxt-only and the control group (-1.07 [-3.05 to 0.92], p = 0.291). Differences between ConTxt plus health-coaching calls and ConTxt only were not significant (-1.95 [-3.96 to 0.06], p = 0.057). These findings were consistent across other weight-related secondary outcomes, including changes in absolute weight, BMI, and percent body fat at 12 months. Exploratory subgroup analyses suggested that Spanish speakers responded more favorably to ConTxt plus health-coaching calls than English speakers (Spanish contrast: -7.90 [-11.94 to -3.86], p < 0.001; English contrast: -1.82 [-4.03 to 0.39], p = 0.107). Limitations include the unblinded delivery of the intervention and recruitment of a predominantly female sample from a single site. CONCLUSIONS:A 1-year intervention that delivered theory- and evidence-based weight loss content via daily personalized, tailored, and interactive SMS was most effective when combined with brief, monthly phone calls. TRIAL REGISTRATION:ClinicalTrials.gov NCT01171586.

7004 Background: A pivotal multicenter, single-arm study evaluated moxetumomab pasudotox, a first-in-class recombinant immunotoxin, in patients (pts) with relapsed/refractory hairy cell leukemia (HCL). Methods: Eligible pts (≥2 prior systemic therapies, including ≥1 purine nucleoside analog) received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 of 28-d cycles, up to 6 cycles. Disease response and immunohistochemistry (IHC) minimal residual disease (MRD) status were determined by blinded independent central review. Primary end point was durable complete response (CR), defined as CR with hematologic remission (blood count normalization, HR) for > 180 d. Results: Eighty pts (63 male; median age 60 y) received moxetumomab pasudotox. Median number of prior systemic therapies was 3 (2–11); 39 pts (49%) had > 3 prior lines of therapy and 60 (75%) had prior rituximab. At 16.7 months median follow-up, objective response (OR) rate was 75% (60/80), HR rate 80% (64/80), CR rate 41% (33/80), and durable CR rate 30% (24/80). Of 33 pts achieving CR, 27 (82%) had IHC MRD negative status. Median time to HR was 1 mo. Median duration of OR and median PFS were not reached. Most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%); 8% had infections and 3% had neutropenia deemed treatment related. Three deaths occurred; none were treatment related. Treatment-related AEs leading to discontinuation were hemolytic uremic syndrome (HUS; 4 [5%]), capillary leak syndrome (CLS; 2 [3%]), and increased blood creatinine (2 [3%]). Seven pts (9%) had CLS (grade 2: n = 5; grade 4: n = 2), 7 (9%) had HUS (grade 2: n = 2; grade 3: n = 3; grade 4: n = 2), and 4 (5%) had both. CLS and HUS were manageable and reversible (no plasma exchange in HUS). Median immunoglobulin levels remained unchanged after treatment. Median CD4 cell counts were stable or improved after the first week of treatment. Conclusions: Moxetumomab pasudotox achieved a high rate of independently assessed durable CR, with the ability to eradicate MRD in heavily pretreated HCL patients, and showed a favorable safety profile without immuno/myelosuppression. Clinical trial information: 01829711.

Background: MEDI4276 is a HER2-bispecific antibody targeting two different epitopes on HER2, with site-specific conjugation via maleimidocaproyl linker to a potent tubulysin-based microtubule inhibitor. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2+ tumor cells in vitro, including T-DM1 resistant cells.

Background: PD-1/L1 axis blockade shows durable responses and extended overall survival across cancer types in a subset of patients. Tumour Necrosis Factor Receptor (TNFR) superfamily activation is also being tested clinically to improve patient responses. Current interventions using therapeutic CD137 agonists to activate T cells are limited by adverse safety effects and poor efficacy as monotherapies. The generation of a bispecific agonist of CD137 following PD-L1 crosslinking allows a greater therapeutic window with improved safety and efficacy. Methods: An anti-CD137/PD-L1 mAb2 was generated by introducing a CD137-binding specificity into the Fc-region of a human IgG1 targeting PD-L1 mAb. FcgR binding was decreased by introducing a LALA mutation. Binding characterisation was assessed and in vitro activity measured in a mouse primary OT-1 CD8+ T cell assay. The anti-tumour activity and PK/PD of anti-CD137/PD-L1 mAb2 was tested in mouse tumour models. Results: An anti-CD137/PD-L1 mAb2 was developed, which binds to mouse PD-L1 enabling CD137 agonism (in vitro EC50: 3 pM in primary antigen-specific OT-1 assay). The mAb2 significantly reduced tumour growth in 3 syngeneic mouse tumour models (MC38, CT26 and B16-F10) with dose-dependent inhibition seen in CT26, resulting in a significant survival benefit at concentrations of 0.3 mg/kg or above. This growth inhibition was coincident with increases in tumour and peripheral activated CD8 T cells. Liver pharmacology was minimal as defined by histopathology. Conclusions: We report intra-tumoural and peripheral PD changes leading to an increase in the proliferative CD8+ T cell response following dosing with an anti-CD137/PD-L1 bispecific mAb2. These changes were dose dependent and coincident with tumour growth inhibition. In in vitro T cell activation assays the bispecific was superior to control antibodies and relevant combinations. Minimal liver pharmacology and no toxicity was observed with the anti-CD137/PD-L1 mAb2 unlike with other monoclonal antibodies targeting CD137. This warrants the development of a first-in-class anti-human CD137/PD-L1 bispecific antibody with a novel mode of action and improved therapeutic index for the treatment of human cancer. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: PD-1/L1 blocking agents have transformed the treatment of multiple cancers, but some tumor types including MSS-CRC appear to be refractory. Monalizumab (anti-NKG2A) and Durvalumab (anti-PD-L1) may promote antitumor immunity via non-redundant mechanisms targeting innate and adaptive immunity. The safety and preliminary efficacy of this combination (NCT02671435) was previously reported (ASCO 2018). Here, we present the results of baseline and longitudinal pharmacodynamic biomarker assessments in peripheral blood and tumor in patients with MSS-CRC treated with Monalizumab plus Durvalumab. Methods: Peripheral biomarkers evaluated included NKG2A receptor occupancy (RO), and frequency and functional status of immune cells (N = 23). In tumors, changes in NK and CD8 cells in pre/post-tumor biopsies were evaluated by immunohistochemistry (IHC, N = 7). Gene expression profiling of tumors was determined by RNAseq in N = 15 pretreated and N = 4 paired biopsies. Results: In peripheral blood, full and sustained NKG2A RO was observed. Expansion of activated or proliferating NK cells was detected in 14/23 and 10/20 patients respectively, while increases in T cell proliferation (KI67+) were observed at levels expected for Durvalumab monotherapy (1.5-2-fold). In an in vitro assay system, similar changes on T/NK cell phenotyping were observed upon exposure to Monalizumab and Durvalumab. No consistent pharmacodynamics changes in tumoral NK and CD8 cells by gene expression or IHC were observed. However, modulation of pathways associated with metabolism, DNA repair and cell cycle were detected in tumors on treatment. Conclusions: In peripheral blood, pharmacodynamic effects consistent with the proposed mechanism of action of Monalizumab and Durvalumab were observed in patients with MSS-CRC. Clinical trial identification: NCT02671435; February 22, 2016. Legal entity responsible for the study: MedImmune. Funding: MedImmune. Disclosure: N. Standifer, M.L. Ascierto, C. Morehouse, H. Ghadially, J. Rodriguez Canales, M.C. Rebelatto, X. Song, D.C. Jones, X. Li, S. Marshall, S. Abdullah, M. Jure-Kunkel: Employee: MedImmune. All other authors have declared no conflicts of interest.

Concurrent chemoradiation (CCRT) is the preferred treatment approach in inoperable non-small cell lung cancer (NSCLC) patients. However, CCRT increases the risk of acute esophagus toxicity (AET) compared to radiotherapy alone or sequential chemoradiation. To minimize the risk of AET, an international RT-dose constraint of either V50Gy or V60Gy <50% is used. However, clinical applicability of those models is not evident since assessment of the model accuracy and validity should be performed before generalizing to other populations. Therefore, the aim of this study was to clinically validate the two NTCP-models to predict acute esophagus toxicity in NSCLC patients treated with CCRT. To validate the NTCP-models, clinical data of 274 inoperable NSCLC patients receiving CCRT using IMRT was used. The planned V50Gy and V60Gy and the prospectively scored grade ≥2 AET (CTC-AE) were retrieved and independently reviewed. The grade ≥2 AET probability for the V50Gy and V60Gy was calculated as; [1/1+exp[-0.515 + (0.027∗V50] and [1/1+exp[-0.701 + (0.029∗V60]]. Validity of the model was assessed with the ability to predict the number of grade ≥2 AET events (calibration) and the ability to distinguish between those who develop grade ≥2 AET from those who do not (discrimination, area under the curve (AUC)). Furthermore, sensitivity and specificity for different cut-off points were determined. From the 274 NSCLC patients, 125 (45.6%) patients developed grade ≥2 AET (93.8% grade 2, 6.2% grade 3), median V50Gy 23% (interquartile range 10.1-35.6%), median V60Gy 4.3% (interquartile range 0-20.5%). Calibration showed that the V50 overestimated the risk of developing grade ≥2 AET in low-risk patients while the V60 underestimated the risk of developing grade ≥2 AET in high-risk patients. Discrimination of both algorithms demonstrated a similar moderate fit (AUC 0.70 95%CI 0.64 to 0.76 and AUC 0.69 95%CI 0.63 to 0.76 for the V50Gy and V60Gy, respectively). For V50Gy, a cut-off point of more than 40% probability of developing grade ≥2 AET resulted in the most favorable sensitivity of 95.8% for grade ≥2 and 100% for grade 3, with specificity scores of 54.6% and 40.7% respectively. For V60Gy, a cut-off point of more than 60% resulted in the most favorable sensitivity of 95.1% for grade ≥2 and 100% for grade 3, with remarkably low specificity scores of 9.1% and 18.8%, respectively. The NTCP-models to predict acute esophagus toxicity in NSCLC patients both showed good predictive accuracy. For clinical practice, the V50Gy seems to be the most sensitive without compromising safety and efficacy.

ABSTRACTArts therapists within the field of learning disabilities have long struggled to record the subtle and often silent changes that take place for their vulnerable clients in the course of treatment. In this article, I reflect on outcome evaluation and the challenge of maintaining curiosity with clients whose emotional intelligence can appear hidden, and where a parallel process of worthlessness can pervade the work of arts therapists. I briefly outline possible forms of inquiry, and describe the conversations within the arts therapies team that I am part of that led to the development of carer focus groups to capture a perception of change in clients resulting from treatment across modality for clients of all ability. I note how this approach enables collaboration with health workers and colleagues as witnesses, and the place of broad, collaborative conversations as evidence.

Background: Chronic stress and/or lifetime traumatic stress can create a self-reinforcing cycle of unhealthy behaviors, such as overeating and sedentary behavior, that can lead to further increases in stress. This study examined the relationship between stress and sedentary behavior in a sample of Hispanic/Latino adults (N = 4244) from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. Methods: Stress was measured as the number of ongoing difficulties lasting 6 months or more and as lifetime exposure to traumatic events. Sedentary behavior was measured by self-report and with accelerometer. Multivariable regression models examined associations of stress measures with time spent in sedentary behaviors adjusting by potential confounders. Results: Those who reported more than one chronic stressor spent, on average, 8 to 10 additional minutes per day in objectively measured sedentary activities (P < .05), whereas those with more than one lifetime traumatic stressor spent (after we adjusted for confounders) 10 to 14 additional minutes in sedentary activities (P < .01) compared with those who did not report any stressors. Statistical interactions between the 2 stress measures and age or sex were not significant. Conclusion: Interventions aimed at reducing sedentary behaviors might consider incorporating stress reduction into their approaches.

BackgroundThe PD-1/PD-L1 pathway is a key regulator of T-cell activation and a promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4&kgr; mAb specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Blocking both the PD-1 receptor and its ligand by combining M + D offers the potential for complete PD-1/PD-L1 axis inhibition.MethodsThis ongoing Phase 1 open-label, dose-escalation and expansion study is evaluating M + D in patients (pts) ≥18 years with relapsed/refractory advanced solid malignancies and ECOG performance status 0-1 (NCT02118337). The primary objectives are safety and maximum tolerated dose (MTD). Secondary objectives include antitumor activity.ResultsTabled 1Cohort123456TotalDose every 2 weeks (Q2W) (mg/kg), M + D0.1 + 30.1 + 100.5 + 102.5 + 1010 + 1020 + 10N45339630Patients with drug-related AEs, n (%)All grades2 (50)3 (60)3 (100)2 (67)8 (89)3 (50)21 (70)Grade ≥31 (25)01 (33)03 (33)05 (17)All grades leading to discontinuation1 (25)1 (20)1 (33)1 (33)2 (22)06 (20)Responses*Objective response rate (CR + PR), n/N (%)1/4 (25)0003/8 (38)04/26 (15)Disease control (CR + PR + SD ≥8 weeks), n/N (%)2/4 (50)1/5 (20)1/3 (33)05/8 (63)09/26 (35)*Response evaluable population Open table in a new tab ConclusionsM 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population.Clinical trial identification: NCT02118337Legal entity responsible for the study: MedImmuneFundingMedImmuneDisclosureO. Hamid: Consulting/Advisory: Merck, Merck Serono, Pfizer, Amgen, Novartis, Roche, BMS, Genentech Speakers Bureau: BMS, Genentech, Novartis Research funding: None. L.Q. Chow: Honoraria: Astellas Consulting/Advisory: Novartis, Amgen, Emergent Research funding: Novartis, BMS, Eli Lilly/Imclone Advisory board; travel & accommodations/Research funding: Merck. R.E. Sanborn: Consulting/Advisory: Amgen Research funding: BMS, Medimmune. S. Marshall: Employment: MedImmune, Amplimmune Stock options: MedImmune. C. Black: Employment: MedImmune Stock/ownership: AZ. M. Gribbin: Employment: Medimmune Stock ownership: MedImmune. J. McDevitt: Employment: MedImmune Stock/ownership: MedImmune (AZ). J.J. Karakunnel: Employee of MedImmune and own stock or options in AstraZeneca. JJK is also an employee of MedStar Montgomery Medical Center and Fauquier Hospital. J.E. Gray: Consulting/Advisory: AZ Travel, accommodation, expenses: AZ. BackgroundThe PD-1/PD-L1 pathway is a key regulator of T-cell activation and a promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4&kgr; mAb specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Blocking both the PD-1 receptor and its ligand by combining M + D offers the potential for complete PD-1/PD-L1 axis inhibition. The PD-1/PD-L1 pathway is a key regulator of T-cell activation and a promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4&kgr; mAb specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Blocking both the PD-1 receptor and its ligand by combining M + D offers the potential for complete PD-1/PD-L1 axis inhibition. MethodsThis ongoing Phase 1 open-label, dose-escalation and expansion study is evaluating M + D in patients (pts) ≥18 years with relapsed/refractory advanced solid malignancies and ECOG performance status 0-1 (NCT02118337). The primary objectives are safety and maximum tolerated dose (MTD). Secondary objectives include antitumor activity. This ongoing Phase 1 open-label, dose-escalation and expansion study is evaluating M + D in patients (pts) ≥18 years with relapsed/refractory advanced solid malignancies and ECOG performance status 0-1 (NCT02118337). The primary objectives are safety and maximum tolerated dose (MTD). Secondary objectives include antitumor activity. ResultsTabled 1Cohort123456TotalDose every 2 weeks (Q2W) (mg/kg), M + D0.1 + 30.1 + 100.5 + 102.5 + 1010 + 1020 + 10N45339630Patients with drug-related AEs, n (%)All grades2 (50)3 (60)3 (100)2 (67)8 (89)3 (50)21 (70)Grade ≥31 (25)01 (33)03 (33)05 (17)All grades leading to discontinuation1 (25)1 (20)1 (33)1 (33)2 (22)06 (20)Responses*Objective response rate (CR + PR), n/N (%)1/4 (25)0003/8 (38)04/26 (15)Disease control (CR + PR + SD ≥8 weeks), n/N (%)2/4 (50)1/5 (20)1/3 (33)05/8 (63)09/26 (35)*Response evaluable population Open table in a new tab *Response evaluable population ConclusionsM 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population.Clinical trial identification: NCT02118337Legal entity responsible for the study: MedImmune M 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population.

Programmed cell death-1 (PD-1) inhibits T-cell activation. Blocking the PD-1/programmed cell death ligand 1/2 (PD-L1/2) axis has an acceptable safety profile, induces antitumor responses, and provides clinical benefit across tumors. MEDI0680 is a humanized IgG4&kgr; mAb specific for human PD-1 that blocks interaction with PD-L1/2. This is an ongoing Phase 1, multicenter, open-label, first-in-human, dose-escalation and expansion study of single-agent MEDI0680 in immunotherapy-naïve pts with advanced solid tumors. Primary objectives are safety/tolerability and maximum tolerated dose (MTD). Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (modified RECIST v1.1). As of 2 Nov 2015, 58 pts have enrolled across 9 cohorts (0.1–20 mg/kg given Q3W, Q2W, QWx2 then Q2W, or QWx4 then Q2W). MTD was not reached. Treatment-related AEs occurred in 46 pts; most common (>10%) were fatigue (21%), nausea (14%) and arthralgia (14%). Related Grade 3/4 AEs occurred in 10 pts; most common (>1 pt) were anemia, arthralgia and increased AST (3% each). 2 pts discontinued due to related AEs: pyrexia in 1 pt; and increased AST, myasthenia gravis and myositis in 1 pt. There were no Grade 5 related AEs. MEDI0680 had a linear PK profile with dose-proportional increases in peak serum concentration. Median PD-1 receptor occupancy on CD3+ T cells was ≥70% after 1 cycle of 10 or 20 mg/kg Q2W. Increased percentages of Ki67 + , ICOS+ and HLA-DR+ T cells; increased levels of plasma IFNγ; and enhanced intra-tumor gene expression for these factors were seen after treatment, demonstrating biological activity of MEDI0680. Of 51 evaluable pts, 9 (18%) had an objective response (8 had renal cancer or melanoma), including 1 (2%) complete response (renal cancer). 14 (28%) pts had stable disease as their best response. The recommended dose is 20 mg/kg Q2W, based on PK, PD, safety and efficacy. MEDI0680 has an acceptable safety profile, with preliminary signs of efficacy. A Phase 1 combination study with durvalumab to test the concept of complete PD-1/PD-L1 axis blockade is ongoing in advanced solid tumors.

Background Few weight loss interventions are evaluated for longer than a year, and even fewer employ social and mobile technologies commonly used among young adults. We assessed the efficacy of a 2 year, theory-based, weight loss intervention that was remotely and adaptively delivered via integrated user experiences with Facebook, mobile apps, text messaging, emails, a website, and technology-mediated communication with a health coach (the SMART intervention).Methods In this parallel-group, randomised, controlled trial, we enrolled overweight or obese college students (aged 18-35 years) from three universities in San Diego, CA, USA. Participants were randomly assigned (1:1) to receive either the intervention (SMART intervention group) or general information about health and wellness (control group). We used computer-based permuted-block randomisation with block sizes of four, stratified by sex, ethnicity, and college. Participants, study staff, and investigators were masked until the intervention was assigned. The primary outcome was objectively measured weight in kg at 24 months. Differences between groups were evaluated using linear mixed-effects regression within an intention-to-treat framework. Objectively measured weight at 6, 12, and 18 months was included as a secondary outcome. The trial is registered with ClinicalTrials. gov, number NCT01200459.Findings Between May 18, 2011, and May 17, 2012, 404 individuals were randomly assigned to the intervention (n=202) or control (n=202). Participants' mean (SD) age was 22.7 (3.8) years. 284 (70%) participants were female and 125 (31%) were Hispanic. Mean (SD) body-mass index at baseline was 29.0 (2.8) kg/m(2). At 24 months, weight was assessed in 341 (84%) participants, but all 404 were included in analyses. Weight, adjusted for sex, ethnicity, and college, was not significantly different between the groups at 24 months (-0.79 kg [ 95% CI -2.02 to 0 . 43], p=0.204). However, weight was significantly less in the intervention group compared with the control group at 6 months (-1.33 kg [95% CI -2.36 to -0.30], p=0.011) and 12 months (-1.33 kg [-2.30 to -0.35], p=0 .008), but not 18 months (-0.67 kg [95% CI -1.69 to 0.35], p=0.200). One serious adverse event in the intervention group (gallstones) could be attributable to rapid and excessive weight loss.Interpretation Social and mobile technologies did not facilitate sustained reductions in weight among young adults, although these approaches might facilitate limited short-term weight loss.