660MO - First-in-human study of SGN-B7H4V, a B7-H4-directed vedotin ADC, in patients with advanced solid tumors: Preliminary results of a phase I study (SGNB7H4V-001)

Background

B7-H4 is a B7 immune checkpoint ligand expressed at low levels in normal tissue and is upregulated in solid tumors, including breast, ovarian, and endometrial cancers. SGN-B7H4V is an investigational vedotin ADC comprising a B7-H4-directed monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable linker. We report first results from dose escalation (Part A) of this ongoing phase 1 study.

Methods

SGNB7H4V-001 is a first-in-human, multicenter study evaluating the safety, tolerability, pharmacokinetics, and antitumor activity (objective response rate per RECIST v1.1) of SGN-B7H4V in patients with advanced solid tumors. Part A enrolled patients with histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumors irrespective of B7-H4 expression. Patients received SGN-B7H4V on Days 1 and 8 of a 21-day cycle (2Q3W, 0.75, 1.0, 1.25, or 1.5 mg/kg), or on Days 1 and 15 of a 28-day cycle (2Q4W, 1.25, 1.5, 1.75, or 2.0 mg/kg).

Results

As of 10 March 2023, 75 patients were enrolled and received SGN-B7H4V. In 2Q3W (n=35), 3 patients (8.6%) had dose-limiting toxicities (DLTs) of hyperglycemia (1.25 mg/kg), arterial embolism (1.5 mg/kg), and neutropenia (1.5 mg/kg). The most common TEAEs across doses were fatigue (20.0%), peripheral sensory neuropathy (20.0%), and neutropenia (17.1%). The most common grade ≥3 TEAE was neutropenia (14.3%). In 2Q4W (n=40), 2 of 39 DLT-evaluable patients (5.1%) had DLTs of peripheral sensory neuropathy (1.5 mg/kg) and transaminitis (2.0 mg/kg). The most common TEAEs were fatigue (27.5%), peripheral sensory neuropathy (27.5%), and nausea (22.5%). The most common grade ≥3 TEAEs were anemia, dyspnea, hypotension, and pneumonia (5.0% each). Confirmed objective responses (starting at 0.75 mg/kg) were observed in evaluable patients with breast (7/25 patients), ovarian (2/15 patients), endometrial (1 [complete response]/16 patients), and biliary tract cancers (2/9 patients).

Conclusions

SGN-B7H4V showed a manageable safety profile in patients with advanced solid tumors. Responses were observed at all tested dose levels and across various tumor types. Dose expansion in select tumor types is planned.

Clinical trial identification

EudraCT 2021-002107-35, NCT05194072; Release date: 03 April 2023.

Editorial acknowledgement

Irina Mordukhovich, PhD (MMS Holdings, Canton, MI), provided medical writing.

Legal entity responsible for the study

Seagen Inc.

Funding

Study funding was provided by Seagen Inc., Bothell, WA, USA.

Disclosure

C.A. Perez: Financial Interests, Institutional, Principal Investigator: Accutar Biotech, Dracen Pharmaceuticals, Elpiscience Biopharmaceuticals, Elucida Oncology, Genentech Inc., Hyamab Inc., Jazz Pharmaceuticals, Kinnate Biopharma, Kura Oncology, Mirati Therpeutics, Relay Therapeutics, Ribbon Therapeutics, Seagen Inc., Tallac Therapeutics, Xilio Therapeutics, Zhuhai Yufan Biotechnologies Co. J.T. Henry: Financial Interests, Personal, Full or part-time Employment, Associate Director/Oncologist: Sarah Cannon Research Institute; Financial Interests, Personal, Stocks/Shares: HCA; Financial Interests, Institutional, Invited Speaker: Abbiscko Therapeutics, ABl bio, Accutar biotech ADC therapeutics, Agenus, Aileron Therapeutics, Amgen Inc., Artios, Astrazenaca, Bicycle therapeutics, BioAlta, BioInvent pharma, Biosplice therapeutics, Black diamond therapeutics, Boehringer, Ingelheim, Cyteir, Daiichi Sankyo, Eli Lilly, Epizyme, Erasca, Exelixis, FujiFilm, GSK, Hutchison MediPharma, ICON plc, IGM Biosciences, Immunogen, Jacobio pharmaceuticals, Jounce pharma, Jubilant therapeutics, Loxo Oncology, Merck& CO, Metabomed, Molecular templates, Navire Pharma, Nikang pharmaceuticals, Oncorus, Prelude therapeutics, Poseida, PureTech, Pyramid, Rascal Therapeutics, Regeneron, Relay Therapeutics, Rgenix Inc., Ribon therapeutics, Sapience, Sarah Cannon Development Innovations, Sarah Cannon Research Institute, Seagen, Simcha Therapeutics, Siranomics, Stingthera, Synthorx Inc., Teneothree, Takeda pharmaceuticals, Tallac therapeutics, Tarveda, Tesaro, Turning point pharma, Xencor. N. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Invited Speaker: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, GSK, Alkermes, Servier, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, cytomX, KSQ Therapeutics, Repare Therapeutics. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, EMD Serono, AstraZeneca, Tesaro, Macrogenics, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Cascadian Therapeutics, Artios, BeiGene; Financial Interests, Institutional, : Bliss BioPharmaceuticals. G. Colon-Otero: Financial Interests, Institutional, Full or part-time Employment, employed full time by the Mayo Clinic: Mayo Clinic; Financial Interests, Institutional, Invited Speaker, NIH grant 2022-2027: NIH; Financial Interests, Institutional, Invited Speaker, Co-Investigator for U54 grant with FAMU: National Institute of Minority Health; Financial Interests, Institutional, Invited Speaker, Research grant for clinical trial Y40482: A phase 1b study of cobimetinib in combination with niraparib 2019- August 2023: Hoffmann-LaRoche; Financial Interests, Institutional, Invited Speaker, Research funding for phase 1b/2trial of TG4001 and avelumab in patients with HV-16 positive recurrent or metastatic malignancies 11/21- 12/23: Transgene SA; Financial Interests, Institutional, Invited Speaker, A Phase 1 Study of SGN-B7H4V in Advanced Solid Tumors.Funded by Seagen. (SGNB7H4V-001) August 2022- July 2026: Seagen; Financial Interests, Institutional, Invited Speaker, A Randomized, Phase 2 Study of Pembrolizumab AndChemotherapy With or Without MK-4830 as NeoadjuvantTreatment for High-Grade Serous Ovarian Cancer. Funded byMerck & Co., Inc. November 2022- November 2024: Merck; Financial Interests, Institutional, Invited Speaker, (ECTx) RP-6306-02 (MCF): Phase 1 Study of the PKMYT1Inhibitor RP-6306 in Combination with Gemcitabine for theTreatment of Advanced Solid Tumors (MAGNETIC Study).Funded by Repare Therapeutics. (RP-6306-02) June 2022- May 2024: REPARE; Non-Financial Interests, Advisory Role, May 2023- no personal renumeration: REPARE; Non-Financial Interests, Member of Board of Directors: Florida Society of Clinical Oncology; Non-Financial Interests, Officer: AACR MICR Council; Non-Financial Interests, Member, Member of MICR Council: AACR. J.R. Diamond: Financial Interests, Institutional, Other, Consultant, Chief Medical Officer: OnKure Therapeutics; Financial Interests, Institutional, Advisory Board: Gilead; Financial Interests, Institutional, Other, stock options: OnKure Therapeutics; Financial Interests, Institutional, Invited Speaker, PI of clinical trial at my institution with payments to my institution: HutchMed, Gilead, Merck, Cosmo, Adlai Nortye, Takeda, Seattle Genetics, BMS. B. O’Neil: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. A. Kalyan: Financial Interests, Personal, Advisory Board, Consulting and advisory board: AstraZeneca; Financial Interests, Personal, Advisory Board, Consulting and Advisory Board: Genentech; Financial Interests, Personal, Invited Speaker, Speaking for Nurses and Doctors: Genentech; Financial Interests, Personal, Advisory Board: Exelixis, Boston Scientific; Financial Interests, Personal, Other, Consulting: Boston Scientific; Financial Interests, Institutional, Invited Speaker: Boston Scientific, Exelixis; Non-Financial Interests, Principal Investigator, Investigator: Exelixis; Non-Financial Interests, Principal Investigator: Boston Scientific. G.P. Sonpavde: Financial Interests, Personal, Advisory Board: Bicycle Therapeutics, Bristol Myers Squibb, EMD Serono/Pfizer, Exelixis, G1 Therapeutics, Genentech, Janssen, Loxo Oncology, Lucence, Merck, Sanofi, Scholar Rock, Seagen, Syapse, Tempus, Immunomedics/Gilead; Financial Interests, Personal, Advisory Board, Editor of Bladder cancer virtual center of excellence for Practice Update: Elsevier; Financial Interests, Personal, Advisory Board, to develop a trial in bladder cancer: Servier Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Exelixis, Gilead, Research to practice, Seagen, Janssen; Financial Interests, Personal, Other, Member of data safety monitoring board: Mereo; Financial Interests, Personal, Other, Author of chapter: Uptodate; Financial Interests, Institutional, Research Grant, Financial interest: EMD Serono; Financial Interests, Institutional, Research Grant, No financial interest: Gilead, Jazz Pharma, Predicine, QED, Sanofi; Non-Financial Interests, Personal, Principal Investigator, Steering committee of trial: Bristol Myers Squibb; Non-Financial Interests, Personal, Principal Investigator: G1 Therapeutics; Non-Financial Interests, Personal, Other, Steering committee of trial: Merck; Non-Financial Interests, Personal, Leadership Role, Steering committee of trial: QED; Other, Personal, Other, Spouse employment: Myriad Genetics. A.A. Awan: Financial Interests, Personal, Other, Honorarium: Apotex, Roche Canada, AstraZeneca Canada, Oncology Education, Eli Lilly, Exactis Innovation, Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: Exact Sciences, Pfizer, Novartis Canada Pharmaceuticals Inc., Exact Sciences, Eli Lilly, Foundation Medicine, AstraZeneca Canada, Roche Canada, AstraZeneca, Gilead Sciences; Financial Interests, Institutional, Research Funding: Roche, Sermonix Pharmaceuticals, Seagen, Exactis Innovation, Intensity Therapeutics, Astellas Pharma, Canexia Health; Financial Interests, Institutional, Other, Travel/Accomodations/Expenses: Roche/Genentech. E. Fontana: Financial Interests, Personal, Invited Speaker: CARIS Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, HUTCHMED, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma; Non-Financial Interests, Advisory Role: Vivan Therapeutics. P. Xu, F. Zhang, N. Nazarenko: Financial Interests, Institutional, Full or part-time Employment: Seagen Inc.; Financial Interests, Institutional, Stocks/Shares: Seagen Inc. A. Patnaik: Financial Interests, Institutional, Other, Institutional research funding: Compugen. All other authors have declared no conflicts of interest.