657MO - Recommended phase II dose (RP2D) selection and pharmacodynamic (PD) data of the first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients (pts) with advanced HER2-expressing solid tumors

Background

BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. We present new results from the recently completed dose-escalation study (NCT04278144).

Methods

Pts with HER2+ (protein or gene) or HER2-low solid tumors progressing after standard therapies (Txs) were enrolled. BDC-1001 was given IV q3w, q2w, or q1w as monotherapy (mono; n=94) and q2w or q1w with nivolumab 240mg q2w (combo; n=37).

Results

As of 24 March 2023, 131 pts with 16 different tumor types received 0.15 to 20mg/kg of BDC-1001. Mean age 60 yrs, median 4 prior lines of Txs (range 0-13; prior anti-HER2 67%, immune 29%). The RP2D of 20mg/kg q2w (mono/combo) was determined based on safety, efficacy, pharmacokinetic, and PD data. BDC-1001 was well tolerated as mono/combo. Grade 1/2 infusion-related reactions were the most common adverse events (30%). Clinical activity observed in multiple tumor types and doses improved as targeted Cmin ≥10mg/mL was reached, particularly at the RP2D. 6 pts (3 mono) had partial response (PR), 11 pts (9 mono) achieved stable disease (SD) ≥24 wks. Clinical benefit rate in 15 pts with HER2+ tumors at the RP2D was 47% (27% confirmed PR, additional 20% SD ≥24wks), 60% tumor shrinkage and 33% pts still on active Tx. Comprehensive plasma and fresh biopsies (bx) studies performed. PD responses in plasma and paired tumor bx (protein/gene analyses) demonstrated immune activation with BDC-1001 (e.g., IFNg, antigen processing, macrophage activation), not observed by trastuzumab treatment, and subsequent T cell recruitment in tumor tissue.

Conclusions

Our novel ISAC BDC-1001 (mono/combo) led to tolerable, encouraging efficacy, translational biomarker data consistent with novel MOA in pts with pretreated HER2+ tumors, particularly at the 20mg/kg q2w RP2D. International phase 2 expansions in HER2+ colorectal, gastroesophageal, and endometrial cancers and a new phase 2 in breast cancer (BDC-1001 ± pertuzumab) have been initiated.

Clinical trial identification

NCT04278144.

Editorial acknowledgement

The Phillips Group Oncology Communications, Inc.

Legal entity responsible for the study

Bolt Biotherapeutics, Inc.

Funding

Bolt Biotherapeutics, Inc.

Disclosure

B.T. Li: Financial Interests, Personal, Other, Travel, Accommodations: MORE Health, Jiangsu Hengrui Medicine; Financial Interests, Institutional, Other, Patent: US62/514,661, US62/685,057; Financial Interests, Personal, Royalties: Karger Publishers-Book Royalty, Shanghai Jiao Tong University Press-Book royalty; Financial Interests, Institutional, Research Funding: Roche/Genentech, AstraZeneca, Daiichi Sankyo, Hengrui Therapeutics, Amgen, Lilly, MORE Health, Bolt Biotherapeutics, Ambrx. K. Lee: Financial Interests, Personal, Advisory Board: BMS (Korea), Bayer (Korea), Daiichi Sankyo (Korea), Merck Sharp & Dohme (Korea), Metafines, Vifor pharma (Korea), Astellas (Korea); Financial Interests, Personal, Invited Speaker: Boryung Co.; Financial Interests, Institutional, Local PI: ABLBIO, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bolt therapeutics, Daiichi Sankyo, Exelixis, Genexine, Green Cross Corp, InventisBio, LSK BioPharma, Leap therapeutics, Macrogenics, MedPacto, Merck KGaA, Merck Sharp & Dohme, Oncologie, Ono pharmaceutical, Pfizer, Pharmacyclics, Seagen, Taiho Pharmaceutical, Trishula therapeutics, Y-BIOLOGICS, Zymeworks,; Non-Financial Interests, Leadership Role, SMC chair of ASPEN-06 study: ALX Oncology. M. Pegram: Financial Interests, Personal, Full or part-time Employment: Lilly; Financial Interests, Personal, Advisory Role: Genentech/Roche, Pfizer, Seagen, Lilly; Financial Interests, Personal, Speaker, Consultant, Advisor: Genentech/Roche, Pfizer, Seagen. M.R. Sharma: Financial Interests, Personal, Advisory Role: Pliant; Financial Interests, Personal, Stocks or ownership: Abbott Laboratories, AbbVie, Biogen, Bristol Myers Squibb, Lilly, Merck, Pfizer, Regeneron, Amgen, Gilead Sciences, Johnson & Johnson/Janssen, Moderna Therapeutics, Vertex, West Pharmaceutical; Financial Interests, Institutional, Research Funding: Ascentage Pharma, AstraZeneca, Bolt Biotherapeutics, Bristol Myers Squibb, Compugen, Constellation Pharmaceuticals, CytomX Therapeutics, Exelixis, Ikena Oncology, InhibRx, Jounce Therapeutics, KLUS Pharma, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Symphogen, Syros Pharmaceuticals, Astellas Pharma, Celgene, Treadwell Therapeutics, eFFECTOR Therapeutics, Genmab, Arrys Therapeutics, PureTech, GSK/Tesaro, Seagen, Shattuck Labs, Sapience Therapeutics, Epizyme, Odonate Therapeutics, Tempest Therapeutics, Mersana, NGM Biopharmaceuticals, Samumed, Onconova Therapeutics, Gilead Sciences, AbbVie, Agenus, Alkermes, Alpine Immune Sciences, Alexo Therapeutics, Johnson & Johnson/Janssen, Seven and Eight Biopharmaceuticals, Cullinan Oncology, Debiopharm Group, Palleon Pharmaceuticals, Helsinn Therapeutics, Kinnate Biopharma, KSQ Therapeutics, Repare Therapeutics, SK Life Sciences, Theratechnologies, Tizona Therapeutics, Inc. J. Lee: Financial Interests, Steering Committee Member: Seattle Genetics, AZ; Non-Financial Interests, Principal Investigator: AstraZeneca, Daiichi Sankyo, Merck MSD, BMS, Leaptherapeutics; Non-Financial Interests, Project Lead: Samsung Bioepis, Genome and Company, Oncxerna; Non-Financial Interests, Advisory Role: Mirati Therapeutics; Non-Financial Interests, Member: KSMO; Non-Financial Interests, Other, AP Council: ASCO. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche, Liscure. K.N. Moore: Financial Interests, Personal, Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, VBL Therapeutics, Merck, Eisai, Myriad Genetics, OncXerna Therapeutics, Onconova Therapeutics, Mereo BioPharma, Novartis, Verastem/Pharmacyclics, AADi, Clovis Oncology, Caris Life Sciences, Hengrui Pharmaceutical, Novartis/Pfizer, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Role: Mersana, Alkermes, Blueprint Medicines, GSK/Tesaro, I-Mab, InxMed; Financial Interests, Personal, Leadership Role: GOG Partners; Financial Interests, Institutional, Leadership Role: NRG Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: GSK, AstraZeneca; Financial Interests, Institutional, Other Relationship: GOG Partners; Financial Interests, Personal, Other, Honoraria: Research To Practice, Prime Oncology, Physicans' Education Resource, Great Debates and Updates; Financial Interests, Institutional, Research Funding: PTC Therapeutics, Lilly, Merck, Tesaro, Genentech, Clovis Oncology, Lilly Foundation, Regeneron, Bristol Myers Squibb, Verastem, Novartis Pharmaceuticals UK Ltd., AstraZeneca, Agenus, Takeda, Immunogen, Novogen, artios, Bolt Biotherapeutics, Amgen, Daiichi Sankyo/Lilly, Cyteir, Immunocore. D. Rasco: Financial Interests, Institutional, Research Funding: Celgene, Eisai, Merck, Ascentage Pharma, AbbVie, Constellation Pharmaceuticals, Astex Pharmaceuticals, Compugen, Coordination Therapeutics, GSK, Gossamer Bio, Seven and Eight Biopharmaceuticals, Bolt Biotherapeutics, Boehringer Ingelheim, PureTech, Takeda, Arcus Biosciences, Surface Oncology, 23andMe, Cullinan Oncology, TD2; Financial Interests, Personal, Research Funding: Kronos, Molecular Templates. G.J. Hanna: Financial Interests, Personal, Full or part-time Employment: Dana-Farber Cancer Institute; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck, Kura Oncology, Sanofi, Prelude Therapeutics, Bicara Therapeutics, Naveris, Exicure, Remix Therapeutics, General Catalyst, Boxer Capital, Rain Therapeutics, KSQ Therapeutics, SIRPant Immunotherapeutics; Financial Interests, Personal, Expert Testimony: Aaronson Rappaport Feinstein & Deutsch, Ahmuty, Demers, & McManus, Wilson Elser Moskowitz Edelman & Dicker, LLP; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Kura Oncology; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Regeneron, Kartos Therapeutics, Exicure, GSK, Elevar Therapeutics, Genzyme, Kite/Gilead, NantKwest, Actuate Therapeutics, Bicara Therapeutics, Kite/Gilead, Secura Bio; Financial Interests, Personal, Research Funding: Conquer Cancer, the ASCO Foundation, V Foundation, Gateway for Cancer Research. B.A. Weinberg: Financial Interests, Personal, Invited Speaker: Sirtex, AstraZeneca, Daiichi Sankyo, Bayer, Taiho, Seagen, Merus; Financial Interests, Personal, Advisory Board: Bayer, Taiho; Financial Interests, Institutional, Research Grant: Ipsen. T. Yu: Financial Interests, Personal, Full or part-time Employment: Bolt Biotherapeutics; Financial Interests, Personal, Leadership Role: Bolt Biotherapeutics ; Financial Interests, Personal, Stocks or ownership: Bolt Biotherapeutics ; Financial Interests, Personal, Other, Honoraria: Bolt Biotherapeutics. M. Alonso: Financial Interests, Personal, Full or part-time Employment: Bolt Biotherapeutics; Financial Interests, Personal, Stocks or ownership: Bolt Biotherapeutics; Financial Interests, Personal, Royalties: Bolt Biotherapeutics. J. Ptacek, M. Yin: Financial Interests, Personal, Full or part-time Employment: Bolt Biotherapeutics; Financial Interests, Personal, Stocks or ownership: Bolt Biotherapeutics. L. Xu: Financial Interests, Personal, Full or part-time Employment: Bolt Biotherapeutics; Financial Interests, Personal, Leadership Role: Bolt Biotherapeutics; Financial Interests, Personal, Stocks or ownership: Bolt Biotherapeutics; Financial Interests, Personal, Other, Honoraria: Bolt Biotherapeutics. E.A. Perez: Financial Interests, Personal, Full or part-time Employment: Genentech, Bolt Biotherapeutics; Financial Interests, Personal, Advisory Role: Seagen, Puma Biotechnology, Daiichi Sankyo; Financial Interests, Personal, Leadership Role: Bolt Biotherapeutics; Financial Interests, Personal, Stocks or ownership: Genentech/Roche. E.E. Dumbrava: Financial Interests, Institutional, Other, Research/grant funding: Bayer HealthCare Pharmaceuticals, Immunocore Ltd., Amgen, Aileron Therapeutics, Compugen Ltd., Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum, PMV Pharma, Triumvira, Seagen Inc., Mereo BioPharma 5 Inc., Sanofi, Rain Oncology, Astex Therapeutics, SOTIO, Mersana Therapeutics, Poseida, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: PMV Pharma; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics. All other authors have declared no conflicts of interest.