Background

SHR-A1811 is a novel ADC composed of trastuzumab (anti-HER2), a cleavable linker, and a topoisomerase I inhibitor payload, with optimized drug-antibody ratio of 6 and strong bystander killing effect. We initiated this global, dose escalation, PK expansion, and indication expansion phase 1 study in HER2-expressing/mutated advanced STs. The primary analysis showed that SHR-A1811 was well-tolerated and had promising antitumor activity, especially in HER2-positive or low-expressing breast cancer ( AACR 2023 , CT175). Here we report the findings focusing on non-breast STs.

Methods

Patients (pts) with advanced, unresectable, or metastatic HER2-expressing/mutated STs that were refractory or intolerant to standard therapies were treated with SHR-A1811 at 1.0–8.0 mg/kg Q3W (IV).

Results

As of Feb 28, 2023, 98 pts with non-breast STs were enrolled. Pts had a median 2 prior lines of therapy (range 1–9), and 66.3% had ≥2. ORR was 45.9% (39/85 evaluable pts; 95% CI 35.0–57.0); DCR was 88.2% (75/85; 95% CI 79.4–94.2); and median TTR was 1.4 mo (range 0.7–5.8). ORR was 54.1% (20/37) in pts with HER2 IHC3+, 41.7% (10/24) with IHC2+, and 50.0% (7/14) with IHC1+. For individual tumor type, ORR was 56.3% (9/16) in BTC pts, 59.1% (13/22) in UC, 50.0% (6/12) in GC/GEJA, and 36.4% (4/11) in CRC (data by HER2 status for each tumor type are shown in table). Overall, 38 (38.8%) of 98 pts had disease progression or died; the 6-mo PFS rate was 52.1%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 50 (51.0%) of pts; the most common (≥10%) were decreased neutrophil count and anemia. Serious TRAEs were reported in 15 (15.3%) pts. Of note, only 1 (1.0%) pt had interstitial lung disease. Table: 656MO

ORR by tumor type and HER2 status

Conclusions

SHR-A1811 had favorable antitumor activity and acceptable safety profile in heavily pretreated HER2-expressing/mutated advanced non-breast STs, including BTC, UC, GC/GEJA, and CRC.

Clinical trial identification

NCT04446260, Release date: 24 June 2020.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals.

Funding

Jiangsu Hengrui Pharmaceuticals.

Disclosure

K. Liu, S. Gu: Financial Interests, Institutional, Funding: Jiangsu Hengrui Pharmaceuticals. S. Rong: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. All other authors have declared no conflicts of interest.

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.

Background

T-DXd has shown significant survival benefit for pts with HER2-expressing breast and gastric cancers. Interim DP-02 data showed a promising objective response rate (ORR) and duration of response (DOR) in HER2-expressing tumors (ASCO 2023). Here we report the primary analysis including progression-free (PFS) and overall survival (OS).

Methods

This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing), locally advanced/metastatic disease after ≥1 systemic treatment (Tx), or without alternative Tx options. Primary endpoint was investigator-assessed confirmed ORR. Secondary endpoints included safety, DOR, PFS and OS.

Results

At data cut off (Jun 2023), 267 pts with biliary tract (BTC), bladder (URO), cervical (CC), endometrial (EC), ovarian (OC), pancreatic (PC), or other tumors had received Tx (median [m] follow up: 12.75 [range 0.4–31.6] months [mo]); 72.3% received ≥2 prior lines of therapy. In all pts, investigator-assessed ORR (95% CI) was 37.1% (31.3, 43.2); mDOR (95% CI) was 11.3 mo (9.6, 17.8); mPFS (95% CI) was 6.9 mo (5.6, 8.0); and mOS (95% CI) was 13.4 mo (11.9, 15.5). In pts with IHC 3+ expression (central; n=75) ORR was 61.3% (49.4, 72.4); mDOR was 22.1 mo (9.6, not reached); mPFS was 11.9 mo (8.2, 13.0); and mOS was 21.1 mo (15.3, 29.6). Table shows ORR, PFS and OS by tumor type in all pts and IHC 3+. Grade (G) ≥3 Tx-related adverse events (AEs) occurred in 40.8% of pts; 8.6% discontinued Tx due to Tx-related AEs. Adjudicated Tx-related interstitial lung disease/pneumonitis occurred in 10.5% (n=28) of pts (9.0% [n=24] G≤2; 1.1% [n=3] G5). Table: LBA34

Conclusions

We observed durable responses to T-DXd and clinically meaningful PFS and OS in pretreated pts across HER2-expressing tumors, with safety consistent with the known profile. These data support T-DXd as a potential tumor-agnostic treatment in HER2-expressing tumors. (Funded by BioNTech; ClinicalTrials.gov number; NCT04503278).

Clinical trial identification

NCT04482309.

Editorial acknowledgement

Medical writing and editorial support was provided by Neil Patel, MSc, of Helios Medical Communications, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca and Daiichi Sankyo.

Funding

AstraZeneca and Daiichi Sankyo.

Disclosure

F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffman-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, Loxo-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation. V. Makker: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Clasi, Duality, Eisai, Faeth, Karyopharm, Merck, Takeda, Zymeworks, Cullinan; Other, Support for attending meetings and/or travel: Merck, Eisai; Other, Unpaid Consultant: Clovis, Duality, Eisai, Faeth, GSK, Iteos, Karyopharm, Lilly Moreo, Morphosys, Novartis, Zymeworks, Merck, MSD, Immunocore, Regeneron, iTEOS, Sutro, Cullinan. A. Oaknin: Financial Interests, Institutional, Research Grant: AbbVie, Advaxis Inc, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol Myers Squibb, Clovis Oncology Inc, Eisai, Immunogen Inc, Merck Sharps & Dohme de Espana, Millenium Pharmaceuticals Inc, PharmaMar, Regeneron Pharmaceuticals, Roche, Tesaro Inc; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting fees: Agenus, AstraZeneca, Clovis Oncology, Corcept Theraupeutics, Deciphera Pharmaceuticals, Eisai Exelisis, EMD Serono, F.Hoffman-La Roche, Genmab, GSK, ImmunoGen, Itheos, Merck Sharps & Dohme de Espana, SA, Mersana Therapeutics, Novocure, OneXerna Therapeutics Inc, PharmaMar, Regeneron, Sattucklabs, Seagen, Sutro Biopharma; Financial Interests, Personal, Speaker, Consultant, Advisor: NSGO, Peerview, Peervoice, Medscape, Asociación Colombiada de Ginecológos Oncólogos, ESO, AstraZeneca, GSK; Other, Personal, Other, Support for attending meetings and/or travel: AstraZeneca, PharmaMar, Roche; Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelisis, EMD Serono, F.Hoffman-La Roche, Genmab, GSK, ImmunoGen, Itheos, Merck Sharps & Dohme de Espana, SA, Mersana Therapeutics, Novocure, OneXerna Therapeutics Inc, PharmaMar, Regeneron, Sattucklabs, Seagen, Sutro Biopharma; Financial Interests, Personal, Leadership Role, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Gynecologic Cancer Intergroup, European Society for Medical Oncology; Other, Personal, Other: Gynecologic Cancer Intergroup, European Society for Medical Oncolog, American Society of Clinical Oncology, Spanish Society of Medical Oncology, Spanish Society of Medical Oncology, GOGFoundation. D. Oh: Financial Interests, Personal, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok; Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck, Serono, Bayer, Taiho, Aslan, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD. S. Banerjee: Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Epsilogen, GSK, Immunogen, Merck Sharpe Dohme, Mersana, Novartis, Oncxerna, Seagen, Shattuck Labs, Regeneron, Verastem; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Clovis, GSK, Immunogen, Merck, Sharpe Dohme Mersana, Pfizer, Roche, Takeda, Novacure, Research to Practice, Medscape; Financial Interests, Personal, Leadership Role, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: International Cancer Foundation; Financial Interests, Personal, Stocks/Shares: PerciHealth; Other, Support for attending meetings and/or travel: Verastem, GSK. A. Gonzalez Martin: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, GSK, Clovis, Roche, Novocure, MSD, Takeda, Zaylab; Other, Personal, Other, Support for attending meetings and/or travel: AstraZeneca, GSK, MSD; Financial Interests, Personal, Advisory Board: Alkermes, AstraZeneca, Amgen, Clovis, Eisa, GSK, Immunogen, GenMab, Kartos, Sutro, Roche, Sotio, Macrogenics, Mersana, MSD, Pharmamar, Novartis, Oncoinvent, Regeneron, HederaDx, Illumina, Tubulis, Daiichi Sankyo; Other, Institutional, Other: GlazoSmithKline, Roche. K.H. Jung: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting fees: AstraZeneca, Bixink, Celgene, Daiichi Sankyo, Eisai, Everest Medicine, Gilead Science, MSD, Novartis, Pfizer, Roche, Takeda Pharmaceuticals. I. Lugowska: Financial Interests, Institutional, Research Grant: Agenus, Roche; Other, Personal, Other: Roche, European Society of Medical Oncology, Morgan Stanley Capital International, Clininote; Other, Personal and Institutional, Other: Agenus, Bristol Myers Squibb, MSD, Roche, Janssen, AstraZeneca, Amgen, RyVu, Incyte, Siropa, Mennarini, Celon, Pfizer, Rhizen, Organisation of European Cancer Institutes (OECI). A. Manzano Fernández: Financial Interests, Research Grant: AstraZeneca; Financial Interests, Speaker, Consultant, Advisor: AstraZeneca, GSK, Leo Pharma, Sanofi, Pharmamar, MSD; Other, Support for attending meetings and/or travel: GSK, MSD, AstraZeneca; Financial Interests, Advisory Board: Boehringer, GSK, PharmaMar. B. Melichar: Financial Interests, Speaker, Consultant, Advisor, Consulting fees: Roche, Pfizer, BMS, Novartis, MSD, Merck Serono, Servier, AstraZeneca, Amgen, Eli Lilly; Financial Interests, Speaker, Consultant, Advisor, Honoraria for speeches: Roche, Pfizer, BMS, Novartis, MSD, Merck Serono, Servier, AstraZeneca, Amgen, E. Lilly; Other, Support for attending meetings and/or travel: AstraZeneca, Merck; Financial Interests, Other, Support for attending meetings and/or travel: Serono, BMS, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche. S. Siena: Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Bristol Myers Squibb, ChecKMab, Daiichi Sankyo, GSK, MSD, Novartis, Seagen, T-One-Therapeutics. A. Fielding: Financial Interests, Personal, Stocks/Shares: AstraZeneca; Other, Personal, Other: AstraZeneca; Financial Interests, Other, Employee: AstraZeneca. Y. Ma: Financial Interests, Other, Employee: AstraZeneca; Financial Interests, Stocks/Shares, Ex Beigene employee and hold Beigene stock: Beigene. S.D. Puvvada: Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Other, Employee: AstraZeneca. J. Lee: Financial Interests, Personal, Advisory Board: Eisai, GI Innovation; Other, Personal, Other: AstraZeneca, Takeda, MSD, Roche, Eisai, AstraZeneca, ImmunoGen, MSD, OncoQuest, MSD, ONO, Takeda; Other, Institutional, Other: Alkermes, AstraZeneca, BeiGene, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon. All other authors have declared no conflicts of interest.

Background

HER3 is widely expressed in solid tumors and associated with tumor growth/spread, drug resistance and poor prognosis. SHR-A2009 is a novel ADC composed of a fully human anti-HER3 IgG1 mAb, cleavable peptide linker and DNA topoisomerase I inhibitor. We report preliminary results from the first-in-human, multinational phase 1 trial of SHR-A2009 in patients (pts) with advanced solid tumors refractory to standard therapy.

Methods

SHR-A2009 was given at doses of 1.5-10.5 mg/kg (Q3W, iv) in an i3+3 dose escalation scheme, followed by cohort expansion at selected doses. The primary endpoints were MTD/MAD, RP2D and safety.

Results

At data cutoff (Apr 24, 2023), 42 pts were enrolled (ECOG 1, 83.3%; stage IV, 100%; NSCLC, 85.7%; brain metastasis, 31.0%); median prior lines of systemic therapy was 3 (range, 1-11). Among 36 NSCLC pts, 34 (94.4%) had EGFR mutations; all were resistant to EGFR-TKI, with 85.3% (29/34) previously treated with 3^rd generation agents. Up to 10.5 mg/kg, no DLT was observed; dose-escalation is ongoing. Grade≥3 TRAEs were reported in 13 (31.0%) pts, with all occurring in ≥5% being hematotoxicities. TRAEs led to drug discontinuation in 3 (7.1%) pts. Interstitial lung disease occurred in 2 (4.8%) pts. In evaluable pts, ORR was 25.0% (9/36; 95% CI 12.1-42.2) across all tumor types and 30.0% (9/30; 95% CI 14.7-49.4) in NSCLC; median DoR was 7.0 mo (range, 2.8-8.5) in both pt sets. Tumor response by dose is shown in the table. 1. 6-mo PFS rate was 46.4% (95% CI 27.0-63.8) across all tumors and 49.8% (95% CI 28.8-67.8) in NSCLC. Systemic exposure of SHR-A2009, total antibody and free toxin increased approximately dose proportionally after single/multiple doses at 1.5-9.0 mg/kg; plasma toxin exposure was low across all levels (data not available for 10.5 mg/kg). Table: 658MO

Tumor response by dose

Conclusions

SHR-A2009 showed a tolerable safety profile and encouraging anti-tumor activity in pts with heavily pretreated advanced solid tumors. The trial is ongoing to assess SHR-A2009 at higher doses and in selected cancer types (NSCLC and other solid tumors).

Clinical trial identification

NCT05114759.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

Y. Wu: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, Hengrui; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Roche, Boehringer Ingelheim, Takeda; Financial Interests, Personal, Research Funding: Boehringer Ingelheim, Roche, Pfizer, Bristol Myers Squibb. Y. Kuboki: Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Taiho, ONO, Bayer, Sanofi; Non-Financial Interests, Personal, Principal Investigator: Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas; Financial Interests, Personal, Advisory Role: Takeda, Boehringer Ingelheim, Taiho. N. Yamamoto: Financial Interests, Institutional, Research Grant: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, Rakuten Medical; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios; Financial Interests, Personal, Speaker, Consultant, Advisor: ONO, Chugai, Daiichi Sankyo, Eisai. Z. Zhu, J. Shuang, F. Qiu, W. Shi: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.

Background

Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors and could be a potent therapeutic target. 9MW2821 is a monoclonal antibody-drug conjugate (ADC) that delivers monomethyl auristatin E to cells expressing Nectin-4. Here we report the first-in-human, multicenter, phase I/II study designed to explore the safety, pharmacokinetics and efficacy of 9MW2821 in advanced solid tumors.

Methods

9MW2821 was administered by intravenous infusion on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included urothelial cancer (UC) and other Nectin-4 positive solid tumors. Primary objectives were assessment of safety and preliminary efficacy.

Results

As of April 27, 2023, 97 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Median age was 57 years (range, 32-78). Only 1 dose limiting toxicity of grade 4 neutropenia lasted more than 5 days was observed at 1.5mg/kg group. Maximum tolerated dose was not yet reached. Treatment related adverse events (TRAEs) of any grade occurred in 64.9% pts. The most common TRAEs were white blood cell (WBC) count decreased (36.1%), neutropenia (35.1%), nausea (22.7%), aspartate aminotransferase increased (22.7%), rash (19.6%), alopecia (19.6%), fatigue (18.6%), decreased appetite (18.6%), anemia (17.5%), vomiting (16.5%), peripheral sensory neuropathy (16.5%). Grade 3/4 TRAEs occurred in 35.1% pts. The most common grade 3/4 TRAEs were WBC count decreased (18.6%) and neutropenia (18.6%). Treatment related death was not observed. Among 39 pts treated with 9MW2821 at 1.25mg/kg or above and evaluable for tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 38.5% and 84.6%, respectively. In 18 pts with UC who progressed after platinum-based chemotherapy and immune checkpoint inhibitors and dosed at 1.25mg/kg, ORR and DCR was 55.6% and 94.4%, respectively. Objective responses were also observed in pts with breast cancer and cervical cancer.

Conclusions

The results showed that 9MW2821 had manageable safety profile and promising antitumor activity. Enrollment continues to determine efficacy of 9MW2821 in certain solid tumors.

Clinical trial identification

NCT05216965.

Legal entity responsible for the study

Mabwell (Shanghai) Bioscience Co., Ltd.

Funding

Mabwell (Shanghai) Bioscience Co., Ltd.

Disclosure

P. Wang: Financial Interests, Institutional, Full or part-time Employment: Mabwell (Shanghai) Bioscience Co., Ltd. All other authors have declared no conflicts of interest.

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.

Background

Chimeric antigen receptor (CAR) T cells targeting CLDN6 ± CARVac showed promising activity against relapsed/refractory (r/r) CLDN6+ tumors (ESMO 2022 LBA38). We present data from a repeat 3+3 dose escalation trial with CAR T cells manufactured by an automated process and increased CARVac dosage.

Methods

BNT211-01 is recruiting patients (pts) with CLDN6-positive r/r solid tumours and no further treatment options. Following lymphodepletion, CAR T cells are flat dosed at 4 dose levels (DLs, 1×10⁶ up to 2-5×10⁸ CAR-T cells) ± repeat CLDN6 CARVac dosing (1×50 μg, then 100 μg doses). Primary endpoints are safety and tolerability. Additional endpoints are efficacy and pharmacokinetics.

Results

As of 24.07.2023, 38 pts primarily with ovarian cancer (n=14) and germ cell tumors (n=11) have been treated. Treatment related TEAEs ≥G3 were observed in 23 (61%) pts, including 20 (53%) pts with TEAEs related to CAR T cells. From 21 pts treated with the combination, 9 (43%) pts had TEAEs ≥G3 related to both IMPs, and 2 (10%) to CARVac. Related TESAEs have been observed in 8 pts (21%). DLTs occurred in 2 pts from different cohorts, G4 CRS at 5×10⁸ CAR-T cells and G4 pancytopenia at 1×10⁸, hence an MTD could not be determined. One death was assessed as treatment-related after the data cut-off. CRS was predominantly (95%) G1-2 and observed in 18 (47%) pts. 2 cases each of G1 ICANS and G1 hemophagocytic lymphohistiocytosis were reported (both 5%). Of 28 efficacy-evaluable patients, 9 pts (32%) had partial responses (PRs) and a further 9 had stable disease ([SD], unconfirmed overall response rate [ORR]: 32%, disease control rate [DCR]: 64%). Of 19 pts treated with ≥ 1x10⁸ CAR T cells, 8 PRs and 8 SDs resulted in an ORR of 42% and a DCR of 84%. CAR-T expansion was dose dependent, with improved persistence by addition of CARVac.

Conclusions

CLDN6 CAR T cells ± CARVac demonstrated encouraging antitumor activity. Addition of CARVac improved CAR-T cell persistence. The safety profile in terms of CRS, ICANS and DLTs observed is in line with previously reported observations. We intend to present data on up to 42 pts, with a data cut-off of 10.09.2023.

Clinical trial identification

NCT04503278.

Editorial acknowledgement

Medical writing support was provided by Andrew Finlayson of BioNTech SE.

Legal entity responsible for the study

BioNTech SE.

Funding

BioNTech SE.

Disclosure

A. Mackensen: Financial Interests, Personal, Speaker, Consultant, Advisor: Miltenyi Biomedicine, KITE/Gilead, Novartis, BMS/Celegene; Financial Interests, Personal, Advisory Board: BioNTech; Financial Interests, Advisory Board: Ixaka. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Editorial Board ESMO Open: ESMO; Other, Editor-in-Chief IOTECH: ESMO; Other, Editorial Board: Kidney Cancer. W. Alsdorf: Financial Interests, Institutional, Local PI: BioNTech. C. Koenecke: Financial Interests, Personal, Speaker, Consultant, Advisor: GSK, Novartis, Roche, Pierre Fabre, AbbVie, Sanofi-Aventis, Takeda, Kite, BMS, Medigene, Janssen, Amgen; Financial Interests, Institutional, Research Funding: BioNTech. E. Wagner-Drouet: Financial Interests, Personal, Speaker, Consultant, Advisor: Kite Gilead, BMS, Novartis; Financial Interests, Personal and Institutional, Coordinating PI: BioNTech. P. Borchmann: Financial Interests, Personal, Advisory Board: Takeda Oncology, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Miltenyi Biotech, Incyte; Financial Interests, Institutional, Coordinating PI: Takeda Oncology, Roche, Novartis, Merck Sharp & Dohme, Amgen, Miltenyi Biotech. D. Heudobler: Financial Interests, Personal, Research Funding: BMS, Janssen-Cilag; Financial Interests, Institutional, Research Funding: BioNTech. S. Klobuch: Financial Interests, Institutional, Advisory Board: Regeneron; Financial Interests, Institutional, Local PI: Neogene. N. Kutsch: Financial Interests, Institutional, Research Funding: Gilead, AstraZeneca, BioNTech; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: BMS; Financial Interests, Personal, Advisory Board: AstraZeneca. F. Müller: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS; Financial Interests, Institutional, Research Grant: Medimmune. C. Bokemeyer: Financial Interests, Personal, Advisory Board, advisory boards and speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: Roche Pharma, AOK Germany; Financial Interests, Personal, Advisory Board: Bayer Healthcare, AstraZeneca, Oncology Drug Consult CRO, Jansen Cilag, BioNTech; Financial Interests, Personal, Advisory Board, Boards attended and lectures given: Sanofi Aventis; Financial Interests, Personal, Advisory Board, and lectures given: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, orgaistion for medical education: med update; Financial Interests, Institutional, Local PI, our department is involved in several clincal trials sponsored by industry and cooperative groups where we hold praticipants roles and local PI roles and PI roles: more than 95 clinical trials; Non-Financial Interests, Member of Board of Directors: DGHO, Northern German Society of Internal Medicine; Non-Financial Interests, Leadership Role: Hamburg Cancer Society, National Network of German Cancer Centers (DKH); Non-Financial Interests, Advisory Role, Board of DGHO Advisors: DGHO. A. Desuki: Financial Interests, Institutional, Research Funding: BioNTech. F. Lueke: Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Personal, Advisory Board: Janssen, MSD; Financial Interests, Institutional, Funding: Novartis. T. Ho: Financial Interests, Personal, Full or part-time Employment: BioNTech US; Financial Interests, Personal, Stocks/Shares: BioNTech. K. Vemuri: Financial Interests, Personal, Full or part-time Employment: BioNTech US; Financial Interests, Personal, Stocks/Shares: BioNTech US. L. Preussner: Financial Interests, Personal, Financially compensated role: BioNTech; Financial Interests, Personal, Leadership Role: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. B. Rengstl: Financial Interests, Personal, Financially compensated role: BioNTech; Financial Interests, Personal, Licencing Fees or royalty for IP: BioNTech; Financial Interests, Personal, Project Lead: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. Ö. Türeci: Financial Interests, Personal, Licencing Fees or royalty for IP: BioNTech; Financial Interests, Personal, Leadership Role: BioNTech; Financial Interests, Personal, Member of Board of Directors: BioNTech; Financial Interests, Personal, Ownership Interest, CMO: BioNTech; Financial Interests, Personal, Stocks or ownership: BioNTech. U. Sahin: Financial Interests, Personal, Leadership Role, CEO: BioNTech; Financial Interests, Personal, Licencing Fees or royalty for IP: BioNTech; Financial Interests, Personal, Member of Board of Directors: BioNTech; Financial Interests, Personal, Ownership Interest: BioNTech; Financial Interests, Personal, Stocks or ownership: BioNTech. All other authors have declared no conflicts of interest.

Background

Belvarafenib (Belva) is a type II selective RAF dimer inhibitor that, in combination with Cobimetinib (Cobi) has shown clinical activity in patients with NRAS-mutant melanoma ( ASCO 2021 , ESMO 2021 ). One cohort in this phase I trial evaluated BRAF fusions (including indel/rearrangement) or class II/III point mutations, which are considered potential therapeutic targets for Belva +/- Cobi. Here, we present findings on activity and safety of Belva and Cobi in patients with BRAF fusion including indel/rearrangement.

Methods

A total of 23 patients harboring BRAF non-canonical aberration were enrolled and treated with Belva 300mg PO BID and Cobi 20mg PO TIW (3 times a week) in the HM-RAFI-103 study (NCT03284502). Sub-cohort A (SC-A) enrolled patients with BRAF fusions and sub-cohort B (SC-B) enrolled patients with BRAF class II/III point mutations. Safety results were updated based on 133 patients who were treated with Belva and Cobi as of Jan 31, 2023.

Results

In SC-A, a total of 15 patients harboring BRAF fusions (Melanoma (10), NSCLC (3), CRC (1), Pancreatic cancer (1)) and 8 patients with BRAF class II/III point mutation were in SC-B (Biliary tract cancer (3), CRC (3), SCLC (1), Glioblastoma (1)) were enrolled. The confirmed objective response rate (ORR), assessed by investigators’ assessment, for SC-A was 60.0%, median progression-free survival (mPFS) was 13.7 months, and median duration of response was 12.0 months (95% CI: 7.43 to 22.34) with median follow-up time 12.9 months, while patients in SC-B showed best response of stable disease. As of cut-off date, the most common treatment related adverse events from 133 patients is dermatitis acneiform (54.1%), rash (28.6%), and blood creatine phosphokinase increased (24.1%). No new safety signals were found.

Table: 661MO

Conclusions

The combination of Belva with Cobi showed promising anti-tumor activity as well as durable responses in patients with BRAF fusions regardless of cancer type.

Clinical trial identification

NCT03284502.

Legal entity responsible for the study

Hanmi Pharmaceutical.

Funding

Hanmi Pharmaceurical.

Disclosure

T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech. 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. S. Han: Financial Interests, Institutional, Local PI: Hanmi, Genentech, Roche, Loxo, Mirati, MSD, Janssen, Lilly, Seagen, Arcus. J. Kim: Financial Interests, Personal, Invited Speaker: CJ Healthcare, AstraZeneca, GeneCKer, Sanofi/Aventis, Gencurix, Boryung; Financial Interests, Personal, Advisory Board: ABION, CJ Healthcare; Financial Interests, Personal, Member of Board of Directors: IMBdx; Financial Interests, Local PI: AstraZeneca, Boehringer Ingelheim, Sanofi, Lilly, CJ Healthcare, Hanmi, Ono Pharmaceutical, Pfizer, Novotech, Astellas Pharma, Merck, Alpha Biopharma, Yuhan, MSD, IL-Yang Pharm, AbbVie, Boryung, ChongKeunDang Healthcare, Daiichi Sankyo, BeiGene. D.H. Lee: Financial Interests, Personal, Advisory Board, honoraria for lectures and consulting: AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Mundipharma, Ono, Pfizer, AbbVie, Takeda, BluePrint Medicine, BC Pharma; Financial Interests, Personal, Advisory Board, honoraria for lectures: Novartis; Financial Interests, Personal, Advisory Board, honoraria for consulting: ST Cube, Menarini, BMS, Bayer; Financial Interests, Personal, Advisory Board: Eli Lilly, ChongKeunDang; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Stocks/Shares: STCube. Y. Hong: Financial Interests, Personal, Full or part-time Employment: Hanmi. S. Kim, T. Kim: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharm. B. Lee: Financial Interests, Personal, Full or part-time Employment: Hanmi Pharmaceutical Co., Ltd. J. Eng-Wong, Y. Yan: Financial Interests, Personal, Full or part-time Employment: Genentech. C. Chou: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. Y.S. Noh: Financial Interests, Institutional, Full or part-time Employment: Hanmi Pharmaceutical Company. All other authors have declared no conflicts of interest.

Background

IMP7068 is a potent and highly selective WEE1 inhibitor. Ongoing phase 1 study showed preliminary antitumor activity with a manageable safety profile in patients (pts) with advanced solid tumors.

Methods

Eligible pts were enrolled in escalation cohorts starting with 30mg (administered orally, once [QD] or twice daily [BID] for 3 days, followed by 4 days off [3/4] every week for 21-day cycles).

Results

As of April 12, 2023, 50 pts were enrolled across 10 dose cohorts (Table). Additional schedules including 2 days of dosing followed by 5 days off (2/5) and 5 days of dosing followed by 2 days off (5/2) every week were suggested by SMC after the notice of grade 3 ECG QT prolongation. The most common (＞10%) treatment related adverse events were QT prolongation (28%), vomiting (16%), diarrhea (14%) and nausea (14%). 9 dose-limiting toxicities (DLTs) of grade 3 QT prolongation and pulmonary embolism were observed in 8 pts (Table). The mean QT interval prolongation in 80mg BID is lower than that in 160mg QD in schedule 3/4. 35 pts were efficacy evaluable, 1 patient with uterine serous cancer in cohort 4 has maintained complete response for 30 weeks, 18 pts had stable disease (SD), of which 1 patient with ovarian cancer in cohort 7 has maintained SD for 24 weeks. 5 pts are still on treatment. The pharmacokinetic (PK) analysis showed the exposure of IMP7068 in cohort 7 was comparable to that in cohort 4. The phosphorylated cyclin-dependent kinase 1 level in cohorts 4, 7 and 9 was reduced by ≥50% after treatment. Based on safety, PK and pharmacodynamic data, 80mg BID can be considered as a recommended phase 2 dose (PR2D) of 3/4 schedule. Table: 662MO

DLT by escalating cohorts

Conclusions

IMP7068 conferred promising antitumor activity and good tolerability as QT prolongation has been mitigated by altering schedule. 80mg was defined as a potential PR2D in 3/4 schedule, and a second potential RP2D is being explored in 5/2 schedule. RP2D for IMP7068 will be determined soon.

Clinical trial identification

NCT04768868.

Legal entity responsible for the study

IMPACT Therapeutics, Inc.

Funding

IMPACT Therapeutics, Inc.

Disclosure

C. Lin: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Eli Lilly, Novartis, Roche; Financial Interests, Personal, Advisory Role: AbbVie, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Novartis, PharmaEngine, Rakuten; Financial Interests, Personal, Other, travel support: BeiGene, Eli Lilly, Impact. J.C. Baranda: Financial Interests, Institutional, Other, Consultant: Sanofi; Financial Interests, Personal, Stocks/Shares: Aprea, Moderna, Zyme, Merus, Hutchmed; Financial Interests, Institutional, Local PI: Astellas, Nektar, Sanofi, Takeda, Pfizer, SQZ, Synermore, Changchun Intellicrown, Genome and Company, Sumitomo Pharma, Xencor. D. Sommerhalder: Financial Interests, Personal, Other, Ad-hoc advisory role: Syneos SAG; Financial Interests, Personal, Other, Medical consulting: Guidepoint; Financial Interests, Institutional, Full or part-time Employment, Employed as a physician by Texas Oncology, a for-profit entity: Texas Oncology/US Oncology; Financial Interests, Institutional, Local PI: Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Biosciences, BioNTech, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, Monopteros Therapeutics, Navire, Nimbus Saturn, NGM Biopharmaceuticals, Parthenon, Pfizer, Revolution Medicines, Mirati Therapeutics, Symphogen, Teon Therapeutics, MediLink Therapeutics, ZielBio. L. Shen: Financial Interests, Personal, Other, Consulting fees: Mingji biopharmaceutical, Haichuang pharmaceutical, Herbour biomed; Financial Interests, Personal, Advisory Board: MSD, Merck, BMS, BI, Sanofi, Roche, Servier, AZ; Financial Interests, Institutional, Funding: Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Alphamab Oncology, Yaojie Ankang (Nanjing) Technology Co., Ltd., BeiGene, Ltd., Qiyu Biotechnology (Shanghai) Co., Ltd., BriSTAR immunotech; Financial Interests, Institutional, Local PI: Merck Healthcare KGaA, Roche; Financial Interests, Institutional, Trial Chair: Rongchang Pharmaceutical, Innovent, BeiGene, Ltd., Qilu Pharmaceutical, NovaRock Biotherapeutics Limited. O. Alese: Other, Institutional, Research Grant: Taiho Oncology, Ipsen Pharmaceuticals, GSK, Bristol Myers Squibb, PCI Biotech AS, ASCO, Calithera Biosciences, Inc., SynCore Biotechnology Co. Ltd., Suzhou Transcenta Therapeutics Co., Ltd., Corcept Therapeutics Inc., Hutchison MediPharma, Boehringer Ingelheim, Xencor Inc., Cue Biopharma, Inc., Merck, Syros Pharmaceuticals Inc., Inhibitex Inc., Arcus Biosciences Inc., ImmunoGen; Other, Personal, Advisory Role: Ipsen Pharmaceuticals, Aadi Bioscience, Taiho, Pfizer, Seagen Inc., Bristol Myers Squibb, AstraZeneca. All other authors have declared no conflicts of interest.