Background

NUC-7738 is an anti-cancer ProTide designed to overcome the key limitations of 3’-deoxyadenosine (3’-dA; cordycepin). The cytotoxicity of 3’-dA is largely attributed to intracellular generation of 3’-dATP, which interferes with RNA polyadenylation. NUC-7738, a phosphorylated and protected version of 3’-dA that is resistant to breakdown by adenosine deaminase, enters cancer cells independently of the hENT1 transporter and bypasses the need for initial, rate-limiting phosphorylation. In vitro, NUC-7738 generated higher intracellular levels of 3’-dATP and had greater anti-cancer activity compared to 3’-dA. Unlike 3’-dA, NUC-7738 retains cytotoxicity under cancer resistance conditions.

Methods

NuTide:701 is a phase I/II study of NUC-7738 in patients with advanced solid tumours. NUC-7738 is administered Q1W by IVI. In phase I, primary objectives were safety, tolerability and determination of the MTD. In phase II, the primary objective is efficacy. Secondary objectives include PK, efficacy and safety. Translational work will establish the pharmacodynamics of NUC-7738 and metabolites in blood and tumour.

Results

Phase I is complete and recruitment for phase II is ongoing. As of April 2022, 38 patients (58% female, median 2 prior lines; range: 0-7) with 17 advanced cancers in phase I and 1 patient (3 prior lines) in phase II received NUC-7738. NUC-7738 was well-tolerated, with no grade 4 treatment related AEs (TRAEs) and 4 patients with Grade 3 TRAEs (2 at doses above the MTD) of anaemia, fatigue and vomiting. The most frequent (≥15%) TRAEs were nausea (42%), fatigue (37%), anaemia (21%), diarrhoea and vomiting (both 18%). MTD was defined as 1350 mg/m2 Q1W based on two DLTs (G3 fatigue; 2000 mg/m2 cohort). RP2D is currently being defined and will be reported. NUC-7738 generated high levels of intracellular 3’-dATP that were detectable up to 50 hours after dosing. Encouraging anti-cancer signals were observed in several tumour types, particularly melanoma, with prolonged stable disease and symptom benefit. Additional data from phase I and phase II will be presented.

Conclusions

NUC-7738 has a favourable toxicity profile. Single-agent MTD is 1350 mg/m². Encouraging efficacy signals were observed in several tumour types including melanoma.

Clinical trial identification

NCT03428958.

Legal entity responsible for the study

NuCana plc.

Funding

NuCana plc.

Disclosure

S.N. Symeonides: Financial Interests, Institutional, Advisory Board: Ellipses, Vaccitech, Medannex, EUSA, Eisai, MSD, BMS, Pfizer, Merck Serono; Financial Interests, Institutional, Research Grant: MSD, Verastem, Roche; Financial Interests, Institutional, Invited Speaker: MSD, BioNTech, Nouscom, Roche, Nucana, Sapience Therapeutics, BioLineRx, Boston Pharmaceuticals, Sierra Oncology; Other, Conference attendance (no personal gain): Ipsen, BMS, EUSA. A. Skolariki: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche. M. Myers: Financial Interests, Personal, Full or part-time Employment: NuCana plc. E.M. Oelmann: Financial Interests, Personal, Full or part-time Employment: NuCana plc. J.D. Bloss: Financial Interests, Personal, Full or part-time Employment: NuCana. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. S.P. Blagden: Financial Interests, Personal, Advisory Role: UCB, Oxford Investment Consultants; Financial Interests, Personal, Royalties: WO 2016075455 A1 circulating LARP1; Financial Interests, Personal, Stocks/Shares: RNA Guardian; Financial Interests, Personal, Other, honoraria: Amphista Therapeutics, Theolytics, UCB, RApport Global; Financial Interests, Institutional, Research Grant: NuCana, Redx Pharma, UCB, MINA THERAPEUTICS, Nurix, BerGenBio, MSD Oncology. All other authors have declared no conflicts of interest.

Background

PRMT5 methylates arginines in proteins important for tumor development. GSK3326595, a first-in-class selective PRMT5 inhibitor, suppressed tumor growth in animal models. METEOR-1 is a phase I, dose escalation/expansion, 3-part study in patients (pts) with relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL). Here we describe results from the part 2 dose expansion phase.

Methods

Eligible pts >18 years were enrolled in the following cohorts: triple-negative breast cancer (TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), glioblastoma multiforme (GBM), NHL, adenoid cystic carcinoma (ACC), hormone receptor-positive breast cancer (HR+BC), human papillomavirus positive solid tumors (HPV+), and non-small cell lung cancer (NSCLC). Pts were treated with 300 or 400 mg GSK3326595 once daily.

Results

In part 2, most pts had discontinued study treatment (211/218, 97%) at data cut off. There were 3/158 confirmed responses in pts with solid tumors (2 ACC and 1 HR+BC) and 3/29 responses in pts with NHL (efficacy evaluable population). Primary efficacy endpoint is shown in the table. Median time on treatment across cohorts was 1.87 (0–34.8) months. Treatment-related (tr) AEs occurred in 95% of pts; most common were fatigue (45%), anemia (41%), and nausea (39%); 51% of pts had a grade 3/4 trAE, which were mainly anemia (24%), thrombocytopenia (9%)/platelet count decrease (6%), and fatigue (8%). No grade 5 trAEs occurred. Seventy % of pts had dose interruption, 56% dose reduction, and 13% discontinued treatment due to any AE.

Conclusions

Some monotherapy efficacy was observed in a largely heavily pretreated population. Safety was consistent with that previously reported for GSK3326595. Toxicities were generally manageable, with a need for treatment interruption/reduction observed across cohorts. Longest median time on treatment were in the ACC cohorts. Table: 456MO

Clinical trial identification

NCT02783300.

Editorial acknowledgement

Editorial Assistance was provided by Sarah Hummasti, PhD of AOIC, LLC and was funded by GlaxoSmithKline.

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline.

Disclosure

S. Postel-Vinay: Financial Interests, Institutional, Research Grant, Laboratory research funding: AstraZeneca, Roche – IMCore, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting Fees: Merck KgA. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, CHUGAI, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, IPSEN, MERCK. P. Martin Romano: Financial Interests, Institutional, Sponsor/Funding, For this study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen-Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, OncoEthix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, PharmaMar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals Inc, Taiho Pharmaceutical Company Ltd, Tesaro, Turning Point Therapeutics, Xencor; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GlaxoSmithKline, INCA Pharma, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Other, Supplied drug for study: AstraZeneca, Bayer, BMS, Boringher Ingelheim, GlaxoSmithKline, Medimmune, Merck, NH TherAGuiX, Pfizer; Non-Financial Interests, Institutional, : Roche. P.A. Cassier: Financial Interests, Personal, Advisory Board: Merck Serono/EMD, Roche, Amgen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Advisor: OSE immunotherapeutics; Financial Interests, Institutional, Invited Speaker: AbbVie, Amgen, Blueprint, Exelixis, GSK, Janssen, Novartis, Roche, Taiho, LOXO/Eli Lilly; Non-Financial Interests, Institutional, Product Samples: plexxikon, Novartis, MSD, AstraZeneca, GSK. L.L. Siu: Financial Interests, Institutional, Principal Investigator: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Financial Interests, Personal, Advisory Role, Consulting Fees: Merck, Pfizer, AstraZeneca, Roche, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko, Coherus, Marengo, InteRNA; Non-Financial Interests, Personal, Advisory Role, Data Safety Monitoring Board: Mirati; Financial Interests, Personal and Institutional, Officer, Cofounder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares: Agios; Financial Interests, Institutional, Sponsor/Funding, Support for this trial: GlaxoSmithKline. I.S. Lossos: Financial Interests, Personal and Institutional, Research Grant: NHI grant; Financial Interests, Personal, Advisory Board: Janssen Scientific, Verastem, Adaptive Biosciences . J.F. Hilton: Financial Interests, Personal, Advisory Board: Merck, Novartis, AstraZeneca, Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: Merck, Novartis; Financial Interests, Personal, Other, DSMC committee - relatlimab program: BMS; Financial Interests, Personal, Research Grant: GSK. M.A. Mckean: Financial Interests, Institutional, Advisory Board: Array BioPharma, AstraZeneca, MedPage Today, Pfizer, Regeneron; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, TMUNITU Therapeutics, TopAlliance Biosciences. J. Strauss: Financial Interests, Institutional, Advisory Role, Consulting fee paid to institution: Binhui Biopharmaceuticals, Synlogic; Financial Interests, Personal, Leadership Role, Medical Director: Dialectic Therapeutics; Financial Interests, Personal, Stocks/Shares: AbbVie, Abbott Laboratories, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, Regeneron. G.S. Falchook: Financial Interests, Institutional, Sponsor/Funding, For the study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Other, Receipt for equipment, materials, and drugs: GlaxoSmithKline. M.J.A. de Jonge: Financial Interests, Institutional, Principal Investigator, Contract with Department of Medical Oncology for study conduct: ErasmusMC. F.L. Opdam: Financial Interests, Institutional, Principal Investigator: AstraZeneca, Boehringer Ingelheim, Cytovation, GlaxoSmithKline, InteRNA technologies, Merus, Pierre-Fabre, Taiho. D. Rasco: Financial Interests, Institutional, Research Grant: GlaxoSmithKline , Amgen, Mirati. J.S. Vermaat: Financial Interests, Institutional, Sponsor/Funding, For the study: GlaxoSmithKline. T. Crossman: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline . M. Zajac: Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline; Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. A. Hainline: Financial Interests, Institutional, Full or part-time Employment, Statistician for this study: GlaxoSmithKline. B. Kremer: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline. O. Barbash: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline. M.M. Gounder: Financial Interests, Personal, Advisory Role, Honoraria: Medscape, More Health, Physicians Education Resource, touchIME; Financial Interests, Personal, Advisory Role, Consulting: Athenex, Ayala, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Epizyme, Karyopharm, Rain Therapeutics, Springworks Therapeutics, Tracon, TYME Technologies; Financial Interests, Personal and Institutional, Research Grant, (P30CA008748)—core grant (CCSG shared resources and core facility for MSKCC): National Cancer Institute, National Institutes of Health; Non-Financial Interests, Personal, Royalties, Patents with MSKCC (GODDESS PRO): Wolters Kluwer; Financial Interests, Personal, Other: Guidepoint, GLG, Third Bridge, Flatiron Health; Financial Interests, Institutional, Funding, For the study: GlaxoSmithKline.

Background

Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor, exerts antitumour activity in preclinical models.

Methods

Part A1 of this open-label, single-arm study (NCT04170153) evaluated the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of M1774 in patients with advanced solid tumours. A safety monitoring committee determined dose escalation, guided by a Bayesian 2-parameter logistic regression model. Biomarkers were assessed, and target engagement evaluated via γ-H2AX modulation in peripheral blood mononuclear cells (PBMCs).

Results

55 patients received M1774 in 21d cycles over 14 cohorts (Table). 11 patients experienced DLTs (Table). The Bayesian model suggested the MTD was 180 mg (QD continuously). Across doses, M1774 was rapidly absorbed and eliminated (median t_max ∼0.5–3.5h; mean t_½ ∼1.2–5.6h) with ≤2.4-fold accumulation. Up to 180 mg, exposure was approx. dose proportional but was slightly more than proportional at higher doses. At 180 mg QD, mean exposure over 24h at steady state was ∼30-fold higher than the in vitro pCHK1 drug concentration required for 90% inhibition. From 130 mg QD, γ-H2AX levels in PBMCs reduced by >80% 3h after the first dose, showing target engagement. In 13/35 patients of cohorts 1–11, loss of function mutations were detected by next-generation sequencing in baseline ctDNA samples, among them BRCA1/2 (6), ATM (3), ARID1A (4), ATRX (2). One patient with platinum and PARP inhibitor resistant BRCA^wt ovarian cancer and ATRX mutation achieved RECIST v1.1 partial response. Table: 457MO

Dose-limiting toxicities by ascending dose

Conclusions

These early data show M1774 monotherapy in patients with advanced solid tumours is well-tolerated. The DDRiver 301 study is ongoing, investigating M1774 monotherapy in biomarker-selected patients and M1774 + niraparib.

Clinical trial identification

NCT04170153.

Editorial acknowledgement

Medical writing assistance (funded by Merck) was provided by Lesley Taylor on behalf of Bioscript Stirling Ltd, Macclesfield, UK.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.

Funding

Merck (CrossRef Funder ID: 10.13039/100009945).

Disclosure

T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Beigene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GlaxoSmithKline, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith. A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Adagene, Inc., ARO Biotherapeutics, BIOINVENT, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD Serono/ MERK KGaA, IMMUNOME, Janssen Global Services, LLC, Jazz Pharmaceuticals, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Senti Biosciences, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Other, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Asana BioSciences, LLC., Axlmmune, Bayer, Blu Print Oncology, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Immunomet Therapeutics, Inc., Karma Oncology, Lengo Therapeutics, Menarini Ricerche, Mersana, NANOBIOTIX, Partner Therapeutics, Pfizer Inc., PIERRE FABRE, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., ABBVIE, Inc, AGENUS, Inc., Ascentage, Mekanistic Therapeutics, Zentalis; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the President and Founder.: Aclaris Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Other, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of NEXT Oncology: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, Apros Therapeutics, Inc., ABBVIE, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Codiak BioSciences, Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, IDEAYA Biosciences, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc, Nitto BioPharma, Inc., Odonate Therapeutics, Inc., Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Shanghai Haihe Pharmaceutical Co., Ltd, Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, Zymeworks Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder.: ORIC Pharmaceuticals; Non-Financial Interests, Principal Investigator: ABBVIE, Inc; Non-Financial Interests, Principal Investigator, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: ABL Bio Inc., Adagene Inc, ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, Boehringer Ingelheim Pharmaceutical, Inc., BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., IDEAYA Biosciences, GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc.; Financial Interests, Institutional, Other, Note: Provided expert testimony. Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder: Immunogen; Financial Interests, Institutional, Other, Note: Received travel, accommodation and expenses. Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder: Sotio. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. J. Mukker: Financial Interests, Personal and Institutional, Full or part-time Employment: EMD Serono. M. Enderlin, C. Hicking, G. Locatelli: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. Z. Szucs: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Serono Ltd., Feltham, UK. I. Gounaris: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Serono Ltd., Feltham, UK; Financial Interests, Personal, Stocks/Shares: Novartis, Alcon. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline.

Background

Tumor-specific homologous recombination (HR) DNA defects and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway have been shown in preclinical studies to modulate the tumor immune microenvironment, forming the rationale for triplet combination of Cap+Ola+Durva. Our previous work showed safety of Ola+Durva with Cap at both 200mg and 320mg BD (Lim et al, ESMO2021). Here, we present efficacy data from both dose escalation and expansion cohorts.

Methods

Safety, tolerability and efficacy data in both dose escalation (Cap 4 days on 3 days off, dose level 1 [DL]:160mg BD, DL2:200mg BD, DL3:320mg BD) and dose expansion at DL2 and DL3 of this phase Ib study was analysed. After 2 week run-in Cap, Durva and Ola were commenced at standard doses of 1500mg once 4-weekly and 300mg BD continuous dosing respectively.

Results

39 pts were enrolled (DL1 3pts, DL2 12pts, DL3 24pts); 28 had evaluable disease (DL1 3pts, DL2 10pts, DL3 15 pts). Median age 66 (range 36-81); median lines of prior therapy 3 (range 0-13); most common histology: breast (41.0%), endometrium (17.9%), ovary (15.4%). 64.1% and 5.1% had PIK3CA/AKT pathway or BRCA mutations; 12.8% had PDL1+/high TMB tumors. 15.4% had prior pathway-directed therapy based on known molecular aberration. In the evaluable population, objective response rate (ORR) was 20.0% (3/15) at DL3, including a pt with PIK3CA-mutant breast Ca with ongoing response for 10.9 months (m); median duration of response (DOR) was 8.7m (range 4.1-9.3m). No objective responses were observed at DL1 or DL2. Disease control rate (DCR) >6m was 0%, 30.0% and 33.3% at DL1, DL2 and DL3 respectively, and 44.4% in PIK3CA/AKT pathway enriched population. Both pts with BRCA-mutant cancers (1 breast Ca, 1 ovarian Ca) had progression-free survival of 6.4m and 8.1m respectively, despite prior progression on PARP inhibitors. Most frequent all-grade toxicities (tox) were fatigue (n=22, G3:1), diarrhoea (n=19, G3:2), nausea (n=18, G3:0) and rash (n=15, G3/4:4).

Conclusions

Triplet Cap+Ola+Durva showed anti-tumor activity with meaningful DOR at Cap 320mg BD, with good tolerability. A phase II expansion investigating its role in breast and gynaecological cancers is ongoing.

Clinical trial identification

NCT03772561.

Legal entity responsible for the study

National University Health System, Singapore.

Funding

National Medical Research Council, Singapore; AstraZeneca.

Disclosure

J. Lim: Financial Interests, Personal, Advisory Board: pfizer, Novartis, AstraZeneca, DKSH; Financial Interests, Personal, Invited Speaker: DKSH, Roche, Pierre Fabre, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Synthon pharmaceuticals, Daiichi, Taiho pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma. S. Raghav: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, BMS, Roche, Taiho, AstraZeneca; Non-Financial Interests, Advisory Role: Paxman Coolers; Non-Financial Interests, Principal Investigator: MSD. A. Wong: Financial Interests, Institutional, Research Grant: Ostuka Pharmaceutical; Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Eisai , AstraZeneca. W.P. Yong: Financial Interests, Personal, Advisory Board: AbbVie/Genentech, Amgen, BMS, Ipsen, Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly, Sanofi/Aventis, Eisai, Bayer, MSD. R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, Astra-Zeneca, Bayer, BMS, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Yuhan; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Other, Conference sponsorship: Taiho; Financial Interests, Institutional, Research Grant: Astra-Zeneca, Boehringer Ingelheim. C.E. Chee: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Role: Guardant Health AMEA; Financial Interests, Personal, Other, Travel, accommodations, expenses: Taiho. S.C. Lee: Financial Interests, Personal, Advisory Board, Advisory board, speaker invitations: Pfizer, Novartis, AstraZeneca, Roche, MSD; Financial Interests, Personal, Advisory Board, Advisory Board: Eli Lilly; Financial Interests, Institutional, Research Grant: Pfizer, ACT Genomics, Eisai, Taiho, MSD, Karyopharm, ASLAN Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, Daiichi sankyo, BMS, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. B. Goh: Financial Interests, Institutional, Invited Speaker: MSD, Adagene, Bayer, Pfizer; Financial Interests, Institutional, Advisory Board: Bayer Healthcare; Financial Interests, Personal, Other, Consultancy: Adagene pharmaceutical; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Regereron; Financial Interests, Institutional, Research Grant, Support for investigator initiated trial: MSD; Financial Interests, Institutional, Other, Pharmaceutical support for clinical trial: BMS; Financial Interests, Institutional, Other, Pharmaceutical support for investigator initiated clinical trial: Taiho pharmaceuticals; Non-Financial Interests, Institutional, Other, Lead clinical trial platform of the Singapore Translational Cancer Consortium: Consortium for Clinical Research and Innovation Singapore; Non-Financial Interests, Member: ASCO. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. J.J. Chan: Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, DKSH Singapore, Novartis; Financial Interests, Personal, Other, Conference fee: DKSH Singapore, Merck Sharp & Dohme, Pfizer, Roche; Financial Interests, Institutional, Funding, Investigator initiated trial: OncoQuest, Bristol-Myers Squibb; Non-Financial Interests, Other, Track Chair, Breast Track, 6th Annual Scientific Meeting 2021: Singapore Society of Oncology; Non-Financial Interests, Other, Scientific Committee Member, Masterclass: Gynecologic Cancer Group Singapore; Non-Financial Interests, Member: Singapore Society of Oncology, Gynecologic Cancer Group Singapore, Chapter of Medical Oncologists, College of Physicians, Academy of Medicine Singapore.

G. Schiavon: Financial Interests, Personal, Other, Employee: AstraZeneca. A. Foxley: Financial Interests, Personal, Other, Employee: AstraZeneca. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bergen Bio, Zeria Pharmaceutical Co Ltd, Bayer, Byondis B.V.; Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Advanced-stage tumors harboring a KRAS G12C mutation have limited treatment options. GDC-6036, a highly potent and selective KRAS G12C inhibitor, has shown robust tumor growth inhibition in multiple preclinical models of a variety of tumor types.

Methods

As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), patients (pts) with KRAS G12C mutant other solid tumors (oST), exclusive of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) (NSCLC and CRC reported elsewhere), were administered GDC-6036 orally once a day in 21-day cycles until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1).

Results

As of 28 Jan 2022, 14 pts with pretreated oST (4 cholangiocarcinoma, 3 pancreatic adenocarcinoma, and 1 each: anus, appendix, breast, duodenum, endometrial, lung neuroendocrine, and stomach cancers) had received GDC-6036 monotherapy at 400 mg. Median (range) number of prior cancer therapies was 2 (1-8). No dose-limiting toxicities were reported across NSCLC, CRC and oST. Median (range) time on study treatment was 63.5 (8-151) days among oST pts, and median GDC-6036 dose intensity was 99%. Five (36%) pts had discontinued study treatment (4 radiographic progression and 1 death due to disease progression). The most frequent GDC-6036-related AEs reported in ≥ 2 pts were nausea, vomiting, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased. Two (14%) pts required a dose modification (interruption, 1 pt; reduction, 1 pt; no withdrawal) for GDC-6036-related AEs. Across NSCLC, CRC and oST pts, the mean half-life for GDC-6036 ranged from 13-17 hours at doses of 50-400 mg. The unconfirmed overall response rate (ORR) in the oST pts was 21% (3/14 pts; anus, lung neuroendocrine and stomach cancers), while the confirmed ORR was 14% (2/14 pts).

Conclusions

GDC-6036 demonstrated an acceptable safety profile, a PK profile compatible with once-daily dosing, and encouraging efficacy in pts with pretreated oST with a KRAS G12C mutation. Data from additional pts will be presented.

Clinical trial identification

NCT04449874.

Editorial acknowledgement

Andrew Occiano (Genentech, Inc.) provided editing and writing assistance, which was funded by Genentech, Inc.

Legal entity responsible for the study

Genentech, Inc.

Funding

Genentech, Inc.

Disclosure

M. Patel: Financial Interests, Personal, Speaker’s Bureau: Exelis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Financial Interests, Personal, Advisory Board: Mirati, Daiichi; Financial Interests, Personal, Advisory Role: Pharmacyclics/Janssen, Pfizer/EMD Serono; Financial Interests, Personal, Other, Travel Expenses: Pfizer, Pharmacyclics, Bayer, Janssen Oncology, Genentech; Non-Financial Interests, Institutional, Funding: Acerta Pharma ADC Therpeutics Agenus Aileron Therapeutics AZ Bicycle Therapeutics BioNTech AG Blueprint Boehringer Ingelheim Calithera Biosciences Celgene Checkpoint Therapeutics CicloMed Clovs Oncology Curis Cyteir Daiichi Sankyo eFFECTOR Therapeutics L. M.J. De Miguel: Financial Interests, Personal, Advisory Role: Syneos, Janssen, MSD; Financial Interests, Institutional, Funding: AbbVie, Array, Achilles, Basilea, Bayer, Biontech, Faron, MSD, Novartis, Cytomex, Genentech, Genmab, Janssen, Menarini, Nektar, Catalym, Regeneron, Zenith. T. Burns: Financial Interests, Personal, Advisory Board: Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals Inc, Blueprint Medicines Corporation (BPMC), Emd Serono Inc., Mirati Therapeutics, Inc.; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Other, DSMB: Advarra, Inc. A. Falcon Gonzalez: Financial Interests, Personal, Advisory Board: Seagen, Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly, Grunenthal pharma, Roche. T.W. Kim: Financial Interests, Institutional, Research Grant: AstraZeneca, SanofiAventis. M.G. Krebs: Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal and Institutional, Advisory Role: Roche, Seattle Genetics; Financial Interests, Personal, Invited Speaker: Roche, Janssen, AstraZeneca; Financial Interests, Personal, Other, Travel Expenses: Immuntep, BerGenBio, Janssen; Financial Interests, Personal, Other: Janssen; Financial Interests, Personal, Advisory Board: Roche, Bayer, Guardant Health. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. J. Desai: Financial Interests, Personal, Advisory Role: Beigene, Pierre Fabre, Bayer, GlaxoSmithKline, Merck KGaA, Boehringer Ingelheim, Roche/Genentech, Daiichi Sankyo EUrope Gmbh; Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Institutional, Funding: Roche, GlaxoSmithKline, Novartis, Bionomics, BeiGene, Lilly, Bristol-Myers Squibb, AstraZeneca/MedImmune. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: Sotio, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board - Member: University of Arizona; Other, External Scientific Advisory Board - Member: University of New Mexico; Other, Scientific External Advisory Board - Member: University of California at San Diego. A. Sacher: Financial Interests, Institutional, Invited Speaker: Genentech-Roche, BMS, AstraZeneca, Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly. Y. Choi, N. Dharia, M.T. Lin, S. Mandlekar, S. Royer-Joo, J.L. Schutzman: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol-Mayers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. All other authors have declared no conflicts of interest.

Background

ZW49 is a novel ADC comprised of a HER2-targeting bispecific antibody (directed against 2 non-overlapping HER2 epitopes) attached to a proprietary auristatin toxin with a protease-cleavable linker. The results from this ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233) are presented.

Methods

DE: In a 3+3 design, patients (pts) with HER2+ cancers were dosed with ZW49 IV QW (3 weeks on, 1 off; 1-1.75 mg/kg), Q2W (1-2 mg/kg) or Q3W (2-3 mg/kg). DX: Pts with centrally confirmed HER2+ cancers and measurable disease received ZW49 at the recommended dose(s)(RD[s]) determined in DE. Primary endpoints are safety and tolerability assessments; secondary endpoints include response assessments per RECIST v1.1.

Results

As of 10 Mar 2022, 76 pts (DE [51] and DX [25]; female: 58%; median age: 59 years [range, 24-83]) have been treated with ZW49. Overall, the most common histologies were gastric (28%) and breast (22%) cancers; 70% received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range: 1-16). A RD of 2.5 mg/kg was identified for the Q3W schedule. One dose-limiting toxicity of Grade [Gr] 2 keratitis > 14 days was observed in 1 pt and resolved to Gr 1 (2.5 mg/kg Q3W DX cohort). 68 (89%) pts had treatment-related adverse events (TRAEs); majority were Gr 1 or 2 in severity. The most common TRAEs (≥ 20% pts) included keratitis (42%), alopecia (25%), and diarrhea (21%). 7 (9%) pts had Gr ≥ 3 TRAEs, including 2 Gr 4 events (infusion-related reaction [1 pt] and decreased neutrophil count [1 pt]). Serious TRAEs were reported in 3 pts, leading to 1 discontinuation (D/C); 2 other pts had D/C due to TRAE. No interstitial lung disease nor TR deaths were reported. Among 29 response-evaluable pts treated with ZW49 at 2.5 mg/kg Q3W, the confirmed objective response rate across multiple cancer types was 28% and disease control rate was 72%.

Conclusions

ZW49 has a manageable safety profile with encouraging single-agent antitumor activity in heavily pretreated pts with HER2+ cancers. Enrollment continues at 1.75 mg/kg QW in DE and 1.5 mg/kg QW in DX.

Clinical trial identification

NCT03821233.

Legal entity responsible for the study

Zymeworks Inc.

Funding

Zymeworks Inc.

Disclosure

K. Jhaveri: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, AbbVie, Taiho Oncology, Seattle Genetics, Daiichi Sankyo, Loxo Oncology, Gilead, Blueprint Medicines, Biotheranostics; Financial Interests, Personal, Other, Consultant: Pfizer, Genentech, Sun Pharma Pvt Ltd; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, AstraZeneca, Lilly Pharmaceuticals, Genentech, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals; Non-Financial Interests, Leadership Role: Lilly/Loxo Oncology. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, SeaGen, Quantum Leap Healthcare Collaborative. E. Dotan: Financial Interests, Personal, Advisory Board: Incyte, Helsinn, QED, Basilea; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant, Research Grant: Pfizer; Financial Interests, Institutional, Invited Speaker, Clinical trial: Zymeworks, Incyte, Medimmune, Relay, NGM Biopharmaceuticals, Inc., AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical trial chair: Ipsen. D. Oh: 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; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. C. Ferrario: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Merck, Knights Therapeutics; Financial Interests, Institutional, Invited Speaker: Astellas, AstraZeneca, Lilly, Merck, Novartis, Roche - Genetech, Sanofi, Seattle Genetics, Sermonix, Zymeworks; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Bayer; Non-Financial Interests, Advisory Role: AstraZeneca, Knights Therapeutics, Merck. A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Adagene, Inc., ARO Biotherapeutics, BIOINVENT, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD Serono/ MERK KGaA, IMMUNOME, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Other, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Asana BioSciences, LLC., Axlmmune, Bayer, Gilde Healthcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Menarini Ricerche, Mersana, NANOBIOTIX, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., AbbVie, Inc, AGENUS, Inc., Ascentage, Mekanistic Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the President and Founder.: Aclaris Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Other, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of NEXT Oncology: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, Apros Therapeutics, Inc., AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Codiak BioSciences, Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, IDEAYA Biosciences, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, : Mirati Therapeutics, Inc. K. Lee: Financial Interests, Personal, Advisory Board: Bayer, Daiichi Sankyo, BMS; Financial Interests, Personal, Other, Consultation: ISU ABXIS; Financial Interests, Institutional, Invited Speaker: Merck Sharp & Dohme, Ono pharmaceutical, AstraZeneca, Merck KGaA, Pfizer, BeiGene, ALX Oncology, Zymeworks, Macrogenics, Five Prime Therapeutics, Oncologie, Pharmacyclics, Green Cross Corp, ABLBIO, Y-BIOLOGICS, Genexine, LSK BioPharma, Daiichi Sankyo, Taiho Pharmaceutical. C. Liao: Financial Interests, Personal, Advisory Board: AstraZeneca, FirstThought LLC, Transthera, BluePrints Medicine, QED, Genentech, Cancer Experts Now, Histosonics, Ipsen, Exelixis; Financial Interests, Personal, Other, Speaker Bureau: Eisai, Incyte; Financial Interests, Personal, Invited Speaker: OncLive; Financial Interests, Institutional, Invited Speaker, Research funding for investigator initiated trial: BMS. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche. Y.H. Kim: Financial Interests, Personal, Ownership Interest: OncoMASTER; Financial Interests, Institutional, Invited Speaker: MSD Oncology, Ono Pharmaceutical, Macrogenics, Korea Astellas, Zymeworks. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, 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, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, ImmunoGen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Vincerx Pharma. A. 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, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Astellas Pharma, MedImmune, 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, Mersana, Mirati Therapeutics, Rubius, Synthekine, Blueprint Medicines. N. Patel: Financial Interests, Institutional, Invited Speaker, Updates in Breast Cancer talk annually: OncLive; Financial Interests, Personal, Other, Consultant to trial breast cancer guideline based treatment platform: Node.Health. C.S. Karapetis: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Ipsen, Eli Lilly, Eisai, Roche, Takeda, Beigene; Financial Interests, Institutional, Invited Speaker: Takeda, Roche, Mirati, Daiichi Sankyo; Non-Financial Interests, Member: Medical Oncology Group of Australia, American Society of Clinical Oncology. L.A. Boyken: Financial Interests, Institutional, Full or part-time Employment: Zymeworks; Financial Interests, Personal, Stocks/Shares: Zymeworks. J. Woolery: Financial Interests, Personal, Full or part-time Employment, I am a full-time employee: Zymeworks Biopharmaceuticals; Financial Interests, Personal, Stocks/Shares: Zymeworks Biopharmaceuticals, Seagen. P.L. Bedard: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Invited Speaker, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, MSD, Amgen, LG biochemical, GSK; Financial Interests, Personal, Invited Speaker: Lilly, Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daichii Sankyo; Financial Interests, Institutional, Invited Speaker: Indivumed, zy,meworks, Beigine; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Drug supply for clincal trial: MSD.