A phase 1 FIH study of AMG 701, an anti-BCMA - PowerPoint Presentation

A phase 1 FIH study of AMG 701, an anti-BCMA
A phase 1 FIH study of AMG 701, an anti-BCMA

A phase 1 FIH study of AMG 701, an anti-BCMA - Description


halflife extended HLE BiTE bispecific Tcell engager molecule in relapsed refractory multiple myeloma Simon J Harrison 1 Monique C Minnema 2 Hans C Lee 3 Andrew Spencer ID: 920179 Download Presentation

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Slide1

A phase 1 FIH study of AMG 701, an anti-BCMA half-life extended (HLE) BiTE® (bispecific T-cell engager) molecule, in relapsed / refractory multiple myeloma

Simon J. Harrison,1 Monique C. Minnema,2 Hans C. Lee,3 Andrew Spencer,4 Prashant Kapoor,5 Deepu Madduri,6 Jeremy Larsen,7 Sikander Ailawadhi,8 Jonathan Kaufman,9 Marc S. Raab,10 Parameswaran Hari,11 Shinsuke Iida,12 Ravi Vij,13 Faith E. Davies,14 Robin Lesley,15 Vijay V. Upreti,16 Zhao Yang,17 Anjali Sharma,18 Alex C. Minella,18 Suzanne Lentzsch191Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia, Sir Peter MacCallum Dept of Oncology, Melbourne University, Melbourne, Australia, 2 University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands, 3The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, 4Alfred Hospital-Monash University, Melbourne, Australia, 5Mayo Clinic, Rochester, MN, USA, 6Icahn School of Medicine at Mount Sinai, New York, NY, USA, 7Mayo Clinic, Phoenix, AZ, USA, 8Mayo Clinic, Jacksonville, FL, USA, 9Emory University, Atlanta, GA, USA, 10Heidelberg University Hospital, Heidelberg, Germany, 11Medical College of Wisconsin, Milwaukee, WI, USA, 12Nagoya City University Hospital, Nagoya, Japan, 13Washington University School of Medicine, St. Louis, MO, USA, 14NYU Langone, New York, NY, USA, 15Clinical Biomarkers and Diagnostics, Amgen Inc., South San Francisco, CA, USA, 16Clinical Pharmacology, Modeling & Simulation, Amgen Inc., South San Francisco, CA, USA, 17Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA, 18Early Development, Oncology, Amgen Inc., Thousand Oaks, CA, USA, 19Columbia University Medical Center, New York, NY, USA

presented by: Professor Simon J. Harrison

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Slide2

Anti-BCMA BiTE® Therapy in Multiple Myeloma2

1. Madry Int Immunol. 1998, 10:1693-1702. 2. Coquery, Erickson. Crit Rev Immunol. 2012, 32:287-305. 3. Laabi Nucleic Acids Res. 1994, 22:1147-54. 4. Gras Int Immunol. 1995, 7:1093-1106. 5. Topp J Clin Oncol 2020, 38:775-783. There is an unmet need for treatments for patients with MM relapsed and / or refractory to available therapies. BCMA expression is restricted to MM cells, plasma cells, and mature B cells, making it an ideal therapeutic target.1-4Proof of concept for BiTE® therapy in MM was shown by AMG 4205A continually infused anti-BCMA canonical BiTE® molecule70% response rate (50% MRD- CRs) at 400 µg/day3L+ MM (prior IMiD and PI)BCMAMM cellAMG 420T cell

Slide3

AMG 701: An Anti-BCMA Half-life Extended BiTE® Molecule Allowing Weekly Administration3

BCMA, B-cell maturation antigen; MM, multiple myeloma. Fc domain intended to extend molecule half-life per Weidle Cancer Genomics Proteomics 2013; 10:1-18. AMG 701: Goldstein Blood Advances 2020; 4:4180-4194. Cho Blood Advances 2020; 4:4195-4207.Memory T cellsT cell activation + expansionT cells engage tumor-associated antigen via AMG 701 bindingT cellsMM cells

AMG 701

Myeloma

cell killing

Slide4

AMG 701 FIH: Key Study Features 4

FeatureDescriptionInclusionMM relapsed / refractory to ≥3 prior lines, including PI, IMiD, and anti-CD38 Ab*ExclusionNon-secretory diseaseAuto / allo stem cell transplant within 3 or 6 months, respectivelyPrior treatment with anti-BCMA agentTreatmentWeekly IV infusions in 4-week cycles until disease progressionPremedication8 mg dexamethasone or equivalent in first 2 cycles†DosingStep-dosing schedules were testedIMiD, immunomodulatory imide; PI, proteasome inhibitor. *In earlier protocol versions, anti-CD38 Ab was required where available; later, anti-CD38 Ab was required for all patients. The initial requirement was for ≥2 lines; later it was ≥3 lines. †Initially, 8 mg dex or equivalent was given before every dose in Cycles 1 and 2; for the last few cohorts, premedication with 8 mg dex occurred in Cycle 1, with the first dose of Cycle 2, and then as needed. Primary objectives: Evaluate safety / tolerability, estimate active doseSecondary objectives: Characterize PK and responses

Slide5

AMG 701 FIH: Study Design 5

1.2 mg* N = 41.6 mg* N = 83 mg* N = 114.5 mg* N = 76.5 mg* N = 119 mg* N = 1012 mg* N ≤25†18 mg* N = 3-10†0.005-1.6 mgN = 15

NCT03287908. AE, adverse event; f/u, follow-up; LTFU, long-term follow-up; PD, progressive disease.

*Some patients received step dosing;

planned enrollment; **

LTFU

 every 3 months until end of

therapy, PD, death, consent withdrawal.

Screening (up to 21 days)

Safety f/u 30 days after last dose

LTFU: 5 years**

Treat with AMG 701; 4-week cycles until PD, AE, death, withdrew consent

Slide6

AMG 701 FIH: Patient Baseline Characteristics

CharacteristicN=85Male, n (%)44 (52%)Age, median (min-max), years64 (34-83)Disease duration, median (min-max), years5.6 (0.5-15.1)ISS stage I / II / III21% / 48% / 26%*Extramedullary disease25%Bone marrow plasma cells at baseline, median (min-max)10% (0%-94%)Prior lines of therapy, median (min-max)6 (2-25)Prior stem cell transplant, any82% Auto / allo80% / 11%Triple-exposed / triple-refractory (PI, IMiD, and anti-CD38 Ab)93% / 62%6As of Sep 17, 2020. *Unknown for 5%. Safety dataset includes patients receiving at least 1 dose of AMG 701; the efficacy dataset includes patients who completed the first cycle or discontinued (eg, due to PD, AE etc.).

Slide7

AMG 701 FIH: Patient Disposition7

As of Sep 17, 2020. Q1, quartile 1 (25th percentile), Q3, quartile 3 (75th percentile). *Other: per investigator (2), required alternative therapy (1), CNS disease (1) which occurred after 1 day, concurrent with grade 4 left eye blindness; as there was no CNS imaging at baseline, time of onset is unknown.Received AMG 701 (N=85)Continuing AMG 701 (N=21)Median (Q1, Q3) treatment duration was 7.6 (4.1, 15.1) weeks.Progressive disease (N=51)Adverse events (N=5)Discontinued (N=64)

Patient choice (N=4)

Other

*

(N=4)

Slide8

AMG 701 FIH: Safety Profile8

As of Sep 17, 2020. D/C, discontinuing; gr, grade; heme, hematological; SAE, serious adverse event. 1 CRS grading as per Lee Blood 2014; 124:188-195. Most common AEs (all grades): Heme: anemia (42%), neutropenia (25%), thrombocytopenia (21%) Non-heme: CRS (65%), diarrhea (31%), hypophosphatemia (31%) SAEs occurred in 38% of patients; the most common SAEs were infections (17%) and CRS (9%).4 deaths, none related to AMG 701, were 2 cases of sepsis (both secondary to intensive chemotherapy after D/C AMG 701), 1 case of retroperitoneal bleeding, and 1 case of subdural hematoma.Adverse eventsCRS grade per Lee 20141Gr 1: 27% (n=23), gr 2: 28% (n=24), gr 3: 9% (n=8)Use of tocilizumab: 29% (n=25); corticosteroids: 17% (n=14)Gr 3 CRS (DLTs)Gr 3: transient LFT increase (n=4), hypoxia (n=4)Reversible with steroids and/or tocilizumabMedian duration 2 daysNon-CRS DLTsGr 3 atrial fibrillation (n=1), acidosis (n=1)Gr 4 thrombocytopenia (n=1)

Slide9

9As of Sep 17, 2020; best overall responses of evaluable patients (n=82). Minimal residual disease (MRD) measured by next-generation sequencing (NGS, ≤10-5

per IMWG) in all but 1 case, which was by flow cytometry (≤3×10-5). Responses to date: 5 sCR, 3 CR, 6 VGPR, 7 PRThe most recent evaluable cohort had 5/6 (83%) responses4 of 5 triple refractoryMRD negative in 6/7 patients tested sCR (n=3), CR (n=3), VGPR (n=1)All 6 have ongoing responses, up to 22 months in 1 patientAMG 701 FIH: Overall Response Rate

Slide10

AMG 701 FIH: Depth, Durability of Responses ≥PR As of Sep 17, 2020. Q1, quartile 1 (25th percentile), Q3, quartile 3 (75th percentile).

As of datacut, the interim median (Q1, Q3) response has lasted 5.6 (2.1, 7.8) months, mean 6 months, max 26 months. Median follow-up time for responding patients is 6.5 (range: 1-27) months. Median duration of response has not been reached, as responses were ongoing in 17/21 patients when last assessed.10

Slide11

11Mean AMG 701 PK Profile Following Target Treatment Dose

Free AMG 701 serum exposures increased in a dose-related manner; the IV PK profile for AMG 701 in its target patient population of relapsed/refractory MM is supportive of once-weekly dosing. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures.As of September 2020.

Slide12

AMG 701 FIH: ConclusionsThis FIH study of AMG 701, an anti‑BCMA HLE BiTE® molecule, in patients with heavily pretreated relapsed/refractory multiple myeloma demonstrated:A manageable safety profile

All Grade 3 CRS events were reversible with a median duration of 2 days; 50% of grade 3 CRS designations were driven by transient LFT increasesEncouraging activity with responses lasting up to 26 months83% ORR at the most recent evaluable cohort in heavily pretreated patients, with 4/5 responders being triple refractory 6/7 patients tested were MRD negative. These 6 patients have ongoing responses, up to 22 months in 1 patientPredictable PK profile with dose-related increases in free AMG 701 exposures and profile supportive of once-weekly dosingThese data support further evaluation of AMG 701.12

Slide13

AMG 701 FIH: Disclosures 13

AuthorCOISimon J HarrisonTakeda: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.Monique MinnemaJanssen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria.Hans C LeeResearch support and consultant/advisor (Amgen, Celgene, Janssen and Takeda), consultant/advisor (Genentech, GlaxoSmithKline and Sanofi), and research support (Daiichi Sankyo).Andrew SpencerConsultant (Celgene, Janssen, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, HaemaLogiX, and Sanofi); speaker’s bureau (Celgene, Janssen, and Takeda); grant/Research Support (Celgene, Janssen, Amgen Inc., Takeda, Servier, HaemaLogiX); honoraria (Celgene, Janssen, Amgen Inc., Takeda, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, HaemaLogiX, and Sanofi).Prashant Kapoor Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.Deepu Madduri Foundation Medicine: Consultancy; Takeda: Consultancy; Celgene, Janssen, BMS, Sanofi, GSK, Kinevant, and Legends Biotech: Consultancy and Advisory Board Jeremy Larsen Janssen: consultancy; Takeda: consultancySikander AilawadhiCelgene: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding.

Jonathan Kaufman

Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; AbbVie: Consultancy; Amgen: Consultancy.

Marc S Raab

Board of Directors/advisory committees: Amgen, Sanofi, Novartis, Celgene, Janssen, BMS, Takeda; Research funding: Sanofi, Heidelberg Pharma, Celgene

Parameswaran Hari

Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.

Slide14

AMG 701 FIH: Disclosures (continued)Study was funded and analyses were conducted by Amgen Inc. Medical writing support was provided by Susanna Mac of Amgen Inc. Kim Pak of study management also supported this publication.The authors wish to thank all patients, caregivers, investigators, and site staff.

14AuthorCOIShinsuke Iida MSD: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.Ravi VijBristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.Faith E DaviesAmgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.Robin Lesley, Vijay V Upreti, Zhao Yang, Anjali SharmaEmployees of and stockholders in Amgen Inc.Alex MinellaWas an employee of Amgen Inc. Patents with and stockholder in Amgen Inc. Employee of and stockholder in Beam Therapeutics Inc.Suzanne LentzschCaelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Clinical Care Options: Speakers Bureau; Proclara: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Sorrento: Other; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Karyopharm: Research Funding; International Myeloma Foundation: Honoraria; Multiple Myeloma Research Foundation: Honoraria; Sanofi: Consultancy, Research Funding.

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