MACROGENICS, INC. Flotetuzumab as Salvage Therapy for Primary Induction
Failure and Early Relapse Acute Myeloid Leukemia
Ibrahim Aldoss, MD; Geoffrey L. Uy, MD; Norbert Vey, MD, PhD; Ashkan Emadi, MD, PhD; Peter H. Sayre, MD, PhD; Roland B. Walter, MD, PhD, MS; Matthew C Foster, MD; Martha L. Arellano, MD; John E. Godwin, MD; Matthew J. Wieduwilt, MD, PhD; Michael Byrne, DO; Laura Michaelis, MD; Patrick J. Stiff, MD; Matteo Giovanni Carrabba, MD; Patrice Chevallier, MD, PhD; Emmanuel Gyan, MD, PhD; Christian Recher MD, PhD;
Anjali S. Advani, MD; Martin Wermke, MD; Harry Erba, MD, PhD; Fabio Ciceri, MD; Gerwin A Huls, MD, PhD; Mojca Jongen-Lavrencic, MD, PhD; Max S. Topp, MD, PhD; Farhad Ravandi, MD; Stefania Paolini, MD; Antonio Curti, MD, PhD; Michael P. Rettig, PhD; John Muth, MS; Teia Curtis, BA; Marybeth Collins, BS; Erin Fehr, BS; Kuo Guo, MSc; Jian Zhao, PhD; Kathy Tran, BS; Patrick Kaminker, PhD; Priyanka Patel, Pharm D.;
Ouiam Bakkacha, MD; Kenneth Jacobs, MD; Maya Kostova, PhD; Jennifer Seiler, PhD, RAC; Bob Löwenberg, MD, PhD; Sergio Rutella, MD, PhD, FRCPath; Ezio Bonvini, MD; Jan K Davidson-Moncada, MD, PhD; John F. DiPersio, MD, PhD
ClinicalTrials.gov #NCT02152956 Abstract # 331
1 | 2020 ASH Annual Meeting | ||
Disclosures
2 | 2020 ASH Annual Meeting | ||
Flotetuzumab (MGD006): CD123 × CD3 Bispecific DART® Molecule
- CD123: low-affinityIL-3 receptor (IL3Rα)
- Normally expressed on plasmacytoid dendritic cells (pDCs), basophils, monocytes and hematopoietic progenitor cells (HPCs)
- Over-expressedon leukemic stem cells (LSCs) in AML and other hematologic malignancies
- Flotetuzumab:
- Investigational bispecific molecule that co-engages T cells (anti-CD3) with a tumor associated antigen (CD123)
- Designed to:
- Redirect T cells to kill tumor cells
- Recognize tumors independent of TCR & MHC
- Phase 1 dose escalation completed1
- Patients currently being enrolled in registrational study
Flotetuzumab
Chain 1 | H2N- | VL1 | VH2 | -COOH | ||||||||||
Cys | ||||||||||||||
Chain 2 | H2N- | VL2 | VH1 | -COOH | ||||||||||
Cys | ||||||||||||||
Anti-CD3Anti-CD123
(1) Uy, et al., Blood 2020
3 | 2020 ASH Annual Meeting | ||
~50% of AML Patients Are Refractory to Induction Therapy or Have Short Remission
Fit for Intensive Chemo (50%)
Goal is complete remission
Induction | "7+3" ± Midostaurin or Gemtuzumab |
(1-2 cycles) | Vyxeos (secondary AML) |
AML
~46,000 new cases (G7 countries1)
Unfit for Intensive Chemo (50%) Goal is to extend survival
HMA ± Venetoclax
Glasdegib+ LDAC
Ivosidenib
Consolidation / Transplant | ||||
No agents | ||||
No CR | CR < 6 | |||
specifically approved | months | |||
for this population | ||||
Primary Induction | Early Relapse | |||
Failure (PIF) | (ER6) |
CR > 6 months
Late Relapsed
(LR)
Salvage Chemo
Clinical TrialsHMA +/- Venetoclax
Targeted Agents (FLT3, IDH1/2)
(1) G7 countries: Canada, France, Germany, Italy, Japan, United Kingdom and United States
4 | 2020 ASH Annual Meeting | ||
Historical CR/CRh Rates in PIF/ER6 Range from 5% to 12%
Median expected overall survival of ~3.5 months
Meta-analysis of PIF/ER6 Pts (n=1328) | Aggregate PIF/ER6 Data | ||||||||||||||||||||||
Extracted From Published Reports1 | from Clinical Trials (n=686) | ||||||||||||||||||||||
CR/CRh is 11.7% [95% CI = 9.2%, 14.6%] | CR/CRh is 5.3% | ||||||||||||||||||||||
Total Population | |||||||||||||||||||||||
n = 686 | |||||||||||||||||||||||
Received "curative" induction therapy? | |||||||||||||||||||||||
No | Yes | ||||||||||||||||||||||
n = 69 | n = 617 | ||||||||||||||||||||||
Achieved CR/CRi/CRh? | |||||||||||||||||||||||
Yes | No | ||||||||||||||||||||||
n = 399 | PIF cohort | ||||||||||||||||||||||
n = 218 | |||||||||||||||||||||||
Relapse ≥ 6 months? | |||||||||||||||||||||||
Unknown | Yes | No | |||||||||||||||||||||
LR cohort | ER6 cohort | ||||||||||||||||||||||
Dropped n = 30 | |||||||||||||||||||||||
n = 212 | n = 157 | ||||||||||||||||||||||
PIF | ER6 | LR | |||||||||||||||||||||
CR/CRh | 4.1% (9) | 7.0% (11) | 11.4% (22) | ||||||||||||||||||||
5.3% (20) | |||||||||||||||||||||||
(1) Unpublished analysis of CLASSIC I, VALOR, ADMIRAL trials and add'l trials that included venetoclax, mylotarg |
5 | 2020 ASH Annual Meeting | ||
TME Immune Infiltration Associated with Cytarabine-Based Induction Failure
Vadakekolathu J, et al. Sci Trans Med 2020
6 | 2020 ASH Annual Meeting | ||
TME Immune Infiltration Associated with Responsiveness to Flotetuzumab
Immune | Immune | |
% (n) | Infiltrated | Depleted |
(n=53) | (n=22) | |
Population: | ||
PIF | 52.8% (28) | 18.2% (4) |
ER6 | 13.2% (7) | 18.2% (4) |
LR | 34.0% (18) | 63.6% (14) |
Response: | 24.5% (13) | |
CR/CRh/CRi | 13.6% (3) | |
Median BM change (%) | -54% | +20% |
Immune-infiltrated
at baseline
Immune-depleted
at baseline
7 | 2020 ASH Annual Meeting | ||
Flotetuzumab in PIF/ER6 AML: Design of Ongoing Registrational Study
Dose Escalation | Expansion Cohort | |||||
n=47 | Relapsed/Refractory AML | Primary Induction Failure | ||||
Recommended Phase 2 | ||||||
& Early Relapse AML | ||||||
Dose (RP2D) n=50 | ||||||
Key Entry Criteria
- Primary Induction Failure (PIF): refractory to cytarabine-based chemotherapy, venetoclax-based combinations or gemtuzumab ozogamicin
- Early relapse (ER6): First relapse with initial CR duration of < 6 months
- Maximum of 3 prior lines of therapy
- No prior allogeneic hematopoietic cell transplant
Study Objectives
- Primary: Complete remission (CR) and/or complete remission with partial hematologic recovery (CRh) rate
- Secondary: mDOR, rate of transfusion independence, time in hospital
8 | 2020 ASH Annual Meeting | ||
Flotetuzumab in PIF/ER6 AML: Demographics
Analysis of all PIF/ER pts (per previous definition) treated at RP2D1
Characteristic | Population (n=44)2 | |
Age, Median (range) | 63.5 (28.0, 81.0) | |
Gender, Female | 13 (29.5) | |
Disease Status at Study Entry | 27 (61.4) | |
Primary Induction Failure | ||
Cytarabine based induction chemotherapy | 20 (74.1) | |
Alternative induction therapy | 7 (25.9) | |
Early Relapse | 17 (38.6) | |
Median duration of CR1 (range) | 3.3 months (0.8-5.7) | |
ELN Risk Stratification (2017) | ||
Adverse | 32 | (72.7%) |
Intermediate | 11 | (25.0%) |
Favorable | 1 | (2.3%) |
Secondary AML | 16 | (36.4%) |
Number of Prior Lines of Therapy, median (range) | 2.0 (1.0, 3.0) | |
Baseline BM Blasts Median (Range)3 | 34.5 (5.0, 84) |
(1) | Recommended Phase 2 Dose = multistep-LID C1W1 followed by 500ng/kg/day continuous infusion through induction | |
(2) | Including ruxolitinib mini-cohort - see Abstract # 2817: "Prophylactic Ruxolitinib for Cytokine Release Syndrome (CRS) in Relapse/Refractory (R/R) AML Patients Treated with Flotetuzumab" | |
(3) | A patient confirmed with AML by IHC not included in baseline BM analysis | Data cut-off Nov 10th, 2020 |
9 | 2020 ASH Annual Meeting | ||
Flotetuzumab in PIF/ER6 AML: Safety
Treatment Related Adverse Events1 | Total RP2D Population (n=44) | |
All n (%) | Grade ≥ 3 n (%) | |
IRR/CRS2 | 44 (100) | 1 (2.3) |
Rash | 17 (38.6) | |
Arthralgia | 11 (25.0) | |
Diarrhoea | 9 (20.5) | 2 (4.5) |
Nausea | 9 (20.5) | |
Pyrexia | 8 (18.2) | |
Decreased appetite | 8 (18.2) | |
Oedema peripheral | 7 (15.9) | |
Febrile neutropenia | 6 (13.6) | 6 (13.6) |
Fatigue | 6 (13.6) | 1 (2.3) |
Alanine aminotransferase increased | 6 (13.6) | 2 (4.5) |
Aspartate aminotransferase increased | 6 (13.6) | 1 (2.3) |
Headache | 5 (11.4) | |
Myalgia | 5 (11.4) |
(1) | Events occurring >10%; Toxicity grading is based on CTCAE criteria version 4.0 | |
(2) | Toxicity grading for events of IRR/CRS (infusion-related reaction and cytokine release syndrome) is based upon modified grading scale proposed by Lee, et al. | Data cut-off Nov 10th, 2020 |
10 | 2020 ASH Annual Meeting | ||
CRS Frequency Decreased with Time on Treatment
- Most CRS events (52%) occurred in first week of treatment during step-up dosing
- Incidence of CRS progressively decreased during dosing, allowing outpatient treatment after day 8
total)of(% | 100 | 500 | Flotetuzumab | |||
75 | 400 | |||||
300 | ||||||
eventsCRS | 50 | (ng/kg/day*) | ||||
200 | ||||||
25 | 100 | |||||
0 | 0 | |||||
1 | 2 | 3 | 4 | 5 |
Time (weeks)
* Planned dose; Data cut-off Nov 10th, 2020
11
Neurologic Events Are of Short Duration and Fully Reversible
- Neurologic AEs have been infrequent, and mostly mild to moderate in severity
- Three pts experienced Grade 3 confusion of short duration (1-2 days) that was fully reversible
Neurological and Psychiatric Adverse Events1 (n=44) | All Adverse Events n (%) | Treatment Related AEs n(%) | |||||
All | Grade ≥ 3 | All | Grade ≥ 3 | ||||
Headache | 13 | (29.5) | 5 (11.4) | ||||
Dizziness | 9 (20.5) | 1 (2.3) | 3 (6.8) | 1 (2.3) | |||
Insomnia | 8 (18.2) | ||||||
Confusional state | 7 (15.9) | 3 (6.8) | 3 (6.8) | 3 (6.8) | |||
Anxiety | 7 (15.9) | 1 (2.3) | |||||
Paraesthesia | 4 | (9.1) | 2 (4.5) | ||||
Tremor | 4 | (9.1) | 2 (4.5) | ||||
Depression | 4 | (9.1) | 1 (2.3) | ||||
Lethargy | 3 | (6.8) | |||||
(1) Events occurring ≥2 individuals; Toxicity grading is based on CTCAE criteria version 4.0 | Data cut-off Nov 10th, 2020 |
12 | 2020 ASH Annual Meeting | ||
Flotetuzumab: Active in Primary Induction Failure & Early Relapsed AML Patients
- 59.1% (26/44) of pts had evidence of reduction in blast count with median decrease of 81.0% in BM blasts
- Median time to first response was 1 cycle (range: 1-3 cycles)
Best BM Change (%)
125 | %(n) | PIF/ER (n=44) | PIF (n=27) | ER6 (n=17) | |||
100 | CR/CRh | 25.0% | (11) | 33.3% (9) | 11.8% (2) | ||
CR/CRh/CRi | 31.8% | (14) | 37.0% (10) | 23.5% (4) | |||
75 | MLFS | 6.8% | (3) | 3.7% (1) | 11.8% (2) | ||
OB/SD | 25.0% | (11) | 25.9% (7) | 23.5% (4) | |||
50 | HSCT | 57.1% (8/14) | 70.0% (7/10) | 25.0% (1/4) | |||
25 | Median BM Reduction (%) | -81 | -83 | -13 | |||
0 | * | * | * | * | * | * | * | * * |
-25 | ||||||||
-50 | ||||||||
-75 | * HSCT | |||||||
-100 | ||||||||
Data cut-off Nov 10th, 2020
13 | 2020 ASH Annual Meeting | ||
Flotetuzumab: Active in TP53MUT PIF/ER6 AML Patients
- 59.1% (26/44) of pts had evidence of reduction in blast count with median decrease of 81.0% in BM blasts
- Median time to first response was 1 cycle (range: 1-3 cycles)
Best BM Change (%)
125
100
75
50
25
0
-25
-50
-75
-100
%(n) | PIF/ER (n=44) | PIF (n=27) | ER6 (n=17) | TP53MUT (n=10) | |||
CR/CRh | 25.0% | (11) | 33.3% (9) | 11.8% (2) | 30.0% (3) | ||
CR/CRh/CRi | 31.8% | (14) | 37.0% | (10) | 23.5% (4) | 50.0% (5) | |
MLFS | 6.8% | (3) | 3.7% | (1) | 11.8% (2) | 10.0% (1) | |
OB/SD | 25.0% | (11) | 25.9% (7) | 23.5% (4) | 20.0% (2) | ||
HSCT | 57.1% (8/14) | 70.0% (7/10) | 25.0% (1/4) | 60.0% (3/5) | |||
Median BM Reduction (%) | -81 | -83 | -13 | -74 | |||
* | * | * | * | * | * | * | * * |
TP53MUT | |||||||
* HSCT |
Data cut-off Nov 10th, 2020
Poster Presentation Abstract ID# 136919: TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response To Flotetuzumab Immunotherapy In Acute Myeloid Leukemia
14 | 2020 ASH Annual Meeting | ||
Duration of Response & Overall Survival in PIF/ER6 AML Responders (CR/CRh/CRi)
Percent Survival
100
50
0
Duration of Response (months)
mDOR 8.13 months
100 | PIF mDOR 15.2 months | ||||||||
Survival | 50 | ER6 mDOR 2.4 months | |||||||
Precent | |||||||||
0 | |||||||||
0 | 12 | 24 | 36 |
Duration of Response (months)
0 | 12 | 24 | 36 |
Percent Survival
100
50
0
0
Overall Survival (months)
mOS 10.7 months
100 | PIF mOS 15.9 months | ||||||||||||||
Survival | 50 | ER6 mOS 5.0 months | |||||||||||||
Percent | |||||||||||||||
0 | |||||||||||||||
0 | 12 | 24 | 36 |
Overall Survival (months)
12 | 24 | 36 |
Data cut-off Nov 10th, 2020
15 | 2020 ASH Annual Meeting | ||
Conclusions
- Flotetuzumab treatment in AML showed manageable safety profile
- Manageable CRS and minimal neurological toxicity
- Single patient with Grade 3 IRR/CRS
- Required minimum 8-day inpatient hospitalization
- Flotetuzumab demonstrated encouraging activity in patients with PIF/ER6 AML, a population with poor prognosis and high unmet medical need
- 31.8% Complete remission rate (CR/CRh/CRi), over half of those went on to successful stem cell transplant
- Historical data indicate CR/CRh rate to salvage therapy of 5-12% for PIF/ER6 AML patients
- Registrational study is currently enrolling PIF/ER6 AML patients [NCT02152956]
16 | 2020 ASH Annual Meeting | ||
Acknowledgements
We are grateful to the patients who participated in this study and their families
Clinical trial teams at the study centers:
Max S. Topp , MD, Universitätsklinikum Würzburg; Martin Wermke, MD,Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden; Norbert Vey, MD, Institut Paoli-Calmettes; Fabio Ciceri, MD, Matteo Carraba, MD, University Vita-Salute San Raffaele; Stefania Paolini, MD, Policlinico Sant'Orsola-Malpighi; Gerwin A. Huls, MD, University Medical Center Groningen; Bob Lowenberg, MD, Mojca Jongen-Lavrenic, MD, Erasmus University Medical Center; Geoffrey L. Uy, MD, Washington University School of Medicine; Harry Erba, MD PhD, Duke University Medical Center; Martha Arellano, MD, Emory University School of Medicine; Matthew C. Foster, MD, UNC Lineberger Comprehensive Cancer Center; John Godwin, MD, Providence Cancer Center; Farhard Ravandi-Kashani, MD, The University of Texas M D Anderson Cancer Center Department of Leukemia; Kendra Sweet, MD, Moffitt Cancer Center; Peter Sayre, MD, University of California, San Francisco; Anjali Advani, MD, Cleveland Clinic; Matthew Wieduwilt, MD, UCSD Moores Cancer Center; Ibrahim Aldoss, MD, City of Hope National Medical Center; Michael T. Byrne, DO, Vanderbilt-Ingram Cancer Center; Ashkan Emadi, MD, University of Maryland; Laura Michaelis, MD, Medical College of Wisconsin; Kristen Petit, MD, University of Michigan; Roland Walter, MD, PhD, Fred Hutchinson Cancer Research Center; Jessica Altman, MD, Northwestern Medicine
NANOSTRING | JVGCRC, NTU | ||
Sarah E. Church | MacroGenics Study Team | ||
Sergio Rutella | |||
Tressa Hood | Carmen Ballesteros-Merino | ||
Sarah E. Warren | Stephen Reeder (GEP) | ||
Carlo B. Bifulco | |||
Jayakumar Vadakekolathu (GEP) | |||
Bernard A. Fox | |||
Please email your questions to ialdoss@coh.org
17 | 2020 ASH Annual Meeting | ||
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MacroGenics Inc. published this content on 06 December 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 07 December 2020 09:14:06 UTC
