steven m. horwitz, jamesm.foran, michaelmaris, ahmed sawas
TRANSCRIPT
1
Steven M. Horwitz, James M. Foran, Michael Maris, Ahmed Sawas, Craig Okada, Tatyana A. Feldman, Mark D. Minden, Lubomir Sokol, Matthew Mei, Ian W. Flinn, Diego Villa, Mary‐Elizabeth M. Percival, Deepa Jagadeesh,
Kerry J. Savage, Oleg E. Akilov, Catherine Diefenbach, Youn H. Kim, Gloria H.Y. Lin, Tina Catalano, Penka S. Petrova, Bob Uger, Naomi Molloy, Kathleen Large, Yaping Shou, Stephen M. Ansell
2
• Many hematologic and solid tumors express high levels of CD47
• High CD47 expression correlated with aggressive disease & poor outcomes
• CD47 delivers an inhibitory “don’t eat me” signal to macrophages through SIRPα
CD47 blockade emerging as a next‐generation checkpoint inhibitor strategy in immuno‐oncology
CD47 Pathway in Cancer
Don’t eat mesignal
DON’T EAT ME
3
• CD47 blockade alone is not sufficient to trigger macrophage anti‐tumor activity
• Macrophages must also receive an “eat” (pro‐phagocytic) signal
• IgG1 Fc delivers a strong “eat” signal, IgG4 Fc a moderate signal
4
Blocks the CD47 DON’T EAT ME signal
Delivers an EATsignal through FcγRs
MacrophagePhagocytosis
Antigen Presentation & Adaptive Immunity
TTI‐621 Mechanism of Action TTI‐621
5
Petrova et al. Clin. Cancer Res. 2017
Unlike anti‐CD47 antibodies, TTI‐621 binds minimally to human RBCs.
Binding of TTI‐621 or anti‐CD47 mAbs to fresh human RBCs at saturating concentrations is shown. Data were analyzed by flow cytometry and the graph represents mean fluorescence intensity for 43 human donors.
Binding of TTI‐621 or CD47 mAbs to RBC
6
0.05, 0.1, 0.2, 0.3 0.2 up to 0.5 (mono)*0.1 up to 0.5 (combo)* 0.2 ramp‐up to 0.5 0.5, 0.7, 1.0, 1.4, 2.0
LymphomaHeme Malignancies(Lymphoma, Leukemia, Multiple Myeloma)
CTCL, PTCL CTCL
CD20+ NHL (+rituximab)cHL (+nivolumab)
Completed (N=18)Identified initial MTD (0.2 mg/kg)
Completed (N=154)Signal seeking across a range of indications
Completed (N=42)** Further efficacy evaluation
in TCLs
Ongoing (N=17)Re‐assess MTD under amended protocol
Dosing (mg/kg)
Monotherapy Indications
Combination Indications
Part 1:Dose Escalation
Part 2: Initial Expansion
Part 3: Focused Expansion
Part 4: Dose Optimization
Indication Expansion at Low doses(Most patients dosed at 0.2 mg/kg; some dose‐intensified up to 0.5 mg/kg per investigator discretion* or by a fixed ramp‐up schedule**)
Status (N)
Completed
Under revised DLT criteria(Grade 4 Thrombocytopenia lasting 72+ hours or ≤10K)
Under initial DLT criteria(Grade 4 Thrombocytopenia of
any duration)
Ongoing
7
Completed
Ongoing
0.5 mg/kgn=3
0.7 mg/kgn=3
1.0 mg/kgn=6
1.4 mg/kgn=3
• Relapsed & refractory CTCL patients
• 3+3 escalation schema
• Stable dose in each cohort (i.e. no priming)
• Weekly infusions
• Treat to progression
Cohorts
2.0 mg/kgn=3
• A total of 17 patients with CTCL were dosed across 5 dose levels (0.5‐2.0 mg/kg) and completed DLT evaluation by November 3rd, 2020
• The 2.0 mg/kg cohort is ongoing; 3rd patient dosed and was being evaluated for DLT (data not included in the summary analysis)
• Two DLTs were observed• 1 Grade 3 infusion related reaction (IRR) at 1.0 mg/kg
• Occurred at the 1st infusion
• Managed by extending infusion from 1.5 to 3 hrs for the initial infusion; no Gr3 IRRs in the 3 patients subsequently enrolled at 1.0mg/kg
• 1 Grade 4 thrombocytopenia with a platelet nadir of 10K/dL at 2.0 mg/kg
• No worsening thrombocytopenia up to 1.4 mg/kg• No Gr4 thrombocytopenia up to 1.4 mg/kg (7‐fold of
initial MTD 0.2 mg/kg)
8
• A total of 231 patients with hematologic malignancies were evaluated (data cut‐off November 3rd, 2020)
• The most common tumor types were CTCL (n=67), including MF (n=44) and SS (n=23), DLBCL (n=37), PTCL (n=33) and HL (n=31)
• The median age was 63 (range, 21–87); 139 males and 92 females were included
• Disease stage was predominantly Stage III or IV (n=128)
• Patients had received a median of 4 prior systemic therapies (range 1‐26)
*Includes Other B‐cell Lymphomas (n=5; 2%), Chronic Lymphocytic Leukemia (n=3; 1%), Myeloid Proliferative Neoplasms (n=3; 1%)^Includes Large Cell Transformation of MF (n=4; P1‐3 n=2; P4 n=2) and Folliculotropic MF (n=1; P4 n=1)ⴕ Includes 40 non lymphoma patientsBased on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
Baseline Characteristics Parts 1‐3 Part 4 Totaln=214 n=17 n=231
Median Age, years (min‐max) 63 (21‐87) 67 (34‐83) 63 (21‐87)Male, n (%) 128 (60) 11 (65) 139 (60)ECOG PS 0‐1, n (%) 197 (92) 17 (100) 214 (93)Primary Diagnoses, n (%)Cutaneous T Cell Lymphoma 50 (23) 17 (100) 67 (29)Mycosis Fungoides 32 (15) 12 (71) 44 (19)Sézary Syndrome 18 (8) 5 (29) 23 (10)Diffuse Large B Cell Lymphoma 37 (17) 37 (16)Peripheral T Cell Lymphoma 33 (15) 33 (14)Hodgkin Lymphoma 31 (14) 31 (13)Acute Myeloid Leukemia 20 (9) 20 (9)Follicular Lymphoma 13 (6) 13 (6)Multiple Myeloma 8 (4) 8 (3)Myelodysplastic Syndrome 6 (3) 6 (3)Mantle Cell Lymphoma 5 (2) 5 (2)Lymphoma Stage at Study Entry, n (%)I or II 34 (16) 8 (47) 42 (18)III or IV 119 (56) 9 (53) 128 (55)Not Specified 61 (29) 61 (26)
Prior Systemic Treatments, median (min‐max) 4 (1‐26) 3 (1‐12) 4 (1‐26)
*
^
ⴕ
9
The most frequent treatment related adverse events of any grade included IRRs in 102 (44%) and thrombocytopenia in 69 (30%) patients
• IRRs reached Gr≥3 intensity in 8 (3%) patients; o Majority IRRs occurred at first infusiono Higher incidence of Gr≥3 IRR in Part 4;
related to higher dose levels receivedo Managed by extending infusion time and
pre‐medication with corticosteroids at initialinfusions only
• Thrombocytopenia of Gr≥3 intensity occurred in 51 (22%) patients overallo Similarly, 4 (24%) patients in Part 4 had
experienced Gr≥3 thrombocytopenia to date
Related AdverseEvents n(%)
TotalN=231
Grade 1-2 3-4 1-2 3-4IRR 86 (40) 6 (3) 8 (47) 2 (12) 102 (44)Thrombocytopenia 17 (8) 47 (22) 1 (6) 4 (24) 69 (30)Chills 46 (21) 2 (12) 48 (21)Fatigue 31 (14) 2 (1) 1 (6) 34 (15)Anaemia 10 (5) 20 (9) 30 (13)Pyrexia 25 (12) 1 (6) 26 (11)Nausea 22 (10) 2 (12) 24 (10)Diarrhoea 19 (9) 1 (0.5) 2 (12) 22 (10)Neutropenia 4 (2) 15 (7) 1 (6) 20 (9)Headache 15 (7) 2 (12) 17 (7)Vomiting 14 (7) 1 (0.5) 1 (6) 16 (7)Hypotension 9 (4) 1 (0.5) 10 (4)
IRR = Infusion Related Reaction 8 (4) 8 (3)Myalgia 8 (4) 8 (3)Leukopenia 1 (0) 7 (3) 8 (3)
Parts 1-3n=214
Part 4n=17
10 20 30 40 50 60
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
P1-3P4
Patients (%)
P1‐3 Gr1‐2 P1‐3 Gr 3‐4P4 Gr 1‐2 P4 Gr 3‐4
P1‐3 ‐ Parts 1‐3; P4 ‐ Part 4Based on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
10
Week 1 Median Plts and HGB Levels:
Parts 1‐3 vs Part 4
Pre‐dose Plts and HGB Levels Weeks 1‐12 in
all patients
Plts ‐ Platelets; HGB ‐ HemoglobinBased on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
11
Indication TherapyResponse
evaluable N CR PR ORR
CTCL TTI‐621 monoTx 53 1 (2%) 8 (15%) 9 (17%)
PTCL TTI‐621 monoTx 22 2 (9%) 2 (9%) 4 (18%)
DLBCL TTI‐621 monoTx 7 0 (0%) 2 (29%) 2 (29%)Based on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
12
Tumor(n)
Response Evaluable n (%) Tmt Duration in
Responders (days)med (min‐max)
Time to Response (days)med (min‐max)CR PR ORR
PTCL (22) 2 (9) 2 (9) 4 (18) 379 (127‐575) 50 (20‐79)
0.2mg/kg
0.3 ‐ 0.4mg/kg
0.5mg/kg
‐100
‐75
‐50
‐25
0
25
50
75
100
Lesio
n Ch
ange (%
)
Based on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
PTCL‐NOSPTCL‐NOS
PTCL‐NOS
AITL
*
*
*
*
Ongoing
90 180 270 360 450 540
Study Days
CR PR SD PD
*Response StartPTCL‐NOS ‐ PTCL not otherwise specified; AITL ‐ Angioimmunoblastic T Cell Lymphoma
13
Tumor (n)
Response Evaluable n (%) Tmt Duration in Responders (days)med (min‐max)
Time to Response(days)
med (min‐max)CR PR ORR
MF (34) 0 7 (21) 7 (21) 162 (41‐1015) 57 (23‐218)
SS (19) 1 (5) 1 (5) 2 (11) 617 (185‐1049) 206 (108‐303)
All (53) 1 (2) 8 (15) 9 (17) 183 (41‐1049) 106 (23‐303)
mSWAT scores not obtained in 5 patients due to clinical PD in 2 MF patients, response assessed by Lugano criteria in 1 MF patient, and no skin involvement in 2 SS patients. Note: 2 patients in the 2.0 mg/kg cohort have their response assessment pending.
Based on the data in clinical database as of 3 Nov 2020; data are subject to change prior to final database lock
0.2mg/kg
0.3 ‐ 0.4mg/kg
0.5mg/kg
0.7 ‐ 1.4mg/kg
**
‐100
‐75
‐50
‐25
0
25
50
75
100
mSW
AT Cha
nge (%
)
Mycosis Fungoides n=31 Sezary Syndrome n=17
* Bridged totransplant
*
*
*
***
*
*
*
90 180 270 360
MFn=34
SSn=19
Study Days
CR PR SD PD
* Response Start
//
Ongoing
OngoingOngoing
450 630 810 990 1170
14
• Dose‐dependent increases in serum trough levels observed
• Steady‐state serum TTI‐621 exposures achieved by approximately week 6+
• End of infusion (EOI) CD47 RO between 40‐65%
• RO does not appear to increase in a dose‐dependent manner between 0.5 and 1.4 mg/kg, possibly due to narrow dose range, high variability and prolonged infusion times in some 1.0 and 1.4 mg/kg patients
Mean Trough Concentrations Week 1 RO Week 6 RO
Mean ± SDULOQ – Upper Limit of Quantification
15
PanCK+ CD4+ CD8+
*
* non-specific staining due to tissue folding, signal not included in the analysis
Cell densities in combined regions of interest (whole tissue) Skin biopsies – representative images
Pre-treatment Week 8 Week 16
Mycosis Fungoides patient @ 1.0 mg/kg dose level: partial response, bridged to transplant
• Increased infiltration of macrophages, NK cells and CD8+ T cells over time
• Results consistent with activation of both innate and adaptive immunity
16
• TTI‐621 administered weekly IV was well tolerated at doses up to 1.4 mg/kg.
• Thrombocytopenia was transient and not dose‐limiting up to a dose level 7‐fold higher than the initial MTD of 0.2 mg/kg.
• Monotherapy activity (17‐29% ORR) had been observed in multiple subtypes of lymphomas including PTCL and CTCL. Dose response is being assessed which may be limited by small sample size.
• Preliminary data indicated dose‐dependent increases in PK exposure in the dose range evaluated; end of infusion RO of 40‐65% at doses between 0.5‐1.4 mg/kg.
• Modulation of immune cells including both innate and adaptive immune cells was seen in a responding CTCL patient.
• Dose optimization is ongoing; currently enrolling at the 2.0 mg/kg dose level in Part 4.
The authors would like to thank: • The patients who participated in this study and their families• Members of the sponsor and CRO study team• The following investigational study site staff members who contributed to the conduct of the study
17
• Memorial Sloan Kettering Cancer Center • Princess Margaret Cancer Centre • University of Washington
• Mayo Clinic, Jacksonville FL • Moffitt Cancer Center • Cleveland Clinic Taussig Cancer Institute
• Colorado Blood Cancer Institute • City of Hope Medical Center • University of Pittsburgh Medical Center
• Sarah Cannon Research Institute, Denver • Sarah Cannon Research Institute, Nashville • NYU, Perlmutter Cancer Center
• Columbia University Medical Center • Tennessee Oncology • Stanford School of Medicine
• Oregon Health and Science University • British Columbia Cancer Agency • Mayo Clinic, Rochester MN
• Hackensack University Medical Center • Fred Hutchinson Cancer Research Center
Please direct correspondence to [email protected]