A Phase 1 Study of ALX148: CD47 Blockade in Combination with Anti-Cancer Antibodies
to Bridge Innate and Adaptive Immune Responses for Advanced MalignancyNehal Lakhani1, Patricia LoRusso2, Laura Q Chow3, Yung-Jue Bang4, Justin Gainor5, Jeeyun Lee6, Hyun Chung7, Keun-Wook Lee8, Stephen Hodi9,
Philip Fanning10, Yonggang Zhao10, Feng Jin10, Hong Wan10, Jaume Pons10, Sophia Randolph10, Wells Messersmith11
START Midwest, Grand Rapids, MI, USA; 2Yale Cancer Center, New Haven, CT, USA; 3Seattle Cancer Care Alliance, Seattle, WA, USA; 4Seoul National University Hospital, Seoul, South Korea; 5Massachusetts General Hospital Cancer Center, Boston, CA, USA; 6Samsung Medical Center, Seoul, South Korea;
7Yonsei University Hospital, Seoul, South Korea; 8Seoul National University Bundang Hospital, Seongnam, South Korea; 9Dana Farber Cancer Center, Boston, MA, USA; 10ALX Oncology, Burlingame, CA, USA, and Dublin, Ireland; 11University of Colorado Cancer Center, Aurora, CO, USA
1

Background

Study Population• CD47, a marker of self, is upregulated by tumors to evade the immune

Part 2 Combination Key Inclusion Criteria

system. CD47-SIRPα signaling represents a myeloid checkpointmechanism in cancer. CD47 engages SIRPα and signals themacrophage to ignore the cell on which it is expressed.1

standard therapy is available.

• Dose Expansion Patients Cohorts with:• NSCLC (locally advanced or metastatic) which has progressed on priorcheckpoint inhibitor therapy, OR with PD-L1 <50% that has progressedfollowing systemic therapy.
• HNSCC with disease progression after platinum-containing
chemotherapy.
• HER2 overexpressing metastatic gastric/gastroesophageal
junction (GEJ) adenocarcinoma that has progressed following afluoropyrimidine-containing regimen.

• AT148001, a first-in-human phase 1 study, evaluates ALX148

administered as a single agent (Part 1) and in combination withestablished anti-cancer antibodies (Part 2).

ALX148: A Unique High Affinity SIRPα Fusion Protein

Part 2 Combination Key Exclusion CriteriaHigh Affinity CD47
Binding Domains of SIRPα• Picomolar binding affinity.
• Molecular weight is half the size ofbinding to all Fc gamma receptors
minimizing toxicity.

limiting toxicity (DLT) in combination with standard regimens ofpembrolizumab and trastuzumab.
• Additional assessments across the Part 2 dose escalation andexpansion portions include:• Adverse events characterization (NCI CTCAE v. 4.03).
ALX148 Increases
the Ratio ofpharmacokinetic
ALX148 Activates•
ALX148parameters and CD47 target occupancy.
Inflammatory M1 Tumor
Dendritic Cells (DCs)
Associated Macrophages(TAMs) assessedand Enhances• InvestigatortumorCrossresponse (RECIST v 1.1) every 8 weeks.

• Fc domain retains binding tothe neonatal Fc receptor for
Inactive extension.
pharmacokinetic half-life
Fc Domain

12

ALX148 Blocks CD47
“Don’t Eat Me” Signal andEnhances Macrophage
Phagocytosis

to Suppressive M2 TAMs

123

ALX148 Increases the Ratio ofInflammatory M1 Tumor
Associated Macrophages (TAMs)
to Suppressive M2 TAMs

Priming of T Cells• The data cut offCD8+
date for this analysis is 12Oct2018.
T Cell

ALX148 Bridges Innate and Adaptive
Immunity
Macrophage
ALX148 Blocks CD47
“Don’t Eat Me” Signal andEnhances Macrophage
Phagocytosis

3IFNγCD47

Results
CD68

TNFαCD47

ALX148 Activates
DendriticCells (DCs)
CD47
and Enhances CrossCD163
Priming of T Cells

iNOS

CytotoxicGranules

CD28

CD8TCR

TNFαCD86

4 (10)AST Increased

3 (8)Anaemia

2 (5)Fatigue

2 (5)Infusion reaction

2 (5)Myalgia2 (5)Pruritus

2 (5)Alkaline Phosphatase Incr

2 (5)

Rash

2 (5)
Total n(%)
3 (16)

Fatigue• Primary Endpoint: Part 2 dose escalation first cycle ALX148 dose

Inactive
Fc Domain

ALT Increased

Adverse Event

Endpoints and Assessments• Fc domain is modified to eliminate

Total n(%)

Table 5 Treatment Related Adverse Events ≥ Grade 3 in Any Patient
ALX148+Pembrolizumab (N=39)
GradeAdverse Event

34Total

AIHA/Pancytopenia–1*

1

ALT Increased

1–1Anaemia

1#–

1Febrile Neutropenia

1#–1Platelet Count Decr

-1#

1

Hyponatremia

1–

1

Lymphocyte Count Decr

1–1

ALX148+Trastuzumab (N=18)

MHC I

PatientM1Baseline
Characteristics
TAM
CD47

CD47

Macrophage

CD68

TNFα
CD47
CD47

IFNγ1
Arginase

CD8+ T Cell

M2 TAM

CD28

CD8
TCRiNOSM1 TAM

Arginase 1

SIRPα

CD47

ALX148Fc Receptor

Dendritic
Cell

M2 TAM

M1M2

ALX148Fc Receptor

Table 2. AT148001: Patient Baseline Characteristics

MHC II

CCR7

Part 2Tumor Antigen

Anticancer Antibody
Canc
CancerCell
Cell
ImpairedDendritic

Activated Dendritic Cell

No Cross-Priming

Cross-Priming
Median Age, Years(range)

Kauder, SE. et al. PLoS ONE. 2018 August;13(8): e0201832

Activated Dendritic Cell

TCR
No Cross-Priming
Cross-Priming• Primary Study Objective: Characterize ALX148 safety profile asa single(Part 1: Lakhani N et al, #3068,
2018) and in
CD8+ ASCO
T CellCD8+ Tagent
Cellcombination with established anti-cancer antibodies (Part 2). Cytotoxic
Cancer Cells
Granules• Here we report preliminary Part 2 results from the fully enrolled
CD28

CD8TCRCD86
ALX148 TCR
plus pembrolizumab or trastuzumab doseescalation
cohorts
MHC Iand ongoing expansion cohorts as of Oct 12, 2018.

Dendritic Cell
Cancer Cells

Cancer Cells

CD47

SIRPα
MHC IICCR7Serum Concentration (µg/mL)

StudyDendritic
DesignCell

1 mg/kg

Dendritic Cell

3 mg/kg• Part 1 (Single Agent): Patients with advanced malignancy were100

administered escalatingdoses
of intravenous
ALX148.
CD47
ALX148TumorAntigen
SIRPα1024487296

Hour

Part 1: Single Agent ALX148

120

144

Dose (mg/kg)

Schedule

10.3

Once a week

224487296

Hour

120

1.033.0

4

10.0

530.0

144

168

192

Once a week

1000.3 mg/kg

1 mg/kg*

80

0.3 mg/kg

Once a week

120TO (RBC)0

1 mg/kg*

120

100

100

10 mg/kg

71421

NSCLC (pembrolizumab);
60
Progressed on Prior CPI/ PD-L1 < 50%

60
40

Dose Expansion
028

Days

35

4000

7

14212835424907142128

Days Gastric/GEJ (trastuzumab);Days
Progressed on Prior Fluoropyrimidine Therapy35–1

Neutrophil Count Decr

1^

–1WBC Count Decr

1^

–1#^All part of the same event in one patient; *Dose Limiting Toxicity• NSCLC ALX148 + pembrolizumab: 13 evaluable pts with NSCLC(progressed on prior CPI and/or PD-L1 <50%) as of data cutoff. Patients
experienced a best response of 1PR, 5SD (one SD >24weeks) with
5 patients continuing on treatment.

• HNSCC ALX148 + pembrolizumab: 4 evaluable patients with HNSCC(progressed on prior platinum therapy) as of data cutoff. Patients
experienced a best response of 2SD (one with ↓16% in measurabledisease) and continue on treatment.

• Her2+ Gastric/GEJ ALX148 + trastuzumab: 3 evaluable patients withGastric/GEJ (progressed on prior fluoropyrimidine-containing regimen)
as of data cutoff. One patient experienced a best response of SD(↓27% followed by ↓48% + new CNS lesion) and continues on trial.

75% of evaluable continuing patients had only 1 response assessment
at data cutoff.

Partial Response Achieved in a NivolumabRefractory NSCLC Patient Administered ALX148 +Pembrolizumab
Baseline

3 mg/kg

10 mg/kg

ALX148 10 mg/kg+Pembrolizumab
n=394211312442494249• 48 yo pt with Her2+ GEJ cancer- adenocarcinoma ALX148 +trastuzumab• Prior therapy-FOLFOX/trastuzumab; pembrolizumab refractory• Day 59 stable disease ↓27%;• Day 108 ↓48%; new central nervous system lesion• The patient continues on treatment

Pharmacokinetics andPharmacodynamics• ALX148 exhibited clinical PK properties typical of antibody
therapeutics directed towards cell-surface targets.

• ALX148 PK approached linear range and maintained complete
peripheral CD47 target occupancy over the dosing intervalat ≥3 mg/kg QW.

• ALX148 (10 mg/kg QW) steady-state half-life is predicted to beResponseDay 45~16 days and ALX148 initial PK/PD profiles are not impacted bycombination drugs.

• Translational PK/PD modeling suggests tissue/tumor TO over 70%
is maintained over the dosing interval at ≥3 mg/kg QW.

Please see SITC 2018 #P340

AT148001: Conclusions
Intended for combination, ALX148 is designed to avoid the doselimiting toxicities associated with other CD47-targeted approaches inthe clinic, while maximizing the efficacy of antibody-based therapies.

• No MTD was reached with ALX148 in combination. The maximum

administered dose of ALX148 is 10 mg/kg QW in combination withstandard regimens of pembrolizumab and trastuzumab.

• ALX148 contains an inactive Fc region that eliminates dose-dependent
hematologic toxicity.

• ALX148 has antibody-like PK and maintains complete peripheral
TO over the dosing interval at ≥3 mg/kg QW (#P340)• ALX148 demonstrates preliminary anti-cancer activity in combination
with pembrolizumab and trastuzumab in patients resistant andrefractory to prior checkpoint inhibitors or trastuzumab.

Enrollment into combination expansion cohorts is ongoing (NCT03013218).
ALX148 10 mg/kg+Trastuzumab
n=182810References

1. Weiskopf, K. Eur J Cancer. 2017 May;76:100-109
2. Kauder, SE. et al. PLoS ONE. 2018 August;13(8): e020183

Acknowledgments
We would like to thank all of the participating patients and their families
as well as site research staff.
Contact email: info@alxoncology.com

40

20

HNSCC (pembrolizumab);
20
Progressed on Prior Platinum Therapy

201• ALX148 in combination with pembrolizumab or trastuzumab was well200Thrombocytopenia

AT148001: Safety

40

Advanced Solid Tumors(Each 0Combo)
80
TO (CD4+)

TO (RBC)

DoseEscalation80

Totalprogression(Table 3).
100• At data
cutoff, 34 pts remained on study, and 1 pt had discontinued
80
due 60to a treatment related AE (Table 2).

Part 2: ALX148 (10 mg/kg QW) Combination Solid Tumor Cohorts
120

4120

Once every 2 weeks

60

57 (45-71)
7
11
101
–
61
7
11––
112–
2
11––
13

• The most common reason for discontinuation was disease

Once a week3 mg/kg

192

Dose Interruptions Due to TRAEs, n
Dose Reductions, nDiscontinuation Due to TRAE, nDiscontinuation Due to PD, nGlobal Deterioration of Health Status, nOngoing Treatment, n1Cohort

168

TO (CD4+)

Serum Concentration (µg/mL)

059 (32-79)
20
1724
3
181
1126
24
9––
2–2–
11–

Adverse EventPart 2

0.1

Table 1. Study Design

Trastuzumab
n=18

GradeTable 3. Patient Drug Exposure and Disposition

administered 1ALX148
10mg/kg QW
in a 3 week cycle with standardmg/kg
3 mg/kg
10 mg/kg
regimens of pembrolizumab (200 mg IV Q3W)1 or trastuzumab
100(8 mg/kg IV→6 mg/kg Q3W).
10Pembrolizumabn=39** Partial demography for 2 pembrolizumab patients in database.

• Part 2 (Combination): Patients with advanced solid tumors were

0.1

FMCD8+ T Cell
Cytotoxic
WhiteGranules
BlackCD28
CD8TCR
Race, nNativeAmerican
CD86
Asian
MHC
I
Other0Cancer Cells
ECOG PS, n1
NSCLC
MHC II
CCR7HNSCC
Gastric/GEJ
Dendritic
BreastCell
Colorectal
Primary
ALX148TumorAntigen
Esophageal
Disease, nOvarian
Pancreatic
10 mg/kg
Peritoneal
AppendicealUrothelial
Sex, nCD8+ T Cell

ImpairedDendritic
CellPrimary
ObjectiveMethods

MHC IIwith the majority (67%) having an ECOG PS score of 1.
•TumorPatients were heavily pretreated with a median of 3 (1-8) prior
Antigen
Anticancer Antibody
Canc
Cancer Cell
treatment
regimens.

TNFα

CD86

CCR7

M2

MHC I

CD163

SIRPα

• 57 solid tumor patients have beenenrolled into Part 2 (Table 2).
Dendritic
Cell• Patients M1were well balanced between
male (51%) and female (49%)

CytotoxicGranules

Day 108

ALX148+Trastuzumab (N=18)• Prior treatment with any anti-CD47 or anti-SIRPα agent.

a typical antibody allowing highermolar
concentrations
to be delivered
High Affinity
CD47Binding
Domains of SIRPα
to tumor.

Adverse Event

Significant Tumor Reduction in a Patient with
Gastroesophageal Junction (GEJ) Cancer
Administered ALX148 + Trastuzumab
Baseline

ALX148 + Pembrolizumab (N=39)• Advanced malignancy resistant to standard therapy or for which noCD47 binding domain of SIRPα genetically linked to an inactive
Fc region of human immunoglobulin (Figure 1) that enhances theactivity of anti-cancer targeted antibodies and checkpoint inhibitors
through Fc dependent and independent mechanisms.2

to block its interaction with SIRPα.

Table 4 Treatment Related Adverse Events in ≥2 Patients• Adequate organ function and hemoglobin ≥9g/dL.
• Dose Escalation Patient Cohorts with:• ALX148 is a fusion protein comprised of an engineered high affinity• Potently and selectively binds CD47

AT148001 Safety: (Part 2, ALX148 + Pembrolizumab
or Trastuzumab)0
tolerated,andmosttreatment
relatedadverse events were of low07142128354249grade and frequency.
Days• The most common treatment related adverse events across these
combinations were Fatigue (9%) and ALT increased (7%). Treatment
related adverse events ≥Grade 3 severity occurred as sole events(Tables 4 and 5).
• One dose limiting toxicity (Autoimmune hemolytic anemia in a pt withovarian ca.; ALX148 + pembrolizumab) was previously reported(ASCO 2018, #3068).
• There was 1G5 event (Disease progression in a pt with GEJ;
ALX148 + trastuzumab).

• 64 yo pt with NSCLC-adenocarcinoma (TPS 10%,CMET/TP53)
ALX148 + pembrolizumab• 6 prior therapies; nivolumab refractory; CMET inhibitor refractory• Day 45 partial response (↓48%), disappearance of chest wall lesion• Day 100 confirmed PR (↓51%)• The patient continues on treatment