MacroGenics : Phase 1 Dose Escalation Study of MGC018, an anti-B7-H3 ADC In Patients with Advanced Solid Tumors

Abstract #2631

NCT03729596

Phase 1 Dose Escalation Study of MGC018, an anti-B7-H3Antibody-Drug Conjugate (ADC),

In Patients with Advanced Solid Tumors

Sekwon Jang1, John Powderly2, Alexander Spira3, Iwona Lugowska4, Girish Mallesera5, Andrew Weickhardt6, Piotr Wysocki7, Jakub Zolniereck8, Ouiam Bakkacha9, Deryk Loo9, Chet Bohac9, Jeanny Aragon-Ching1, Eugene Shenderov10, Emmanuel Antonarakis10, Manish Sharma11

1Inova Schar Cancer Institute, Fairfax, VA; 2Carolina BioOncology, Huntersville, NC; 3Virginia Cancer Specialists, Fairfax, VA; 4Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy, Warsaw, Poland; 5Calvary Mater Newcastle, Waratah, Australia; 6Austin Health-Olivia Newton John Cancer Center, Heidelberg, Australia;
7Samodzielny Publiczny Zakład Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie, Krakow, Poland; 8Magodent Sp. z o.o. Szpital Elbląska Oddział Onkologii Klinicznej/ Chemioterapii, Warsaw, Poland; 9MacroGenics, Inc., Rockville, MD; 10The Johns Hopkins Kimmel Cancer Center, Baltimore, MD; 11START Midwest, Grand Rapids, MI	[e-mail]

Background		Dose Escalation Results

MGC018: B7-H3 Directed ADC with Duocarmycin-based Linker Payload

vc-seco-DUBA						O
						HN		OH	MGC018
					CL	N		OH
						N			HN O
	Cleavable Peptide O	N O		Proteolytic Cleavage
	O O			N
		OH	and Release of Toxin
O	O	N	O	O N	N	O	N	N
NO	O N	H	N	I				O		Duocarmycin	Humanized
s O	H	O	H	Self-elimination Module	O		Payload	IgG1
		NH
						DUBA
		H2N	O

B7-H3 mAb

Drug-antibody ratio ~2.7

MGC018

• MGC018 is an anti-B7-H3antibody-drug conjugate (ADC) with a duocarmycin payload
• vc-seco-DUocarmycin-hydroxyBenzamideAzaindole (DUBA) is a DNA alkylating agent
• DUBA cytotoxic activity is cell-cycle independent
• DUBA retains potency in multidrug-resistant cell lines
• Cleavable peptide linker - facilitates bystander effect
• Induces immunogenic cell death in preclinical models

DUBA Linker Payload provided and conjugated by Byondis.

Rationale for Targeting B7-H3 with MGC018

• B7-H3is highly expressed in multiple solid tumors, with limited expression in normal tissue
• B7-H3may play immune suppressive and tumor-autonomous roles that favor cancer growth
• B7-H3is expressed by vascular endothelium and stroma in tumor microenvironment
• MGC018 is a novel ADC that delivers a potent duocarmycin-based DNA alkylating payload via native cysteines
• Duocarmycin DNA-targeted activity is directed to both dividing and non-dividing cells

Study Design and Objectives

• 3+3+3 Dose escalation design
• Six planned dose escalation cohorts: 0.5 to 5.0 mg/kg IV every three weeks
• Tumor response by investigator per RECIST v1.1 and PSA every 6 weeks (Dose Escalation)
• Tumor response by investigator every 9 weeks and PSA every 3 weeks (Cohort Expansion)
• Cohort Expansion at recommended Phase 2 dose (RP2D) to assess safety and tumor response (metastatic castration resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), triple-negative breast cancer (TNBC), melanoma)

Primary Objective

• Safety and maximum tolerated dose (or maximum administered dose)

Secondary Objectives

• Pharmacokinetics and immunogenicity
• Antitumor activity

Key Eligibility Criteria

Inclusion

■ Patients with histologically proven, relapsed or refractory, unresectable locally advanced or

metastatic solid tumors of any histology for whom no therapy with demonstrated clinical benefit is

available (Dose Escalation)

Enrollment Status

Dose Escalation Complete (N=29)

• Maximum administered dose 4 mg/kg every 3 weeks
• RP2D defined as 3 mg/kg every 3 weeks

Cohort Expansion in mCRPC: Enrollment Ongoing

• 28 enrolled (of 40)
• Disease classification available for 20 of 28 patients: Bone only (7), mixed soft tissue + bone (9), soft tissue only (4)

B7-H3 IHC Data

• 21 of 24 Patients with available tissue had samples evaluable for B7-H3 expression
• H-score:Median 190 (range 17-279); mean 175.7
• Vasculature score: Median 2+ (range 0-3+)

Data cutoff 03 May 2021.

Related Adverse Events ≥ 20%, All Grades

Fatigue, nausea, infusion related reaction, skin disorders, and neutropenia were most common

	0.5 mg/kg	1.0 mg/kg	2.0 mg/kg	3.0 mg/kg	4.0 mg/kg	All
System Organ Class Preferred Term	(N=3)	(N=6)	(N=7)	(N=7)	(N=6)	(N=29)
AT LEAST ONE EVENT	3 (100%)	5 (83.3%)	6 (85.7%)	7 (100%)	6 (100%)	27 (93.1%)
Blood and lymphatic system disorders	0	1 (16.7)	2 (28.6)	3 (42.9)	2 (33.3)	8 (27.6)
Neutropenia	0	1 (16.7)	2 (28.6)	3 (42.9)	2 (33.3)	8 (27.6)
Gastrointestinal disorders	0	5 (83.3)	2 (28.6)	2 (28.6)	3 (50.0)	12 (41.4)
Nausea	0	2 (33.3)	2 (28.6)	1 (14.3)	3 (50.0)	8 (27.6)
General disorders and administration site conditions	2 (66.7)	2 (33.3)	2 (28.6)	4 (57.1)	5 (83.3)	15 (51.7)
Fatigue	1 (33.3)	1 (16.7)	2 (28.6)	4 (57.1)	3 (50.0)	11 (37.9)
Chills	1 (33.3)	0	2 (28.6)	0	4 (66.7)	7 (24.1)
Pyrexia	1 (33.3)	1 (16.7)	2 (28.6)	0	2 (33.3)	6 (20.7)
Injury, poisoning and procedural complications	0	0	2 (28.6)	5 (71.4)	2 (33.3)	9 (31.0)
Infusion-related reaction	0	0	2 (28.6)	5 (71.4)	2 (33.3)	9 (31.0)
Skin and subcutaneous tissue disorders	0	3 (50.0)	5 (71.4)	5 (71.4)	4 (66.7)	17 (58.6)
Skin hyperpigmentation	0	3 (50.0)	1 (14.3)	3 (42.9)	2 (33.3)	9 (31.0)
Palmar-plantar erythrodysaesthesia syndrome	0	0	3 (42.9)	3 (42.9)	2 (33.3)	8 (27.6)

Includes events with causality ratings of 'Possible', 'Probable' or 'Definite'. Subjects are counted once for each Preferred Term reported. Data were extracted on 03May2021.

Grade ≥ 3 Related Adverse Events

Cytopenias were most common

	0.5 mg/kg	1.0 mg/kg	2.0 mg/kg	3.0 mg/kg	4.0 mg/kg		All
System Organ Class Preferred Term	(N=3)	(N=6)	(N=7)	(N=7)	(N=6)	(N=29)
AT LEAST ONE EVENT	2 (66.7%)	2 (33.3%)	6 (85.7%)	4 (57.1%)	5 (83.3%)	19 (65.5%)
Blood and lymphatic system disorders	0	0	2 (28.6)	2 (28.6)	2 (33.3)	6 (20.7)
Neutropenia	0	0	2 (28.6)	2 (28.6)	2 (33.3)	6 (20.7)
Lymphopenia	0	0	1 (14.3)	1 (14.3)	1 (16.7)	3 (10.3)
General disorders and administration site conditions	0	0	0	0	2 (33.3)	2	(6.9)
Fatigue	0	0	0	0	2 (33.3)	2	(6.9)
Investigations	1 (33.3)	2 (33.3)	3 (57.1)	2 (28.6)	2 (33.3)	10	(34.5)
Lymphocyte count decreased	0	1 (16.7)	2 (28.6)	1 (14.3)	0	4 (13.8)
Neutrophil count decreased	0	1 (16.7)	1 (14.3)	0	0	2	(6.9)
Platelet count decreased	0	0	1 (14.3)	1 (14.3)	0	2	(6.9)
Lipase increased	1 (33.3)	0	0	0	1 (16.7)	2	(6.9)
White blood cell count decreased	0	1 (16.7)	0	0	1 (16.7)	2	(6.9)
Metabolism and nutrition disorders	0	0	2 (28.6)	0	0	2	(6.9)
Hypophosphataemia	0	0	2 (28.6)	0	0	2	(6.9)
Skin and subcutaneous tissue disorders	0	0	3 (42.9)	1 (14.3)	0	4 (13.8)
Palmar-plantar erythrodysaesthesia syndrome	0	0	1 (14.3)	1 (14.3)	0	2	(6.9)
Rash maculo-papular	0	0	2 (28.6)	0	0	2	(6.9)

Data were extracted on 03May2021.

Best Percent Change of Target Lesions in Evaluable Population1

50

Cohort:

0.5 mg/kg

1.0 mg/kg

2.0 mg/kg

3.0 mg/kg

4.0 mg/kg

*Ongoing

40

CRC

CRC

(%)

30

CRC

Esophageal

Sarcoma Pancreas

Baseline

20

10

CRC

CRC

Uveal

0

MelanomaOvarian

from

NSCLC

-10

SCLC

Change

-20

Prostate Pancreas

-30

NSCLC Melanoma

MelanomaProstate

-40

B7-H3 H score:

Melanoma*

185

210

190

140

125

NA

125

268

82

159

NA

213

NA

17

180

160

195

130

66

-50

Vasculature score:

2+

3+

NA

3+

3+

2+

3+

NA

3+

NA

2+

2+

3+

2+

1+

3+

2+

3+

2+

¹Patients who received at least one dose and had at least one post-baseline tumor evaluation. CRC = Colorectal cancer. NA = Not available. Data were extracted on 03MAY2021.

Activity in Melanoma Patients

	Prior	B7-H3 H Score				Reason for
Patient	Radiation/	(Vasculature	Line of		Duration of	MGC018	Best Response in
Surgery	Score)	Therapy	Treatment	Therapy	Discontinuation	Target Lesions
Patient #1			1	Nivolumab	10/18 - 07/19
		2	Ipilimumab	08/19 - 09/19
3 target lesions
Radiation and	160	2	Nivolumab	08/19 - 02/20
(lung, liver, chest wall)
Surgery	(3+)	2	Relatlimab	11/19 - 02/20
Non-target pelvic nodes and	SAE hematuria/
		3	Carboplatin/Taxol	04/20 (1 dose)
perirectal/lung lesions
		4	MGC018	05/20 - 07/20	thrombocytopenia	-24%
Patient #2			1	Pembrolizumab	03/20 - 07/20
4 target lesions	Surgery	195	2	Ipilimumab +	07/20 - 08/20
(2 lung, hilar node, soft tissue)	(2+)		Nivolumab
Non-target bilateral lung lesion			3	MGC018	10/20 - 03/21	PD	-28%
Patient #3			1	Ipilimumab	02/15 - 05/15
		2	Pembrolizumab	08/15 - 10/17
2 target lesions (skin)	Radiation and	66
3	Ipilimumab	06/18 - 08/18
Non-target multiple lower	Surgery	(3+)
4	Nivolumab	10/18 - 09/20
extremity lesions
		5	MGC018	10/20 - 04/21	N/A, ongoing	cPR (-36%)

PD = progressive disease; cPR = confirmed partial response; N/A = not applicable.

Data were extracted on 03May2021.

Update on mCRPC PSA Responders from ASCO 2020

	160
	140	142.0							Patient 1
								Patient 2
	120	114.0							Patient 3
(ng/mL)		113.0							Patient 4
100							Patient 5*
80						85.0
PSA	60	60.0
		47.0		60% Reduction
	40				67% Reduction			46.0
	20	17.0			92% Reduction			27.1
						13.0 74% Reduction
					9.5
	0				4.5				0.5 99% Reduction
		Baseline	3	6	12	14	18	22	24
					Weeks

* Patient 5 data scaled (1/10) for charting purposes.

Percent Change of Target Lesions

(%)	90									NSCLC
								Uveal Melanoma
80
Baseline									Prostate
70									SCLC
									Sarcoma
	60									CRC
	50									Ovarian
from									Pancreas
40									Esophageal
									Melanoma
Lesions	30									First new lesion
20									Treatment ongoing
	10
Target	0
-10
in	-20
-30
Change
-40
	-50
	0	5	10	15	20	25	30	35	40	45	50

Weeks Since Treatment Initiation

Data were extracted on 03May2021.

mCRPC Patients with < 50% PSA Reduction

Patient	B7-H3 H Score			Duration
(Vasculature	Line of		of Therapy	MGC018	MGC018	Reason for MGC018
(Dose)	Score)	Therapy	Treatment	(# months)	Best Response	PSA Change	Discontinuation
Patient #6		1	Docetaxel	4
245	2	Sipuleucel-T	2
2 mg/kg
(2+)	3	Abiraterone	18
Bone only disease	SD	+70%	Stasis dermatitis
	4	MGC018	1.5
Patient #7		1	Enzalutamide	Unknown
N/A	2	Docetaxel	4			Palmar plantar
2 mg/kg	(insufficient	3	Abiraterone	12
Bone only disease	tumor)	4	Radium 223	2			erythrodysesthesia/
		5	MGC018	1.5	SD	+25%	maculopapular rash
Patient #8	No biopsy	1	Docetaxel	5
4 mg/kg	2	Enzalutamide	8
available		-12%	Patient decision
Bone only disease	3	MGC018	2	SD
Patient #9		1	Enzalutamide	24
	2	Docetaxel	3
4 mg/kg
Not performed	3	Cabazitaxel	3
Periaortic lymph node			DLT Grade 3 fatigue
	4	Tesetaxel	1
Bone disease
	5	MGC018	.25	Not evaluable	Unknown	> 72 hours

Data were extracted on 03May2021.

Best Percent Change in PSA:

Dose Escalation and Cohort Expansion

>50% PSA Reduction in 11/22 (50%) mCRPC Expansion Patients; (16/31 [52%] in Escalation + Expansion)

	120
	110			*Ongoing
	100	*
(%)	90
80
70
Baseline
60	*
50	*
40
30
20
from
10		*
0
Change	-10
-20
-30		*
-40		*
-50			*

■ ≥ 18 years old; ECOG PS ≤ 2; life expectancy ≥ 12 weeks in Dose Escalation (24 weeks in

Cohort Expansion); measurable disease as per RECIST v1.1

■ Tumor tissue available to evaluate B7-H3 immunohistochemistry (B7-H3 expression not required

for eligibility)

Exclusion

• Abnormal laboratory parameters (hematologic, renal, and/or liver function); clinically significant cardiovascular or pulmonary disease; patients with history of CNS metastasis must have completed treatment, be asymptomatic, and not have had CNS progression within 6 months; no history of leptomeningeal disease or spinal cord compression
• Chemotherapy, biologic, investigational agents or mediastinal/pelvic radiation within 4 weeks;
  small molecule targeted or kinase inhibitors within 14 days; prior therapy with B7-H3 targeted agent (prior radioligand within 6 months in mCRPC Cohort Expansion)

Cohort Expansion Disease-Specific Criteria

■ mCRPC that has progressed during or following 1 prior line of chemotherapy for metastatic disease,

and if approved and available, no more than 2 prior lines of an anti-hormonal agent (e.g., abiraterone,

enzalutamide) with a PSA value of at least 2 ng/mL and meeting at least one of the following:

- Progression in measurable disease (RECIST v1.1)

- Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2 (PCWG2)

- Rising PSA defined as at least 2 sequential rises in PSA (≥ 1 week apart) over a reference value (the last PSA

Treatment-Emergent Adverse Events

Manageable Safety Profile

Patients Experiencing at Least One	0.5 mg/kg	1.0 mg/kg	2.0 mg/kg	3.0 mg/kg*	4.0 mg/kg		All
Adverse Event	(N=3)	(N=6)	(N=7)	(N=7)	(N=6)	(N=29)
Adverse Event	3 (100%)	6 (100%)	7 (100%)	7 (100%)	6 (100%)	29 (100%)
Treatment-Related Adverse Event¹	3 (100)	5 (83.3)	6 (85.7)	7 (100)	6 (100)	27	(93.1)
Adverse Event ≥ Grade 3²	3 (100)	4 (66.7)	7 (100)	5 (71.4)	5 (83.3)	24	(82.8)
Treatment-Related Adverse Event ≥ Grade 3²	2 (66.7)	2 (33.3)	6 (85.7)	4 (57.1)	5 (83.8)	19	(65.5)
Serious Adverse Event	1 (33.3)	1 (16.7)	3 (42.9)	2 (28.6)	2 (33.3)	9 (31.0)
Dose-limiting Toxicity	0	0	1 (14.3)3	0	1 (16.7)4	2	(6.9)
Event that Resulted in Study Discontinuation	1 (33.3)	2 (33.3)	3 (42.9)	4 (57.1)	2 (33.3)	10	(34.5)
Event that Resulted in MGC018 Withdrawal	1 (33.3)	1 (16.7)	3 (42.9)	4 (57.1)	2 (33.3)	11	(37.9)
Event that Resulted in MGC018 Dose Reduction	0	0	1 (14.3)	2 (28.6)	2 (33.3)	5 (17.2)
Event that Resulted in MGC018 Interruption	1 (33.3)	0	1 (14.3)	5 (71.4)	5 (83.3)	12	(41.4)
Fatal Adverse Event (pneumonitis/pneumonia)	1 (33.3)	0	0	0	0	1	(3.4)
Adverse Event of Special Interest (AESI) - Infusion Reaction	0	0	2 (28.6)	5 (71.4)	2 (33.3)	9 (31.0)

1Includes events with causality assessments of 'Possible', 'Probable' or 'Definite'. 2Based on CTCAE criteria version 4.0.3. 3Grade 4 neutropenia resolved to baseline. 4G3 fatigue > 72 hours. *Amendment during 3.0 mg/kg dose level applied to allow dose modification.

Patient

(Dose)

Patient #1 2 mg/kg

One target lesion (lymph node); non-target abdominal adenopathy and bone lesions

Patient #2 3 mg/kg

Bone only disease

Patient #3 3 mg/kg

Bone only disease

Patient #4 3 mg/kg

Bone only disease

Patient #5 3 mg/kg

Bone only disease

B7-H3 H Score

(Vasculature

Score)

130

(1+)

N/A

(insufficient

invasive tumor)

250

(2+)

279

(2+)

215

(1+)

Line of		Duration	MGC018	MGC018	MGC018 Time
	of Therapy	Best	PSA	to Progression	Reason for MGC018
Therapy	Treatment	(# months)	Response	Reduction	(# months)	Discontinuation
1	Docetaxel	4
2	Enzalutamide	24
3	Prostvac	5
4	Abiraterone	6			Unknown	Patient decision due to
5	Nivolumab	6
6	MGC018	4	SD (-29%)	-60%	(>4)	numerous clinic visits
1	Docetaxel	6				New skull lesions on CT
2	Abiraterone	4				scan obtained for head
3	Enzalutamide	12				injury; skull lesions not
4	Radium 223	6				seen on baseline bone scan:
5	MGC018	6	SD	-99%	6	no baseline head CT
1	Docetaxel	8
2	Provenge	2
3	Enzalutamide	6			Not yet	Palmar plantar
4	Abiraterone	9
5	MGC018	3	SD	-67%	progressed (7)	erythrodysesthesia
1	Abiraterone	Unknown			Not yet
2	Nivo + Rucaparib	Unknown
3	MGC018	5	SD	-74%	progressed (7)	Pericardial effusion
1	Docetaxel	4
2	Provenge	12
3	Enzalutamide	7			Initiated
4	Abiraterone	7
5	Docetaxel	4			subsequent
6	MGC018	3	SD	-92%	therapy (6)	Increasing PSA

Best

-60

*

*

*

* *

-70

*

*

-80

* *

-90

*

*

*

-100

Cohort:

2.0 mg/kg

3.0 mg/kg

4.0 mg/kg

Expansion 3.0 mg/kg

Patients who received at least one dose.

Data were extracted on 03MAY2021.

Conclusions

■ Acceptable safety profile with manageable hematologic and skin toxicity

- Recommended Phase 2 dose = 3 mg/kg

■ Anti-tumor activity observed in 3 dose escalation melanoma patients

- Reductions in target lesion sums of 24%, 28%, and 36% (cPR, remains on treatment 6 mos.)

■ Preliminary mCRPC cohort expansion results as of data cutoff (03 May 2021)

- > 50% PSA reduction in 11/22 (50%) patients

- Of 13 patients with measurable disease, 6 not yet evaluable, 7 had first 9-week imaging

- Of the 7 patients, 4 had reductions in target lesion sums of 13%, 21%, 27%, and 35% (uPR)

- 12 of 13 patients remain on treatment

[PSA ≥ 2 ng/mL] measured before the first rise in PSA) (as defined by the PCWG2)

Data were extracted on 03May2021.

Data were extracted on 03May2021.

■ Ongoing enrollment in mCRPC, TNBC, NSCLC, SCCHN, and melanoma

Presented at the 2021 ASCO Annual Meeting, June 4-8, 2021