MacroGenics : Phase 2 Trial of Enoblituzumab Plus Retifanlimab or Tebotelimab in First-Line Treatment of Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (TiP)

Phase 2 Trial of Enoblituzumab Plus Retifanlimab or Tebotelimab in First-Line Treatment of Patients

with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Poster #926TiP

NCT04634825

Gregory Obara,1 Jichao Sun,2 Deryk Loo,3 Chet Bohac4

1Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, United States; 2Biostatistics, MacroGenics, Inc., Rockville, Maryland, United States;

3Research, MacroGenics, Inc., Brisbane, California, United States; 4Clinical Development, MacroGenics, Inc., Rockville, Maryland, United States

Background

Figure 3. Effect of Enoblituzumab With Retifanlimab or Tebotelimab on the Ability of Natural Killer Cells and CD8+ T Cells to Produce Interferon-γ Upon Restimulationa

Study Design

Key Inclusion Criteria

ƒ Patients ≥18 years of age with histologically proven recurrent or metastatic SCCHN not curable

by local therapy

Monoclonal Antibodies

• Enoblituzumab (MGA271) is an investigational, humanized immunoglobulin G (IgG) 1κ monoclonal antibody (mAb) that binds the B7-homolog 3 (B7-H3) immunoligand with enhanced binding to the activating Fc gamma receptors CD16A, particularly the low-affinity allele CD16A-158F (Figure 1)1
• Retifanlimab (MGA012, INCMGA00012) is an investigational humanized, hinge-stabilized, IgG4κ anti-programmed death (PD)-protein 1 (PD-1) mAb blocking binding of PD-ligand 1 (PD-L1) or PD-ligand 2 (PD-L2) to PD-1 (Figure 1)2

Bispecific DART® Molecule

• Tebotelimab (MGD013) is an investigational humanized, Fc-bearing, bispecific, tetravalent DART molecule that concomitantly binds to PD-1 and lymphocyte-activation gene 3 (LAG-3), inhibiting their interaction with PD-L1 or PD-L2 and major histocompatibility complex class II (Figure 2)3

Figure 1. Mechanism of Action of Monoclonal Antibodies in this Study

							Control mAb Plus									Enoblituzumab Plus
	20				(-)		Retifanlimab	Tebotelimab				(-)		Retifanlimab	Tebotelimab
	15
%	10
Cell,
5
-γ-Producing	0	0			5	5	0			5	5	0			5	5	0			5	5	0			5	5	0			5	5
		.	.			.	.			.	.			.	.			.	.			.	.
		0			0			0			0			0			0
30		0	05			0	05			0	05			0	05			0	05			0	05
20
IFN
10
	0	0			5	5	0			5	5	0			5	5	0			5	5	0			5	5	0			5	5
			.	.			.	.			.	.			.	.			.	.			.	.
			0			0			0			0			0			0
			0	05			0	05			0	05			0	05			0	05			0	05
								Enoblituzumab/Control mAb Concentration, µg/mL

NK cell

CD8+ T cell

ƒ This study (NCT04634825) is a Phase 2, open-label,non-randomized trial in the first-line

treatment of patients with recurrent or metastatic SCCHN not curable by local therapy with no

prior systemic therapy for SCCHN in the recurrent or metastatic setting

ƒ The study is planned to be conducted at approximately 35 centers in approximately 5

countries

ƒ Approximately 80 patients will be enrolled based on the combined positive score (CPS) in 1 of

the following cohorts (Figure 5):

- Retifanlimab Cohort (PD-L1-positive CPS ≥1; N=50)

- Tebotelimab Cohort (PD-L1-negative CPS <1; N=30)

ƒ Patients in the Retifanlimab Cohort will receive enoblituzumab 15 mg/kg and retifanlimab

375 mg once every 3 weeks, in cycles of 3 weeks' duration, for a maximum of 35 cycles

ƒ Patients in the Tebotelimab Cohort will receive enoblituzumab 15 mg/kg and tebotelimab

ƒ No prior systemic therapy for SCCHN in the recurrent or metastatic setting

- Patients who completed systemic therapy >6 months before the study, if given as part of

multimodal treatment for locally advanced disease, are eligible

ƒ Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx

ƒ Eastern Cooperative Oncology Group performance status of 0 or 1, verified within 3 days

before Day 1

ƒ Life expectancy ≥6 months

ƒ At least 1 radiographically measurable lesion (target lesion), as defined in Response Evaluation

Criteria in Solid Tumors version 1.1

ƒ An identified formalin-fixed,paraffin-embedded tumor specimen for immunohistochemical

evaluation of pharmacodynamic markers of interest

aPeripheral blood mononuclear cells were co-cultured with SAS tumor cells in the presence of enoblituzumab alone, or in combination with retifanlimab or tebotelimab for 6 days. Cells were collected and restimulated with PMA/ionomycin in the presence of GolgiStop. Levels of NK cell- and CD8+ cell-specific intracellular IFN-γ were measured by fluorescence-activated cell sorting.

600 mg once every 3 weeks, in cycles of 3 weeks' duration, for a maximum of 35 cycles

ƒ PD-L1 expression level that is either:

B7-H3B7-H3

Fc Region (5 amino acid mutations)

PD-1

PD-1

ENOBLITUZUMAB

Fab

• Binds B7-H3 with high affinity

Fc

• Humanized, engineered to enhance Fc-mediated tumor cell killing
• •  Affinity for activating FcγRIIIA (CD16A)
  •  Affinity for inhibitory FcγRIIB (CD32B)
• Potential enhancement of adaptive immune responses

RETIFANLIMABa

Fab

• Binds PD-1 with high affinity (>4× greater than nivolumab and >6× greater than pembrolizumab)
• Blocks binding of PD-L1 or PD-L2 to PD-1

Fc

• Humanized, hinge-stabilized IgG4κ

IFN-γ, interferon gamma; mAb, monoclonal antibody; NK, natural killer; PMA, phorbol 12-myristate13-acetate; SAS, B7-homolog3-expressing head and neck cancer cell line.

• Both retifanlimab and tebotelimab enhanced enoblituzumab-dependent cytotoxicity targeting B7-H3-expressing tumor cells (Figure 4)

Figure 4. Effect of Retifanlimab and Tebotelimab on Enoblituzumab-Dependent Cytotoxicitya

PBMCs Co-Cultured With SAS Tumor Cells Plus

Enoblituzumab

Enoblituzumab

Enoblituzumab

Control mAb

0 μg/mL

0.05 μg/mL

5 μg/mL

5 μg/mL

40,000

(-)

Reti

Tebo

(-)

Reti

Tebo

(-)

Reti

Tebo

(-)

Reti

Tebo

PBMC

only

RLU

30,000

Luminescence,

20,000

ƒ Key study end points are summarized in Table 2

ƒ In the Tebotelimab Cohort, safety (dose-limiting toxicities) will be monitored through Cycle 2

Day 7 after dosing the first 6 patients and the second 6 patients

ƒ The initial tumor assessment will occur at the end of Cycle 2 (after approximately 6 weeks),

and at the end of every 3 cycles thereafter (approximately every 9 weeks)

ƒ After receipt of the last dose of study treatment, patients will enter an efficacy follow-up

period and will be followed for survival

ƒ The study started in March 2021, and patients continue to be recruited

Figure 5. NCT04634825 Study Schema: An Open-Label,Non-Randomized Phase 2 Study

-	Positive (CPS ≥1) for the Retifanlimab Cohort, or
-	Negative (CPS <1) for the Tebotelimab Cohort

Key Exclusion Criteria

ƒ Primary tumor site of upper esophagus, salivary gland, or nasopharynx (any histology)

ƒ Disease suitable for local therapy administered with curative intent

ƒ Progressive disease within 6 months of completion of curatively intended systemic treatment

for locoregionally advanced SCCHN

ƒ Radiation therapy (or other nonsystemic therapy) within 2 weeks before the first dose

of study drug

ƒ Prior therapy with an anti-B7-H3,anti-PD-1,anti-PD-L1,anti-PD-L2, or anti-LAG-3 agent

ƒ Toxicity of prior therapy that has not recovered to Grade ≤1 or baseline, with the exception of

any grade of alopecia and anemia not requiring transfusion support

10,000

0

aPBMCs were co-cultured with SAS tumor cells in the presence of enoblituzumab alone, or in combination with retifanlimab or tebotelimab for 6 days. The values in fluorescence-activated cell sorting plots represent the percent of positive cells within the natural killer cell (CD3-CD56+) gate. Cells were collected and used as effector cells to measure the cytotoxicity targeting B7-homolog3-expressing tumor cell line (NCI H1975-luc) at an enoblituzumab:tebotelimab ratio of 15:1. The loss of luminescence signal was used to measure the target cell lysis.

mAb, monoclonal antibody; PBMC, peripheral blood mononuclear cell; reti, retifanlimab; RLU, relative light units; SAS, B7-homolog3-expressing head and neck cancer cell line; tebo, tebotelimab.

ƒ Enoblituzumab mediated antibody-dependent cellular cytotoxicity (ADCC) activity in preclinical

PD-L1+

(CPS ≥1)

Recurrent/

metastatic SCCHN

Not curable by local therapy

PD-L1-

(CPS <1)

(n=50)

Enoblituzumab, 15 mg/kg Q3W

+

Retifanlimab (anti-PD-1), 375 mg Q3W

(n=30)

Enoblituzumab, 15 mg/kg Q3W

+

Tebotelimab (anti-PD-1 × LAG-3), 600 mg Q3W

Primary

Efficacy

Objective:

ORR

Secondary

Efficacy

Objectives:

PFS, DCR, DOR, OS

ƒ Diagnosis of immunodeficiency or receiving systemic steroid therapy corticosteroids (≥10 mg

per day prednisone or equivalent) or any other form of immunosuppressive therapy within

14 days before the first dose of study drug

References

1. Loo D, et al. Clin Cancer Res. 2012;18(14):3834-3845.

aRetifanlimab is licensed to Incyte

B7-H3,B7-homolog 3; Fab, antigen-binding fragment; Fc, fragment crystallizable; FcγR, Fc gamma receptors; IgG, immunoglobulin G; PD-1, programmed death-protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2.

Figure 2. Mechanism of Action of Tebotelimab

studies across multiple cancer cell lines expressing B7-H3, including melanoma, lung cancer,

prostate cancer, breast cancer, bladder cancer, and renal cancer1

ƒ In a multicenter Phase 1/2 study (NCT02475213), combination of enoblituzumab and

pembrolizumab demonstrated safety and antitumor activity in patients with checkpoint inhibitor-

Safety evaluations (DLTs) through Cycle 2

Day 7 for the first 12 patients (2 mini-cohorts of 6 patients each)

2.	La Motte-Mohs R, et al. J Immunother Cancer. 2017;5(suppl 2):P336.
3.	La Motte-Mohs R et al. J Immunother Cancer. 2017;5(suppl 2):P337.

naïve squamous cell carcinoma of head and neck (SCCHN) and non-small cell lung cancer, with

objective response rates (ORR) of 33.3% and 35.7%, respectively (Table 1)5

ƒ The observed ORR for patients treated with the combination of enoblituzumab and

pembrolizumab represent a potential strategy to improve tumor responses in patients treated

CPS, combined positive score; DCR, disease control state; DOR, duration of response; LAG-3,lymphocyte-activation gene 3; ORR, objective response rate; OS, overall survival; PD-1, programmed death-protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; SCCHN, squamous cell carcinoma of head and neck.

4.	Puhr HC and Ilhan-Mutlu A. ESMO Open. 2019;4(2):e000482.
5.	Aggarwal C, et al. J Immunother Cancer. 2021 (under review).

LAG-3LAG-3

PD-1

PD-1

TEBOTELIMAB

Fab

• Bispecific, tetravalent DART molecule PD-1 ×
  LAG-3co-engages both molecules (PD-1 and LAG-3) for blockade
• Blocks binding of PD-L1 or PD-L2 to PD-1
• Blocks binding of MHC-II to LAG-3

Fc

• Humanized, hinge-stabilized IgG4κ

with checkpoint inhibitors monotherapy (Table 1)

Table 1. Summary of Efficacy Data With Anti-B7-H3 Blockade Plus Anti-PD-1 Blockade in the Context of Anti-PD-1 Blockade Monotherapy in Patients With SCCHN or NSCLC

SCCHN

	Anti-PD-1
Blockade	+ anti-B7-H3		Anti-PD-1 only
	Pembrolizumab
Agent(s)	+ enoblituzumab	Nivolumab	Pembrolizumab	Pembrolizumab
Study	CP-MGA271-03	CheckMate-141	KEYNOTE-012	KEYNOTE-040
(NCT02475213)5	(NCT02105636)6	(NCT01848834)7	(NCT02252042)8
N	18	240	174	247

Table 2. Key Study Objectives

Cohort	Primary objective Secondary objectives	Exploratory objectives

		ƒ	Investigator-	ƒ	Relationships between PK,
			assessed PFS, DCR,		pharmacodynamics, safety, and
			DOR, and OS		antitumor activity
Enoblituzumab +	ƒ Investigator-	ƒ	Safety and	ƒ	Population PK and exposure-
assessed ORR by		tolerability		response analyses
retifanlimab
RECIST v1.1	ƒ	PK and
	ƒ Relationships between PD-1,PD-L1,
			immunogenicity of		B7-H3, and LAG-3 expression on tumor

6.	Ferris RL, et al. N Engl J Med. 2016;375(19):1856-1867.
7.	KEYTRUDA® (pembrolizumab) [Prescribing information]. Whitehouse Station, NJ, USA: Merck & Co,
	Inc.; 2020.
8.	Cohen E, et al. Ann Oncol. 2017;28(suppl 5):1666.
9.	Borghaei H, et al. N Engl J Med. 2015;373(17):1627-1639.
10.	Brahmer J, et al. N Engl J Med. 2015;373(2):123-135.
11.	Garon EB, et al. N Engl J Med. 2015;372(21):2018-2028.

Fab, antigen-binding fragment; Fc, fragment crystallizable; IgG, immunoglobulin G; LAG-3,lymphocyte-activation gene 3; MHC-II, major histocompatibility complex class II; PD-1, programmed death-protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2.

Rationale for Study

• The simultaneous targeting of either PD-1 and B7-H3, or PD-1,LAG-3, and B7-H3 is supported by the complementary biology of these 3 molecules in modulating the immune response against tumor cells4
• In vitro data suggest that both retifanlimab and tebotelimab have potential to sustain enoblituzumab-mediated immune activation and antitumor activity
• Combination of enoblituzumab with retifanlimab or tebotelimab sustained the ability of natural killer cells and CD8+ T cells from peripheral blood mononuclear cells co-cultured with tumor cells to produce interferon gamma upon restimulation (Figure 3)

ORR	33%	13%	16%	15%
		NSCLC
	Anti-PD-1
Blockade	+ anti-B7-H3		Anti-PD-1 only
	Pembrolizumab
Agent(s)	+ enoblituzumab	Nivolumab	Nivolumab	Pembrolizumab
Study	CP-MGA271-03	CheckMate-057	CheckMate-017	KEYNOTE-001
(NCT02475213)5	(NCT01673867)9	(NCT01642004)10	(NCT01295827)11
Histology	Squamous and	Non-squamous	Squamous	Squamous and
non-squamous	non-squamous
N	14	108	54	87
ORR	36%	9%	19%	8%

B7-H3,B7-homolog 3; NSCLC, non-small cell lung cancer; ORR, objective response rate; PD-1, programmed death-protein 1; SCCHN, squamous cell carcinoma of head and neck.

				enoblituzumab +		cells and response
				retifanlimab	ƒ	The immune-regulatory activity in vivo
					ƒ	Circulating immune cells and effect
			ƒ	Investigator-		of treatment
				Peripheral biomarkers and correlation
	ƒ	Safety and		assessed PFS, DCR,	ƒ
Enoblituzumab +		tolerability		DOR, and OS		with potential clinical response
ƒ	Investigator-	ƒ	PK and	ƒ	Gene expression profiles and FcγR
tebotelimab
		assessed ORR by		immunogenicity of		polymorphism in PBMCs and/or
		RECIST v1.1		enoblituzumab +		pretreatment tumor biopsies and
				tebotelimab		correlation with clinical response

B7-H3,B7-homolog 3; DCR, disease control rate; DOR, duration of response; FcγR, Fc gamma receptors; LAG-3,lymphocyte-activation gene 3;

ORR, objective response rate; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD-1, programmed death-protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PK, pharmacokinetics; RECIST, Response Evaluation Criteria in Solid Tumors.

Acknowledgments

This study is sponsored by MacroGenics, Inc. Professional medical writing support was provided by Nikola Vojtov, PhD, Emily Cullinan, PhD, CMPP, and Francesca Balordi, PhD, of The Lockwood Group (Stamford, CT, USA), in accordance with Good Publication Practice (GPP3) guidelines, funded by MacroGenics, Inc.

Disclosures

G. Obara has no conflict of interest to declare.

Presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2021 | September 16-21, 2021 [e-mail]

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