Immatics N : ACTengine® IMA203 Clinical Data Update at Society for Melanoma Research Congress, November 2023

ACTengine IMA203 TCR-T targeting PRAME in PD1 refractory

metastatic melanoma

Martin Wermke1, Winfried Alsdorf2, Dejka Araujo3, Manik Chatterjee4, Norbert Hilf5, Tobias A.W. Holderried6, Amir A. Jazaeri3, Mamta Kalra7, Andrea Mayer-Mokler5, Regina Mendrzyk5, Ali Mohamed7, Sapna P. Patel3, Ran Reshef8, Arun Satelli7, Harpreet Singh9, Apostolia-Maria Tsimberidou3, Steffen Walter7,

Toni Weinschenk9, Cedrik M. Britten9, Jason J. Luke10

1. TU Dresden, NCT/UCC Early Clinical Trial Unit, Germany
2. University Medical Center Hamburg-Eppendorf, Germany
3. The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
4. University Hospital Würzburg, Germany
5. Immatics Biotechnologies GmbH, Tuebingen, Germany
6. University Hospital Bonn, Germany
7. Immatics US, Inc., Houston, Texas, USA
8. Columbia University, New York, USA
9. Immatics N.V., Tuebingen, Germany
10. University of Pittsburgh, Pittsburgh, Pennsylvania, USA

PRAME - a Widely Expressed Cancer Testis Antigen

% PRAME Positive Patients in Selected Indications

0%	100%
Uterine Carcinoma
	97%
Uterine Carcinosarcoma
	100%
Sarcoma Subtypes
	up to 100%

Cut. Melanoma
			≥95%
Uveal Melanoma1
		≥90%
Ovarian Carcinoma
84%
Squamous NSCLC
68%
TNBC
63%
Small Cell Lung Cancer
45%

Target prevalence based on TCGA (SCLC: in-house) RNAseq data combined with proprietary mass spec-guided RNA expression threshold;

1 Uveal melanoma target prevalence based on IMADetect qPCR testing of screening biopsies from 33 trial patients.

PRAME RNA Detection in Melanoma Samples (ISH)

		100 µm
100	90	81
	% PRAME+ cells

ACTengine IMA203 TCR-T - Mechanism of Action

GENETICLEUKAPHERESIS ENGINEERING

PRAME TCR:

• Pairing-enhanced
• High affinity
• High specificity

TUMOR CELL DEATH

HLA-A*02
PRAME TCR	CYTOTOXIC
LYTIC GRANULES

ACTIVATED T CELL

ACTengine	ADMINISTRATION OF
PRAME DIRECTED T CELLS
IMA203

Patient Flow

SCREENING/MANUFACTURING	TREATMENT / OBSERVATION	LTFU

HLA-A*02			Leukapheresis
Testing			ACTengine
			Manufacturing
x	x		by Immatics
			IMA203
Expression			Process time of 14 days
1	Antigen	3	7-day manufacturing process
2	applying CD8/CD4 T cell selection
			7-day QC release testing

ACTengine IMA203

Infusion

Low Dose IL-2

1m IU, daily d1-5

and twice daily d6-10

Target Profiling

Lymphodepletion

IMADetect®	Fludarabine 30mg/m2 and
Biopsy or archived tissue	Cyclophosphamide 500mg/m2
	for 4 days

Key Objectives and Eligibility Criteria

Key Objectives

Primary: Safety

• Investigation of Adverse Events
• Determination of a RP2D

Secondary: Biological and Clinical Activity

• IMA203 T cell engraftment, persistence
• Objective responses (RECIST1.1) & Duration of Response

Exploratory

• IMA203 tumor infiltration

Key Eligibility Criteria

• Patients ≥ 18 years of age with ECOG 0 / 1
• HLA-A*02:01and PRAME positive
• Patients having received, or not been eligible for all available indicated SOC treatment
• Adequate organ function
• No active brain metastasis
• No serious autoimmune disorder
• No immunosuppressive medication

Phase 1 Trial Design in Advanced Solid Tumors

Phase 1a

Dose Escalation:

Dose Level 1-4 (total N=27)

7 patients in DL4 treated at RP2D

RP2D defined at

1-10x109 TCR-T cell

(25 patients)

Phase 1b

Dose Expansion Cohort A:

Dose Level 4/5 (total N=18)

All 18 patients treated at RP2D

Melanoma

Patients at RP2D:

Total N=13

Efficacy population shown: patients treated with IMA203 and with at least one available tumor response assessment post infusion; data cut-off Sep 30, 2023

All Patients: Patient Characteristics

Characteristic	Phase 1a	Phase 1b	Melanoma
Dose Escalation	Cohort A	Subgroup at RP2D
Safety population	28#	21*	16*
Efficacy population	27	18	13
Melanoma	11	8	13
Ovarian cancer	1	4
Synovial sarcoma	6	3
Others	9	3
Age	55.0	52.5	51
Median (min, max)	(18, 72)	(31, 79)	(24, 79)
Prior lines of treatment	4.0	3.0	4.0
Median (min, max)	(1,8)	(0, 10)	(0, 7)
LDH at baseline	66.7	50.0	53.8
>1 x ULN [% of patients]
Baseline tumor burden	133.0	58.9	52.0
Target lesion sum of diameter [mm]
(29.0, 219.7)	(21.0, 207.3)	(21.0, 178.7)
Median (min, max)
Dose Level	DL1-4	DL4/5 (RP2D)	DL4/5 (RP2D)
Total infused dose	0.41	4.33	1.73
Median transduced viable CD8
(0.08, 2.09)	(1.30, 9.36)	(1.07, 5.12)
T cells infused [x109] (min, max)

Detailed Patient Characteristics

Melanoma Subgroup at RP2D	N=13
Melanoma subtype, n (%)
Cutaneous	8 (61.5)
Uveal	4 (30.8)
Unk. Primary	1 (7.7)
Prior therapies for cut. melanoma patients	N=8
Prior lines of treatment, median (min, max)	5.5 (3, 7)
BRAF inhibitor pretreated, n (%)	5 (62.5)
Anti-CTLA-4, n (%)	7 (87.5)
Anti-PD-1 + anti-CTLA-4 combination, n (%)	7 (87.5)
Median lines of CPI (min, max)	3.0 (1, 4)
Retreated with CPI, n (%)	7 (87.5)

#One patient died from sepsis of unknown origin and did not receive IMA203 TCR-T cells;*Three cutaneous melanoma patients treated with IMA203, and pending post infusion scan included in safety population, but not efficacy population; Data cut-off Sep 30, 2023

All Patients: Tolerability Profile

TEAEs by maximum severity for all patients in Phase 1a dose escalation and Cohort A dose expansion (N=49)1

Adverse event	≥ Grade 3
(System organ class, Preferred term)	No.	%
Patients with any adverse event	49	100.0
Adverse Events of Special Interest	2	4.1
Cytokine release syndrome	2	4.1
ICANS	0	0.0
Blood and lymphatic system disorders	48	98.0
Neutropenia	36	73.5
Lymphopenia	27	55.1
Leukopenia	26	53.1
Anaemia	24	49.0
Thrombocytopenia	17	34.7
Cytopenia	1	2.0
Leukocytosis	1	2.0
Lymphocytosis	1	2.0
Investigations	9	18.4
Neutrophil count decreased	4	8.2
Alanine aminotransferase increased	2	4.1
Aspartate aminotransferase increased	2	4.1
White blood cell count decreased	2	4.1
Blood alkaline phosphatase increased	1	2.0
Blood creatinine increased	1	2.0
Blood fibrinogen decreased	1	2.0
Infections and infestations	7	14.3
Appendicitis	1	2.0
COVID-19	1	2.0
Enterococcal infection	1	2.0
Infection	1	2.0
Orchitis	1	2.0
Sepsis2, 3	1	2.0
Septic shock2	1	2.0
Urinary tract infection	1	2.0
Respiratory, thoracic and mediastinal disorders	6	12.2
Hypoxia	3	6.1
Bronchial obstruction	1	2.0
Laryngeal inflammation	1	2.0
Pleural effusion	1	2.0
Respiratory failure	1	2.0
Vascular disorders	6	12.2
Hypertension	4	8.2
Hypotension	2	4.1

Adverse event	≥ Grade 3
(System organ class, Preferred term)	No.	%
table continued…
General disorders and administration site conditions	4	8.2
Condition aggravated2	1	2.0
Fatigue	1	2.0
Pyrexia	1	2.0
Swelling face	1	2.0
Metabolism and nutrition disorders	4	8.2
Hypokalaemia	3	6.1
Failure to thrive	1	2.0
Hypophosphataemia	1	2.0
Gastrointestinal disorders	2	4.1
Abdominal pain	1	2.0
Diarrhoea	1	2.0
Vomiting	1	2.0
Injury, poisoning and procedural complications	2	4.1
Humerus fracture	1	2.0
Infusion related reaction	1	2.0
Renal and urinary disorders	2	4.1
Acute kidney injury	1	2.0
Proteinuria	1	2.0
Skin and subcutaneous tissue disorders	2	4.1
Rash maculo-papular	2	4.1
Cardiac disorders	1	2.0
Atrial fibrillation1	1	2.0
Endocrine disorders	1	2.0
Inappropriate antidiuretic hormone secretion	1	2.0
Eye disorders	1	2.0
Ulcerative keratitis	1	2.0
Hepatobiliary disorders	1	2.0
Cholangitis	1	2.0
Immune system disorders	1	2.0
Contrast media allergy	1	2.0
Musculoskeletal and connective tissue disorders	1	2.0
Muscle spasms	1	2.0
Nervous system disorders	1	2.0
Headache	1	2.0
Reproductive system and breast disorders	1	2.0
Vaginal haemorrhage	1	2.0

• Well tolerated at doses as high as ~10x109 TCR-T cells
• Expected cytopenia (Grade 1-4) associated with lymphodepletion in all infused patients
• No AE ≥Grade 3 was observed with a frequency ≥10% when excluding expected cytopenias associated with lymphodepletion
• One DLT in Phase 1a at DL2
• No IMA203-related Grade 5 Adverse Events

All ≥Grade 3 TEAEs regardless of relatedness to study treatment, experienced by at least 1 patient (except for ICANS with only Grade 1-2; listed for completeness due to being an adverse event of special interest). Patients are counted only once per adverse event and severity classification (CTCAE v5.0 or CARTOX criteria for CRS/ICANS, Neelapu et al., 2018). Two patients with disease progression after first IMA203 infusion received exploratory second IMA203 infusion and 9 ≥Grade 3 TEAEs included in the table occurred only after second infusion. 1 DLT: Dose limiting toxicity in phase 1a at DL2 reported on March 17, 2021; 2 Fatal adverse events were not considered related to any study drug; 3 Patient died from sepsis of unknown origin and did not receive IMA203 TCR-T cells.

1 Three cutaneous melanoma patients treated with IMA203 and pending post infusion scan included in safety population, but not efficacy population; Data cut-off Sep 30, 2023

All Patients: Best Overall Response

Phase 1a (N=27#)

Cohort A (N=18)

ORR	48%	(13/27)
cORR	19%	(5/27)

ORR 50% (9/18) cORR 47% (8/17)

• Maximum change of target lesions and RECIST 1.1 BOR at different timepoints; # Synovial sarcoma patient (DL3) PD at week 6 not shown as target lesions were not evaluable; 1 Patient received one dose nivolumab erroneously; Data cut-off Sep 30, 2023

Melanoma Subgroup at RP2D: BOR and Durability of Response

#

#

#

#

#

Median DOR,	Not reached,
min, max DOR	2.2+, 14.7+ months
Median Follow-up	14.4 months

cORR 50% (6/12)

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# Patients in Phase 1a

Ongoing

#

Scans at approximately week 6, month 3 and then every 3 months

Data cut-off Sep 30, 2023