C4 Therapeutics : CTOS 2023 - CFT8634 Phase 1 Dose Escalation

Initial Results From A Phase 1 Study of CFT8634, A Novel Bifunctional Degradation Activating Compound (or BIDAC™ Degrader) of BRD9, in Synovial Sarcoma and SMARCB1-Null Tumors

Mark Agulnik, MD1, William D. Tap, MD2, Gregory M. Cote, MD, PhD3, Ravin Ratan, MD, M.Ed4, Shaheer A Khan, D.O.5, Sant P. Chawla, MD6, Steven Attia, D.O.7, Anthony Elias, MD8, Mohammed Milhem, MBBS9, Joseph G. Pressey, MD10, Amro Ali, PharmD11, Ingrid Mintautas, B.A11, Riadh Lobbardi, PhD11, Joseph Pariseau, PharmD11, Huan Liu, M.A11,

Eunju Hurh, PhD11, Kathleen Neville, MD11, and Brian A. Van Tine, MD, PhD12

1City of Hope, Duarte, CA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Massachusetts General Cancer Center, Boston, MA; 4University of Texas MD Anderson Cancer Center, Houston, TX; 5Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY; 6Sarcoma Oncology Center, Santa Monica, CA; 7Division of Oncology,

Mayo Clinic, Jacksonville, FL; 8University of Colorado Cancer Center, Aurora, CO; 9University of Iowa Hospitals and Clinics, Iowa City, IA; 10Cincinnati Children's Hospital, Cincinnati, OH; 11C4 Therapeutics, Inc., Watertown, MA; 12Washington University School of Medicine, St. Louis, MO

BACKGROUND

PHASE 1/2 STUDY DESIGN6

• Bromodomain-containingprotein 9 (BRD9) belongs to the non-canonical SWI/SNF complex and is essential to the proliferation of SMARCB1-perturbed cancers1,2
• • SMARCB1-perturbedcancers include synovial sarcoma, defined by the SS18-SSX fusion, and SMARCB1-null tumors such as epithelioid sarcoma2,3
• Synovial sarcoma is a rare soft tissue malignancy comprising ~10% of all soft tissue sarcomas2
• • In the metastatic setting, therapeutic options are limited, and outcomes are poor with a median OS of 17.0 months and 1-year survival rate of ~60%4

CFT8634 BACKGROUND5

• CFT8634 is an orally bioavailable selective bifunctional degradation activating compound, or BiDAC™ degrader of BRD9
• • CFT8634 was developed using C4 Therapeutics' TORPEDO® platform
• Mechanism of Action (Figure 1)
• 1. CFT8634 induces ternary complex formation with BRD9 and cereblon E3 ligase (step 1)
  2. BRD9 is ubiquitinated and subsequently released for degradation in the proteasome (steps 2-4)
• CFT8634 leads to robust and dose-dependent degradation of BRD9 in in vitro and in vivo models of SMARCB1-perturbed cancer, which translates to significant and dose-dependentanti-tumor activity in patient-derived preclinical xenograft models (Figures 2)

Figure 1: Mechanism of Action for CFT86345

• Open-label,multicenter, Phase 1/2 clinical trial with dose escalation and expansion phases*
• Dose escalation phase, beginning with a starting oral dose of 2 mg daily, follows a Bayesian logistic regression model until determination of the MTD and/or RP2D
• • Escalation will enroll patients with synovial sarcoma and SMARCB1-null solid tumors (N = ~40)
  • Enrichment cohort currently enrolling at 30 mg, additional enrichment cohorts may be added

Figure 3: CFT8634-1101 Study Design6

Phase 1: Dose Escalation

50 mg QD; n=6

30 mg QD; n=6

30 mg

15 mg QD; n=7

PHASE 2:

enrichment

8 mg QD; n=6

cohort

Cohort

4 mg QD; n=5

currently

Expansion†

2 mg QD; n=2

enrolling

*CFT8634 is administered in 28-day cycles until disease progression or intolerable toxicity. † Once the RP2D has been declared, expansion arms for synovial sarcoma and SMARCB1-null tumors will begin enrollment.

KEY ELIGIBILITY CRITERIA6	PHASE 1 STUDY
KEY INCLUSION CRITERIA	ENDPOINTS6
• Must be ≥18 years of age, or ≥16 years old and weigh	PRIMARY ENDPOINT
• Assessment of safety and
≥50 kg with measurable disease per RECIST v1.1
tolerability
• Synovial sarcoma or SMARCB1-null tumors with unresectable or
• Defining the RP2D/MTD
metastatic disease, following at least 1 prior line of standard-of-care	SECONDARY
systemic therapy
• Assessment of PK and
• Patients must not be candidates for available therapies that are	pharmacodynamics
• Assessment of preliminary

PRE-CLINICAL DATA: IN VIVO IN PATIENT-DERIVED XENOGRAFTS (PDX)5

Figure 2: Robust Efficacy Response Observed in Two PDX Models of Synovial Sarcoma5

known to confer clinical benefit	anti-tumor activity
BASELINE CHARACTERISTICS
Data cut off date: August 29, 2023

A. PDX SA13412

Synovial Sarcoma Harboring SS18-SSX15

)	2500	Efficacy		125
3			Remaining
volume(mm	2000		100
tumor	1500		BRD9	75
1000		50
SA13412PDX		Percentof
500		25
	0			0

0	7	14	21	28
		Time (days)
	Vehicle (PO QD)		CFT8634 10 mg/kg (PO QD)
	CFT8634 1 mg/kg (PO QD)	CFT8634 30 mg/kg (PO QD)
	CFT8634 3 mg/kg (PO QD)	CFT8634 50 mg/kg (PO QD)

PD analysis at 4 h and 24 h

post-Day 18 dose

Vehicle	4	24
	Time (hours)

B. PDX 310

Synovial Sarcoma Harboring SS18-SSX25

	2500		Efficacy
)
3
(mm	2000
volume	1500
tumor310
1000
PDX	500
	0
	0	7	14	21	28
		Time (days)
	Vehicle (PO QD)			CFT8634 10 mg/kg (PO QD)
	CFT8634 1 mg/kg (PO QD)		CFT8634 30 mg/kg (PO QD)
	CFT8634 3 mg/kg (PO QD)		CFT8634 50 mg/kg (PO QD)

	Table 1: Baseline Patient and Disease Characteristics5	Table 2: Disease History5
	N (%) of patients unless stated	N=32		N (%) of patients unless stated	N=32
	Age in years, median (range)	39.5 (19,65)		Number of lines of prior
	Sex, male	17 (53.1)
		therapy, n (%)
	Sex, female	15 (46.9)
		1	3 (9.4)
	ECOG PS
			2	2 (6.2)
	0	16 (50)		≥3	27 (84.4)
	1	16 (50)
	2	0 (0)		Time since initial diagnosis	3.4 (1,18)
	Race, n (%)			(years), median (range)
	White	28 (87.5)
		Largest target lesion diameter	42 (4,188)
	Asian	4 (12.5)
		(mm), median (range)
	Primary tumor type, n (%)
			Prior doxorubicin	29 (90.6)
	Synovial sarcoma	23 (71.9)
	Epithelioid sarcoma	6 (18.8)		Prior ifosfamide	27 (84.4)
	Poorly differentiated chordoma	1 (3.1)		Prior pazopanib	17 (53.1)
	Yolk sac tumor	1 (3.1)
		Prior tazemetostat	6 (18.8)
	Renal medullary carcinoma	1 (3.1)
Table 3: Treatment Disposition5
	N (%) of patients unless stated			N=32
	Ongoing		9 (28.1)
	Discontinued
	Progressive disease		17 (53.1)
	Death		3 (9.4)
	Adverse event‡		2 (6.2)
	Withdrawal by patient		1 (3.1)
	Duration of treatment (months), Median (range)	1.8 (0,11)

‡1 patient each discontinued due to a dysphagia and respiratory failure, both deemed unlikely related to drug

SAFETY DATA

RESULTS

Figure 4: TEAEs and Related TEAEs by CTCAE Grade (>10%)5

PHARMACODYNAMICS5

Incidence of AEs, SAEs and Grade ≥3 AEs were consistent across all cohorts

Table 4: Overview of AEs Across Cohorts5

	2 mg	4 mg	8 mg	15 mg QD 30 mg QD	50 mg QD Total
	QD	QD	QD
	(N=7)	(N=6)	(N=6)	(N=32)
	(N=2)	(N=5)	(N=6)
	n (%)	n (%)	n (%)	n (%)
	n (%)	n (%)	n (%)
Patients with ≥1 TEAE	2	(100.0)	5	(100.0)	6	(100.0)	7	(100.0)	6	(100.0)	6	(100.0)	32	(100.0)
Patients with ≥1 TESAE	2	(100.0)	2	(40.0)	2	(33.3)	4	(57.1)	1	(16.7)	2	(33.3)	13	(40.6)
≥1 TESAE related to CFT8634	0	(0.0)	0	(0.0)	0	(0.0)	0	(0.0)	0	(0.0)	2	(33.3)	2 (6.3)
≥1 TESAE leading to death	1	(50.0)	1	(20.0)	0	(0.0)	2	(28.6)	0	(0.0)	0	(0.0)	4 (12.5)
Patients with ≥1 possibly	2	(100.0)	3	(60.0)	6	(100.0)	4	(57.1)	5	(83.3)	6	(100.0)	26	(81.3)
related TEAE
Patients with ≥1 TEAE with CTCAE Grade ≥ 3 2	(100.0)	3	(60.0)	3	(50.0)	5	(71.4)	4	(66.7)	4	(66.7)	21	(65.6)

Table 5: TEAEs Occurring in ≥10% or of Interest5

System organ class	Grade 1	Grade 2	Grade 3	Grade 4	Total
Preferred term	(N=32)	(N=32)	(N=32)	(N=32)	(N=32)
General disorders and administration
site conditions
Fatigue	8	(25.0)	3 (9.4)	3 (9.4)	0 (0.0)	14 (43.8)
Non-cardiac chest pain	3	(9.4)	1 (3.1)	1 (3.1)	0 (0.0)	5 (15.6)

TEAE	Related TEAE

Fatigue

Dry mouth

Neutropenia

Dysgeusia

Anaemia

Diarrhoea

Thrombocytopenia

Hypophosphatemia

Non-cardiac chest pain

Leukopenia

Cough

Pneumothorax

Oedema peripheral

Hyperbilirubinemia

Headache

Dyspnoea

Dizziness

Blood alkaline phosphatase increased

Aspartate aminotransferase increased

Figure 6: BRD9 degradation on tumor tissue after 15 days of treatment with CFT86345

	H&E		BRD9
		expression			BRD9 IHC by visit and dose
Baseline				baselinerelativeto
A	B		25
					0
					-25
	100um			expression %	-50
15Day
C	D		-75
					-100
1						g	g	g	g	0mg	50mg
						ning 2m	4m	8	15
Cycle						ree		m	m
					c	Cycle 1 Day 15
					S

A-D: Staining of fresh tumor biopsy at Baseline and at Cycle 1 Day 15 with Hematoxylin and Eosin (A,C) as well as BRD9 immunohistochemistry (IHC) using clone E4Q3F (B,D) is shown for one patient dosed at 15 mg with CFT8634. CFT8634

High levels of BRD9 degradation observed at different doses on tumor tissue after 15 days of treatment with CFT8634

Similar observation done by measuring BRD9 expression in PBMCs via Mass Spectrometry

Oedema peripheral	3	(9.4)	0 (0.0)	1 (3.1)	0 (0.0)	4 (12.5)
Gastrointestinal disorders
Dry mouth	10 (31.3)	2 (6.3)	0 (0.0)	0 (0.0)	12 (37.5)
Diarrhoea	9 (28.1)	0 (0.0)	0 (0.0)	0 (0.0)	9 (28.1)
Nervous system disorders
Dysgeusia	10 (31.3)	1 (3.1)	0 (0.0)	0 (0.0)	11 (34.4)
Dizziness	4	(12.5)	0 (0.0)	0 (0.0)	0 (0.0)	4 (12.5)
Headache	4	(12.5)	0 (0.0)	0 (0.0)	0 (0.0)	4 (12.5)
Blood and lymphatic system disorders

Percentage (%)

	Grade 1		Grade 2		Grade 3		Grade 4

PHARMACOKINETICS5

degrades BRD9 in tumor tissue as seen at Cycle 1 Day 15 (D) in comparison to Baseline (B).

1. BRD9 H-score was plotted for all patients at different doses and the average of BRD9 H-score at screening (including
   archival tissue and fresh tumor biopsy) was used to normalize all data. These data show overall a high degradation level of BRD9, consistent at all doses and very comparable to the level of degradation observed in peripheral blood mononuclear cells (PBMCs, data not shown). All IHCs were performed by CellCarta and sections were quantified by a CellCarta histopathologist.

ANTI-TUMOR ACTIVITY5

Anaemia	5	(15.6)	2	(6.3)	4	(12.5)	0 (0.0)	11 (34.3)
Neutropenia	2	(6.3)	6	(18.8)	2	(6.3)	1 (3.1)	11 (34.3)
Thrombocytopenia	4	(12.5)	2	(6.3)	1	(3.1)	0 (0.0)	7	(21.9)
Leukopenia	1	(3.1)	3	(9.4)	1	(3.1)	0 (0.0)	5	(15.6)
Metabolism and nutrition disorders
Hypophosphataemia	4	(12.5)	3	(9.4)	0	(0.0)	0 (0.0)	7	(21.9)
Respiratory, thoracic and mediastinal disorders
Cough	3	(9.4)	2	(6.3)	0	(0.0)	0 (0.0)	5	(15.6)
Dyspnoea	1	(3.1)	2	(6.3)	1	(3.1)	0 (0.0)	4	(12.5)
Pneumothorax	0	(0.0)	1	(3.1)	2	(6.3)	1 (3.1)	4	(12.5)
Investigations
Aspartate aminotransferase increased	4	(12.5)	0	(0.0)	0	(0.0)	0 (0.0)	4	(12.5)
Blood alkaline phosphatase increased	4	(12.5)	0	(0.0)	0	(0.0)	0 (0.0)	4	(12.5)
Electrocardiogram QT prolonged	1	(3.1)	0	(0.0)	2	(6.3)	0 (0.0)	3	(9.4)
Neutrophil count decreased	0	(0.0)	2	(6.3)	1	(3.1)	0 (0.0)	3	(9.4)
Electrocardiogram T wave inversion	1	(3.1)	2	(6.3)	0	(0.0)	0 (0.0)	3	(9.4)
Hepatobiliary disorders
Hyperbilirubinaemia	1	(3.1)	1	(3.1)	2	(6.3)	0 (0.0)	4	(12.5)

• Table 5 represents all TEAEs reported, including related and unrelated
• Majority of AEs reported are considered mild to moderate in severity
• In review of available AEs, no dose-dependent relationship to incidence/severity of AEs observed
• The most common (occurring in ≥1 patient) TEAEs leading to treatment interruption include QT prolongation, T wave inversion, pneumothorax, and neutropenia
• Figure 4 represents all TEAEs along with all related TEAEs that occurred in ≥10% of enrolled patients
• The most common treatment related AEs include anemia, fatigue, dry mouth, dysgeusia, and neutropenia
• Majority of AEs were mild and were grade 1/2
• Grade 3 and 4 neutropenia occurred in 1 patient each

Figure 5: Dose Proportional Exposure and PK Profile5

1000

(ng/mL)PK				Cycle 1 Day 1
	100
Plasma	10
	1
	0	6	12	18	24
(ng/mL)	1000		Time (hrs)
100			Cycle 1 Day 15	4 mg QD
				2 mg QD
PK						8 mg QD
Plasma
10					15 mg QD
						30 mg QD
	1					50 mg QD
	0	6	12	18	24

Time (hrs)

Plasma exposure of CFT8634 increased proportionally with dose after single and repeat oral administration

Mean half-life of 10-14 hours supports once daily oral dosing

Figure 7: Anti-Tumor Activity5

A.

ChangeBest% from

Baselinein Sum of

TargetLesions

mg50

mg15

mg8

mg30

mg4

mg30

mg50

mg15

mg30

mg8

mg30

mg8

mg2

mg8

mg8

mg15

mg8

mg4

mg4

mg15

mg4

mg15

mg30

BOR

50

PR

0

SD

PD

-50

§

NE

B.

Target lesions assessed by RECIST PR SD PD NE

*

*

§

§PR was confirmed at a date after data cutoff.
Week
*Subjects dose escalated

As of the data cutoff, CFT8634 has shown preliminary evidence of anti-tumor activity in patients with synovial sarcoma and SMARCB1-null tumors across several dose levels, with eight patients demonstrating a best overall response of stable disease and one patient with a partial response

Figure 7A represents the % best change from baseline in the sum of target legions in all patients that received a follow up PET-CTscan

CONCLUSIONS

•	CFT8634 is an orally bioavailable selective bifunctional degrader of BRD9 that demonstrates dose-dependentanti-tumor activity in synovial	• CFT8634 demonstrated a dose proportional peak concentration and AUC across escalating dose levels
	sarcoma PDX models	•	BRD9 degradation was measured across dose levels in tumor tissues after 15 days of treatment
•	In 32 patients treated with CFT8634 at escalating dose levels at the time of the data cutoff date (08/29/2023), CFT8634 showed a manageable	•	CFT8634 has shown preliminary evidence of anti-tumor activity in patients with synovial sarcoma and SMARCB1-null tumors
	safety profile in patients with pre-treated synovial sarcoma and SMARCB1-null tumors		•	Tumor regression was observed across multiple dose levels including an unconfirmed PR in a SMARCB1-null tumor patient
	• Majority of AEs reported were considered mild to moderate in severity		•	At the time of data cutoff, 8 patients had stable disease as best response at 8 weeks per RECIST 1.1 criteria

• No clear dose dependent relationship to incidence/severity of TEAEs was observed

The Phase 1 dose escalation study is currently ongoing and an RP2D has not yet been identified

Abbreviations

AE, adverse event; BiDACTM, bifunctional degradation activating compound; BOR, best overall response; BRD9, bromodomain containing 9; CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; H&E, Hematoxylin and Eosin; IHC, immunohistochemistry; MTD, maximum tolerated dose; NE, not evaluable; OS, overall survival; PBMC, peripheral blood mononuclear cells; PD, progressive disease; PDX, patient-derivedxenografts; PET-CT,Positron Emission Tomography and Computed Tomography; PK, pharmacokinetics; PO, by mouth; PR, partial response; PS, performance status; QD, once daily; RESIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended Phase 2 dose; SD, stable disease; SMARCB1, SWI/SNF-related matrix-associated actin-dependentregulator of chromatin subfamily B member 1; SS, synovial sarcoma; SWI/SNF, SWItch/Sucrose Non-Fermentable; TEAE, treatment emergent adverse event; TESAE, treatment emergent serious adverse event; TORPEDO®, Target ORiented ProtEin Degrader Optimizer.

Disclosures

MA: consulting or advisory role: Lilly, Adaptimmune, Regeneron, AstraZeneca, BMS, Bayer, Deciphera; research funding: Exelixis. WT: research funding: AmMax Bio, Atropos Therapeutics, Ayala Pharmaceuticals, Bayer, Certis Oncology Solutions, Cogent Biosciences, Connecting Humans in Health, Daiichi Sankyo, Deciphera, Eli Lilly, Epizyme, Foghorn Therapeutics, Kowa Research Institute, MedPacto, Novo Holdings A/. GC: research funding: Servier Pharmaceuticals, Epizyme, PharmaMar, Macrogenics, Eisai, Merck, Bavarian Nordic, Bayer,

SpringWorks Therapeutics, Repare Therapeutics, Foghorn Therapeutics, SMP Oncology, Jazz Pharmaceuticals, RAIN Therapeutics, BioAlta, InhibitRX, Ikena, C4 Therapeutics. RR: stock and other ownership interests: J&J, Medtronic; honoraria: touchIME; consulting or advisory role: Epizyme; research funding: Ayala Pharmaceuticals, Bayer, Epizyme, SpringWorks Therapeutics; travel, accommodations, expenses: SpringWorks Therapeutics. SK: no disclosures. SC: research funding: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx

Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, and Thyme; stock or stock options: AADi, Cellestia Biotech, CounterPoint, Immix BioPharma SA: research funding: Desmoid Tumor Research Foundation, AB Science, TRACON Pharma, Bayer, Novartis, Lilly, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda,

Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics, TRACON Pharma, Ayala Pharmaceuticals, Trillium Therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, InhibRx, Noxopharm and Rain Therapeutics. AE: no disclosures. MM: no disclosures. JP: no disclosures. AA: employed by and equity holder in C4 Therapeutics. IM: employed by and equity holder in C4 Therapeutics.

RL: employed by and equity holder in C4 Therapeutics. JP: employed by and equity holder in C4 Therapeutics. HL: employed by and equity holder in C4 Therapeutics. EH: employed by and equity holder in C4 Therapeutics. KN: employed by and equity holder in C4 Therapeutics. BVT: leadership: Polaris; honoraria: Bionest Partner, Horizon CME, Research to Practice, Targeted Oncology; consulting or advisory role: Adaptimmune, ADRx, Apexigen, Ayala Pharmaceuticals, Bayer, Cytokinetics, Daiihi Sankyo, Deciphera, EMD Serono, Epizyme,

GlaxoSmithKline, Immune Design, Intellisphere, Lilly, Novartis, Pfizer; speakers' bureau at Adaptimmune, GlaxoSmithKline, Lilly, Novartis; research funding: GlaxoSmithKline, Merck, Pfizer, TRACON Pharma; patents, royalties, other intellectual property: Accuronix Therapeutics- Licensing agreement, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synth; patent on ALEXT3102; patent

on the use of ME1 as a biomarker; expert testimony: Health Advances; travel, accommodations, expenses: Adaptimmune, Advenchen Laboratories, GlaxoSmithKline, Lilly.

References

1. Jackson KL, et al. AACR 2022. Poster Presentation. 2. Brien GL et al. eLife. 2018;7:e41305. 3. Sergi CM. Biosci Rep. 2022;42(6):BSR20220040. 4. Aytekin MN. J Orthop Surg. 2020;28(2):2309499020936009 5. C4 Therapeutics data on file. 6. NCT05355753. www.clinicaltrials.gov. Accessed September 6, 2023. Acknowledgements

We would like to thank the site support staff, study sponsor, and collaborators as well as participating patients and their families for their contributions to the study. This study is sponsored by C4 Therapeutics, Inc. Editorial support was provided by Red Nucleus and funded by C4 Therapeutics, Inc. All authors contributed to and approved the presentation.

Presented at CTOS Annual Meeting, November 1-4, 2023, Dublin, Ireland.