ASCO 2023 Annual Meeting: A Phase 1/2 Study of CFT1946 Trial-in-Progress Poster

A Phase 1/2 Study Of CFT1946, A Novel Bifunctional Degradation Activating Compound, or BiDAC™ Degrader, of Mutant BRAF V600 as Monotherapy and in Combination with Trametinib, in Mutant BRAF V600 Solid Tumors

Meredith McKean, MD1, Alexander I. Spira, MD, PhD2, Ezra Rosen, MD, PhD3, Vivek Subbiah, MD4, Victor Moreno, MD5, Valentina Gambardella, MD6, Maria Vieito, MD7, Omar Saavedra Santa Gadea, MD8, Sophie Cousin, MD9,

Philippe Alexandre Cassier, MD10, Riadh Lobbardi, PhD11, Oliver Schönborn-Kellenberger, MSc11, Eunju Hurh, PhD11, Mary M. Ruisi, MD11, Elizabeth I. Buchbinder, MD12

1Tennessee Oncology (Sarah Cannon Research Institute), Nashville, TN; 2Virginia Cancer Specialists, Fairfax, VA; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4MD Anderson Cancer Center, Houston, TX; 5Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 6Institute of Hospital Clinico de Valencia, Valencia, Spain;

#356a

7Hospital Universitario Vall d'Hebron, Barcelona, Spain; 8Next Oncology, Barcelona, Spain; 9Institut Bergonié, Department of Medical Oncology, Bordeaux, France; 10Léon Bérard Center, Lyon, France; 11C4 Therapeutics, Inc., Watertown, MA; 12Dana-Farber Cancer Institute, Boston, MA

BACKGROUND

FIRST-IN-HUMAN STUDY DESIGN

• BRAF is a protein kinase that acts as a signal transducer/amplifier in receptor tyrosine kinase (RTK) signaling pathways, specifically, the mitogen activated protein kinase (MAPK) pathway that promotes cell proliferation and survival when activated through extracellular signals1,2
• Constitutively active mutated BRAF, specifically BRAF with valine 600 mutations (BRAF V600), is capable of uncontrolled signaling which signals as a monomer, resulting in hyperactivation of MEK, ERK, and dysregulation of cellular proliferation2

PRE-CLINICAL DATA: IN VIVO (continued)

Figure 5: CFT1946 Induces Tumor Regression in the A375 (homozygous BRAF V600E) Xenograft Mouse Model as a Single Agent and in Combination With the MEK Inhibitor, Trametinib, in a BRAF Inhibitor-Resistant Xenograft

5

KEY ELIGIBILITY CRITERIA6

KEY INCLUSION CRITERIA	KEY EXCLUSION CRITERIA
•	≥18 years of age at time of informed consent	• Subject has had major surgery within 21 days prior
•	Documented evidence of a BRAF V600	to the planned first dose. Minor surgery is

• BRAF V600 is a clinically

validated oncology target in

the follow tumor types1-3

• Melanoma, colorectal

cancer (CRC), non-small

cell lung cancer (NSCLC),

and anaplastic thyroid

carcinoma (ATC)

• Currently approved BRAF

inhibitors (BRAFi) result in

Figure 1: Utilizing a Degrader Approach to Overcome Limitations of BRAF Inhibition5

Mouse Model

A. CFT1946 Treatment of A375 Cell Line In Vivo Shows Dose-Dependent Tumor Regression Superior to Inhibitor

mutation obtained from tumor tissue or	permitted within
liquid biopsy	21 days prior to enrollment
• Received ≥1 prior line of SoC therapy for	• Subject with CNS involvement (primary tumor or
unresectable locally advanced or metastatic	metastatic disease), except if clinically stable
disease, NSCLC, CRC, ATC or other BRAF V600	• Subject with known malignancy other than trial
mutation-positive tumors	indication that is progressing or has required
• Adequate bone marrow, liver, renal, and	treatment within the past 3 years, except for
cardiac organ function	conditions that have undergone potentially
	curative therapy

paradoxical RAF activation

as the mutant BRAF protein

is still able to dimerize with

wtBRAF, resulting in a

dimeric signaling complex4

(Figure 1)

volume (mm3)

2000

1600

1200

Vehicle, PO BID Encorafenib, 35 mg/kg PO QD CFT1946, 0.3 mg/kg PO BID CFT1946, 3 mg/kg PO BID CFT1946, 10 mg/kg PO BID

STUDY ENDPOINTS6

PRIMARY ENDPOINTS	SECONDARY ENDPOINTS
• Frequency and severity of AEs and SAEs of	•	Frequency and severity of AEs and SAEs of CFT1946
	CFT1946 (Phase 1)		(Phase 2)
•	Incidence of DLTs (Phase 1)	•	Number of participants with changes between
•	Number of participants with changes between		baseline and post-baseline safety assessments

CFT1946 BACKGROUND5

• CFT1946 is a novel, orally bioavailable, bifunctional degradation activating compound, or BiDAC™ degrader
• • CFT1946 selectively inhibits and degrades mutant BRAF V600 protein
  • Distinct from approved BRAFi, CFT1946 avoids paradoxical RAF activation as the degraded BRAF V600 mutant protein can no longer incorporate into a dimeric signaling complex (Figure 1)
• CFT1946 is selective for the Figure 2: Mechanism of Action for CFT1946 Compound5
  mutant protein and spares wtBRAF V600
• Mechanism of action

(Figure 2)

i. CFT1946 induces

A375 tumor

800

400

0

0	5	10	15	20	25
		Treatment days

30

35

baseline and post-baseline safety assessments		(Phase 2)
(Phase 1)	•	Frequency of dose interruptions and dose reductions
• Frequency of dose interruptions and dose		(Phase 2)
reductions (Phase 1)	•	Assessment of PK and PD
• Frequency of AEs leading to discontinuation	•	PK-QTcF relationship
(Phase 1)	•	ORR (Phase 1 and 2)
• ORR (Phase 2)	•	DCR
	•	PFS
	•	DOR

STUDY STATUS/ENROLLMENT6

The study opened to accrual in December 2022 and will be recruiting ~N=135patients from 11 sites*

ternary complex

formation with BRAF

and cereblon E3 ligase

(step 1)

ii. BRAF V600 is

ubiquitinated and

subsequently released

for degradation in

the proteasome

(steps 2-4)

• CFT1946 has demonstrated

preclinical activity in BRAF

V600 mutant in vitro and

in vivo models, including

models resistant to BRAFi

(Figures 3-5)

PRE-CLINICAL DATA: IN VITRO

Figure 3: CFT1946 Is an On-Mechanism,CRBN-Based, Highly Selective BRAF V600X BiDAC™ Degrader5

A. CFT1946 Degrades	B.	CFT1946 is an	C.		Proteome Profiling
	BRAF V600E in a Dose-		On-Mechanism		Demonstrates Selectivity of
	Dependent Manner		BiDAC™ Degrader		CFT1946 for BRAF V600E
															CFT1946 (300 nM, 24 h) in A375 Cells
Remaining%													dabrafenibvs.value-p	15
									Emax = 26%	CFT1946 (100 nM) in A375 cells @ 24 h
	100													10
	75									BRAF V600E
	50									pERK
									DC50 = 14 nM
	25												BRAF V600E
										BRAFV600E			5
	0										Vinculin		10			LOXL4
	10	0	10	1	10	2	10	3	10	4		-Log
			[CFT1946] (nM)									ARAF
								*note: +/- refers to presence or absence of 100 nM CFT1946			RAF1
													0
														-4	-2	0	2	4
															Log	Fold Change vs. dabrafenib
															2

• CFT1946 acts as both an inhibitor and a degrader of BRAF V600E as demonstrated in HiBiT assay in panel A. Phospho-ERK levels decrease in a CFT1946 dose-dependent manner. BRAF V600E levels decrease in a CFT1946 dose-dependent manner until "hook effect" concentrations are achieved. Panel B demonstrates that CFT1946 is on-mechanism for a CRBN-based BiDAC™ degrader and Panel C shows the selectivity of CFT1946 in A375 cells using global proteomic profiling.

PRE-CLINICAL DATA: IN VIVO

Figure 4: Dose Proportional PK and PD Profile in the BRAF V600E A375 Xenograft Mouse Model for CFT1946 Compound5

					Dose Proportional PK and PD for CFT1946
A.	(ng/ml)plasmain						B.
concentrationCFT1946	100000					expressionproteinBRAF	vehicletorelative	1.5
		10000				0.3 mg/kg PO							0.3 mg/kg PO
		1000				3 mg/kg PO			1.0				3 mg/kg PO
		100				10 mg/kg PO			0.5				10 mg/kg PO
		10
		1							0.0
		0	12	24	36	48			0	12	24	36	48
				Time (h)						Time (h)
C.	(ng/g)tumorin						D.
concentrationCFT1946	100000					expressionproteinpERK	vehicletorelative	1.5
		10000				0.3 mg/kg PO							0.3 mg/kg PO
		1000				3 mg/kg PO			1.0				3 mg/kg PO
		100				10 mg/kg PO			0.5				10 mg/kg PO
		10
		1							0.0
		0	12	24	36	48			0	12	24	36	48

Time (h)	Time (h)

• Pharmacodynamic data demonstrates a dose-proportional loss of BRAF V600E protein and decreased signaling through the MAPK pathway as determined by loss of phospho-ERK (pERK). As CFT1946 degrades BRAF V600 mutant protein and results in decreases phospho-ERK levels, some MAPK pathway inhibition occurs prior to maximal loss of BRAF V600E protein.

1. Combination Treatment of BRAFi-Resistant Xenograft Model With CFT1946
   and MEKi Shows Tumor Growth Inhibition/Regression

A375 + NRAS-Q61K Xenograft

)	2500
3
(mm		Vehicle (PO BID)
volume	2000	MEKi: Trametinib (0.1 mg/kg BID)
Encorafenib (35 mg/kg QD + MEKi)
tumor	1500
	CFT1946 (10 mg/kg BID)
NRAS	1000	CFT1946 (30 mg/kg BID)
500
A375	CFT1946 (10 mg/kg BID) + MEKi
		CFT1946 (30 mg/kg BID) + MEKi

0
0	7	14	21
	Treatment days

1. In the A375 mouse xenograft model, CFT1946 showed dose-dependent tumor growth inhibition (TGI) when administered PO at 0.3 mg/kg and 3 mg/kg BID, and immediate and sustained tumor regression at 10 mg/kg PO BID.
2. In the BRAFi-resistantA375+NRAS-Q61K xenograft model, CFT1946 showed dose-dependent TGI when administered PO as a single agent at 10 mg/kg (TGI ~35%) and 30 mg/kg (TGI ~60%) BID.
   When CFT1946 at 10 and 30 mg/kg BID was combined with 0.1 mg/kg trametinib, combination treatment resulted in tumor regression up to Day 16 and Day 19, respectively, with slight tumor re-growth emerging at Day 19 and Day 21, respectively.

These preclinical data provide rationale for a first-in-human (FIH) study to

evaluate CFT1946 in BRAF V600 mutant solid tumors

PHASE 1/2: FIRST-IN-HUMAN CLINICAL STUDY DESIGN5,6

• Open-label,multicenter, Phase 1/2 clinical trial with dose escalation and expansion phases*
• Dose escalation Phase 1 comprises CFT1946 (Arm A) with a starting oral dose of 20 mg twice daily and CFT1946+trametinib (Arm B)
• Dose expansion Phase 2 comprises CFT1946 (Arm A1) and CFT1946+trametinib (Arms B1 and B2)†
• • Arms A1 and B1 will include BRAF V600 mutant melanoma and NSCLC with prior BRAFi therapy while Arm B2 will enroll BRAF V600 mutant NSCLC who are BRAFi-naïve
• N=135 (approximately) across 11 US and European sites will be enrolled
• Registered on ClinicalTrials.gov as NCT05668585, study is open for enrollment

Figure 6: CFT1946 Study Design5‡

PHASE 1

PHASE 2

Dose Escalation Monotherapy

Dose Expansion Monotherapy

Arm A:

Expansion Arm A1:

•

CFT1946 Monotherapy

•

V600 Solid Tumors (non-CNS)

•

CFT1946 Monotherapy

RP2D

(s/p BRAFi for lung, CRC, melanoma, ATC)

•

V600 Melanoma + NSCLC (s/p BRAFi)

•

3-6 patients/cohort, BLRM

•

N=~30

•

N=~40

Dose Expansion: combination

Dose Escalation: combination

Expansion Arm B1:

Arm B:

•

CFT1946 + trametinib

Dose determined

•

CFT1946 + trametinib

•

V600 Melanoma + NSCLC (s/p BRAFi)

to be safe by SRC

•

V600 Solid tumors (non-CNS) (s/p

•

N=~20

RP2D

BRAFi for lung, melanoma, ATC, CRC)

Expansion Arm B2:

•

3-6 patients/cohort, BLRM

•

CFT1946 + trametinib

•

N=~25

•

V600 NSCLC (BRAFi naÏve)

•

N=~20

*CFT1946 is administered orally in 28-day cycles until disease progression or intolerable toxicity.

† Phase 2 will be initiated once the RP2D has been identified. Eligible subjects are ≥18 years-old with documented BRAF V600 mutant cancers who have received ≥1 prior therapy.

‡Phase 2 expansion study design will be updated based on Health Authority feedback.

in the US and Europe

• Trial registration: NCT05668585
• As of 05/15/2023, all 5 US sites have initiated recruitment
• Contact information: [e-mail]

United States

WA										ME
MT		ND								NH
		MN					VT
OR							NY		MA
				WI				CT	RI
ID			SD				MI
WY					PA
			IA				NJ
NV			NE		IN	OH		DE
			IL
UT		CO		KS	MO			WV	VA	MD
CA					KY	NC
						TN
				OK			SC
AZ	NM		AR		AL
			MS	GA
				TX	LA
AK									FL

HI

Europe

FR

ES

*Blue-colored US states and EU countries indicate clinical trial sites. 2 sites are located in France and 4 sites in Spain.

Abbreviations

AE, adverse event; ATC, anaplastic thyroid carcinoma; BID, twice daily; BiDACTM, bifunctional degradation activating compound; BLRM, Bayesian logistic regression model; BRAF, v-raf murine sarcoma viral oncogene homolog B1; BRAFi, BRAF inhibitor, Bx, biopsy; CNS, central nervous system; CRBN, cereblon; CRC, colorectal cancer; DCR, disease control rate; DLT, dose limiting toxicities; DOR, duration of response; ERK, extracellular signal-regulated kinases; FIH, first-in-human;HiBiT, high affinity bioluminescent tag; IMiD, immunomodulatory imide drug; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MEKi, MEK inhibitor; MTD, maximum tolerated dose; NRAS, neuroblastoma ras; NSCLC, non-small cell lung cancer; ORR, overall response rate; pERK, phospho-ERK;PD, pharmacodynamics; PDX, patient-derived xenografts; PFS, progression-free survival; PK, pharmacokinetics; PO, by mouth; PoM, proof of mechanism; QD, once daily; QTcF, Fridericia heart-rate- corrected QT interval; RAF, rapidly accelerated fibrosarcoma; RP2D, recommended phase 2 dose; RTK, receptor tyrosine kinase; SAE, serious adverse event; s/p, status post; SoC, standard-of-care;SRC, Safety Review Committee; TGI, tumor growth inhibition; wt, wild-type.

Disclosures

1. consulting or advisory role: AstraZeneca, Pfizer, Astellas Pharma, Bicycle Therapeutics, Castle Biosciences, Eisai, IDEAYA Biosciences, iTeos Therapeutics, Moderna Therapeutics; research funding: Prelude Therapeutics, Genentech, Tizona Therapeutics, Inc., GlaxoSmithKline, IDEAYA Biosciences, Exelixis, Jacobio, Moderna Therapeutics, Regeneron, Epizyme, TopAlliance Biosciences, Ascentage Pharma Group, Oncorus, Ikena Oncology, Bicycle Therapeutics, Tmunity Therapeutics, Inc., Sapience Therapeutics, NBE Therapeutics, Dragonfly Therapeutics, Infinity Pharmaceuticals, Novartis, Plexxikon, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Bayer, BioMed Valley Discoveries, BioNTech, EMD Serono, Erasca, Inc, Foghorn Therapeutics, Gilead Sciences, ImmVira, KeChow Pharma, Kezar Life Sciences, Kinnate Biopharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, PACT Pharma, Pfizer, Pyramid Biosciences, Scholar Rock, Synthorx, Takeda, TeneoBio, Tempest Therapeutics, Xilio Therapeutics, AADI, Accutar Biotech, Astellas Pharma, G1 Therapeutics, OncoC4, Poseida Therapeutics. AIS: consulting or advisory role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Bio, Jazz Pharmaceuticals, Merck, Bristol Myers Squibb, Takeda, Janssen Research & Development, Mersana, Blueprint Medicines, Daiichi Sankyo/Astra Zeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; leadership: Next Oncology; stock and other ownership interests: Lilly; honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer; research funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, MacroGenics, CytomX Therapeutics, LAM Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Bio, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics, Synthekine, Mersana Therapeutics, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Synthekine, Black Diamond Therapeutics, BluPrint Oncology, nalo therapeutics. ER: no disclosures. VS: consulting or advisory role: MedImmune, Helsinn Therapeutics, Relay Therapeutics, Pfizer, Loxo/Lilly; travel, accommodations, expenses: PharmaMar, Bayer, Novartis, Helsinn Therapeutics, Foundation Medicine; other relationship: Medscape; research funding: Novartis, GlaxoSmithKline, NanoCarrier, Northwest Biotherapeutics, Genentech/Roche, Berg, Bayer, Incyte, Fujifilm, PharmaMar, D3 Oncology Solutions, Pfizer, Amgen, AbbVie, MultiVir, Blueprint Medicines, Loxo, Vegenics, Takeda, Alfasigma, Agensys, Idera, Boston Biomedical, Inhibrx, Exelixis, Amgen, Turning Point Therapeutics, Relay Therapeutics. VM: employment: START; consulting or advisory role: Merck, Bristol Myers Squibb, Bayer, Janssen Oncology, Roche, Basilea, Affimed Therapeutics, AstraZeneca; speakers' bureau: Bayer, Pierre Fabre; travel, accommodations, expenses: Sanofi/Regeneron; expert testimony: Medscape/Bayer, Nanobiotix; other relationship: Bristol Myers Squibb, research funding: AbbVie, ACEA Biosciences, Adaptimmune, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eisai, E-therapeutics, GlaxoSmithKline, Janssen, Menarini, Merck, Nanobiotix, Novartis, Pfizer, PharmaMar, PsiOxus Therapeutics, Puma Biotechnology, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho Pharmaceutical, Takeda, Tesaro, Transgene. VG: no disclosures.
   MV: consulting or advisory role: Roche, BMS GmbH & Co. KG; travel, accommodations, expenses: Roche; other relationships: Roche, BMS GmbH & Co. KG, Debiopharm
   Group, Incyte, Novartis, PharmaMar, Mundipharma, Taiho Oncology, SERVIER, HUTCHMED; research funding: Novartis, Roche/Genentech, Thermo Fisher Scientific,
   AstraZeneca, BeiGene, Taiho Oncology. OSSG: travel, accommodations, expenses: Affimed. SC: no disclosures. PAC: consulting or advisory role: OSE Immunotherapeutics,
   Bristol Myers Squibb/Celgene, Janssen Oncology, Boehringer Ingelheim; travel, accommodations, expenses: Roche, OSE Immunotherapeutics, Novartis; honoraria: Amgen;
   research funding: Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme,
   Taiho Pharmaceutical, Toray Industries, Transgene, Loxo, GlaxoSmithKline, Innate Pharma, Janssen, Boehringer Ingelheim. RL: employed by and equity holder in
   C4 Therapeutics. OSK: consulting or advisory role: C4 Therapeutics. EH: employed by and equity holder in C4 Therapeutics. MMR: employed by and equity holder in
   C4 Therapeutics. EIB: employment: Alexion Pharmaceuticals (an immediate family member), Takeda (an immediate family member); consulting or advisory role: Nektar,
   Instil Bio, Novartis, Xilio Therapeutics, Sanofi, Merck, Iovance Biotherapeutics; research funding: Bristol-Myers Squibb, Checkmate Pharmaceuticals, Novartis, Lilly, Genentech/Roche.

Acknowledgements	References
We would like to thank the site support staff, study sponsor,	1.	Ascierto PA, et al. J Transl	4.	Hoyer S, et al. Int J Mol Sci.	Copies of this poster
and collaborators as well as participating patients and their		Med. 2012;10:85.		2021;22(21):11951.	obtained through QR Code
families for their contributions to the study. This study is	2.	Zheng G, et al. BMC Cancer.	5.	C4 Therapeutics data on file.	are for personal use only
sponsored by C4 Therapeutics, Inc. Editorial support was		2015;15:779.	6.	NCT05668585.	and may not be reproduced
provided by Red Nucleus and funded by C4 Therapeutics, Inc.	3.	Chang CF, et al. Am J Cancer		www.clinicaltrials.gov.	without permission from
All authors contributed to and approved the presentation.		Res. 2022;12(11):5342-5350.		Accessed March 3, 2023.	ASCO and the author.

Presented at The American Society of Clinical Oncology Annual Meeting (ASCO 2023), June 2-6