Relay Therapeutics : ESMO Congress 2022 Presentation

Efficacy of RLY-4008

Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients with an FGFR2 fusion or rearrangement, FGFR inhibitor-naïve cholangiocarcinoma: ReFocus trial

Antoine Hollebecque1, Mitesh J. Borad2, Lipika Goyal3, Alison M. Schram4, Joon Oh Park5, Philippe Cassier6, Suneel Kamath7, David Tai8, Efrat Dotan9, Richard Kim10, Vaibhav Sahai11 Do-Youn Oh12, Chih-Yi Andy Liao13, Michael Millward14, Desamparados Roda Perez15, Charles Ferté16, Rick Blakesley16, Beni B. Wolf16, Vivek Subbiah17, Robin Kate Kelley 18

1Institut Gustave Roussy, Paris, France; 2 Mayo Cancer Center, Scottsdale, USA; 3Massachusetts General Hospital, Boston, USA;

4Memorial Sloan Kettering Cancer Center, New York, USA; 5Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 6Centre Léon Berard, Lyon, France; 7The Cleveland Clinic Taussig Cancer Institute, Cleveland, USA; 8National Cancer Centre Singapore, Singapore; 9Fox Chase Cancer Center, Philadelphia, USA; 10H. Lee Moffitt Cancer Center & Research Institute, Tampa, USA; 11The University of Michigan, Ann Arbor, USA; 12Seoul National University Hospital, Seoul, Republic of Korea;

13The University of Chicago, Chicago, USA; 14Linear Clinical Research & University of Western Australia, Nedlands, Australia; 15Hospital Clínico Universitario de Valencia, Spain; 16Relay Therapeutics, Cambridge, USA; 17The University of Texas MD Anderson Cancer Center, Houston, USA; 18UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA

Paris, France, 11 September 2022

Declaration of Interests

Dr. Antoine Hollebecque declares participation on safety monitoring or consulting and advisory boards for Amgen, Basilea, BMS, Incyte, Servier, QED Therapeutics, Relay Therapeutics, and Taiho

Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

Cholangiocarcinoma and Oncogenic FGFR2 Fusions

Cholangiocarcinoma (CCA) is a rare malignancy with a dismal prognosis1

Intrahepatic CCA

FGFR2 fusions/rearrangements drive ~10-15% of intrahepatic cholangiocarcinoma2

Ig-1Ig-2Ig-3			Exon 18
							Y	Y Y	Y Y
						770	780 784	806 813
	IIIb		TM	FGFR2 IIIb C1/WT/FL
		KINASE
					Y L D	L		Grb2-binding
				770			773

Perihilar CCA

Gallbladder cancer

Distal CCA

1st Line: Gemcitabine/Cisplatin +/- Durvalumab mOS ~1 year3-4 2nd Line: FOLFOX mOS ~6m5

				Y	Y	Y
IIIb	TM			770	780 784
KINASE			FGFR2 IIIb C2
		Y	L	D	L
		770			773

IIIb		TM	KINASE	Fusion partner	FGFR2 IIIb C3
IIIb		TM	KINASE	DIMERIZATION	FGFR2 IIIb Fusions
IIIb		TM	KINASE		E18

2nd Line Emerging pan-FGFRi: Infigratinib, Pemigatinib,Futibatinib

Off-isoform toxicities; On-target resistance mutations6-13

1.Banales JM, et al. Nature Rev Gastroenterol Hepatol. 2020;17b(9):557-588. 2. Jusakul A, et al. Cancer Discov. 2017;7(10):1116-1135. 3. Valle J, et al. N Eng J Med. 2010;362:1273-81. 4. Imfinzi (durvalumab) [package insert]. Wilmington, DE AstraZeneca; 2022. 5. Lamarca A, et al. Lancet Oncol. 2021;22(5):690-701. 6. Yu J, et al. OncoTargets Ther. 2021:14:5145-5160. 7. Abou-Alfa GK. et al. Lancet Oncol. 2020;21: 671-684. 8. Javle M. et al. Lancet Gastroenterol Hepatol. 2021;6:803-815. 9. Meric-Bernstam F.et al. Cancer Discov. 2022;12:402-415. 10.Silverman IM. et al. Cancer Discov. 2021;11:326-339. 11. Chen L. et al. Exp Clin Cancer Res. 2021;40:345. 12.Goyal L. et al. Cancer Discov. 2019;9:1064-1079;20. 13. Krook MA. et al. Mol Cancer Ther. 2020;19:847-857.

Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

RLY-4008: The First Highly Selective FGFR2 Inhibitor

In contrast to pan-FGFRi,RLY-4008 is a potent and selective FGFR2 inhibitor

				RLY-4008 selectively inhibits
				FGFR2 based on unique
				conformational dynamics1
	Inhibitor	Mechanism			Biochemical IC50 (nM)2-5
	of Action	FGFR1		FGFR2	FGFR3	FGFR4
		Irreversible	864.3	3.1	274.1	17,633
	RLY-4008	FGFR2
		selective
	Infigratinib	Reversible	1.1		1	2	61
	Pan-FGFRi
	Pemigatinib	Reversible	0.39		0.46	1.2	30
	Pan-FGFRi
	Futibatinib	Irreversible	1.8		1.4	1.6	3.7
	Pan-FGFRi

Potent in-vivo activity against FGFRi-sensitive and resistant cholangiocarcinoma2

FGFR2 fusion	FGFR2 fusion-V565F
FGFRi naïve	pan-FGFRi resistant
Xeno	Xeno

Total daily dose:		Vehicle		Pemigatinib (1 mg/kg)		Erdafitinib (30 mg/kg)
		Infigratinib (30 mg/kg)		Futibatinib (6 mg/kg)		RLY-4008 (30 mg/kg)

1. Schönherr H. et al. Presented at MedChem GRC meeting; August 7-12,2022. 2. Goyal L. et al. Presented at AACR Annual Meeting; April-9-14;2021. 3.Truseltiq(infigratinib) [package insert]. Brisbane,CA QED Therapeutics; 2021.

1. Pemazyre(pemigatinib) [NDA]. Wilmington, DE;2019.www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213736Orig1s000ChemR.pdfAccessed August 25,2022. 5. Sootome H. et al. Cancer Res. 2020;80(22):4986-4997.

Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

ReFocus: A Global, Seamless Phase 1/2 Open Label Study

Phase 2 Expansion (initiated Dec 2021)

Cholangiocarcinoma

Phase 1 Dose Escalation

(completed)

Patients with unresectable or metastatic CCA and other solid tumors harboring an FGFR2 alteration

by local testing

RLY-4008 70 mg QD (RP2D)

FGFR2 fusion+ previously treated with chemotherapy, FGFRi-naïve (n=100) Pivotal Cohort

FGFR2 fusion+ previously treated with FGFRi (n=50)

FGFR2 fusion+ treatment-naïve (n=20)

FGFR2 mutant or amplified (n=20)

Other advanced solid tumors with FGFR2 alterations

3 Cohorts FGFR2 fusion+, amplified and mutant (n=30 each)

Key objectives

Phase 1: Maximum tolerated dose and Recommended Phase 2 Dose (RP2D), safety, PK and preliminary efficacy

Phase 2: Objective response rate (ORR) and duration of response (DoR) by independent review committee

Preliminary data, data cut August 1, 2022 (response investigator assessed)

Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.