Repare Therapeutics : Initial Data from Phase 1 MINOTAUR Clinical Trial – Combination with FOLFIRI

PHASE 1 STUDY OF THE PKMYT1 INHIBITOR LUNRESERTIB (LUNRE) IN COMBINATION WITH FOLFIRI IN ADVANCED GASTROINTESTINAL CANCERS (MINOTAUR STUDY)

Elisa Fontana, MD, PhD

Sarah Cannon Research Institute UK, London, UK

Associate Professor, University of Birmingham, UK

Zev A. Wainberg, Alisha H. Bent, Victor Moreno, Manuel Pedregal, Rutika Mehta, Eric Chen, Jorge Ramon-Patino, Ryan H. Moy, Brian Madajewski, Adam Petrone, Pooja Adesara-Patel, Yajun Liu, Xizi Sun, Elia Aguado-Fraile, Paul Basciano, Sunantha Sethuraman, Nathan Hawkey, Elisa Fontana

DECLARATION OF INTERESTS

Elisa Fontana

Employee of Hospital Corporation of America (HCA) International

Honoraria:

Repare Therapeutics, CARIS Life Science, Seagen, Sapience, BicycleTx Ltd (conference attendance);

Astellas, Pfizer (Advisory Board)

Leadership roles:

European Organisation for Research and Treatment of Cancer (EORTC), Gastrointestinal Tactical Coordinating Group (GITCG) secretary (2021- 2023)

ASCO Annual Meeting Scientific Programme Committee GI cancers, Colorectal and Anal Track (2024-2026)

Funding to Institution:

Acerta Pharma, ADC Therapeutics, Amgen, Arcus Biosciences, Array BioPharma, Artios Pharma Ltd, Astellas Pharma Inc, Astex, Astra Zeneca, Basilea, Bayer, BeiGene, BicycleTx Ltd, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Calithera Biosciences, Inc., Carrick Therapeutics, Casi Pharmaceuticals, Clovis Oncology, Inc, Crescendo Biologics Ltd., CytomX Therapeutics, Daiichi Sankyo, Deciphera, Eli Lilly, Ellipses, Exelixis, F. Hoffmann-La Roche Ltd, Fore Biotherapeutics, G1 Therapeutics, Genentech, GSK, H3 Biomedicine Inc, Hutchinson MediPharma, Ignyta/Roche, Immunocore, Immunomedics, Inc., Incyte, Instil Bio, IOVANCE, Janssen, Jiangsu Hengrui, Kronos Bio, Lupin Limited, MacroGenics, Menarini, Merck KGaA, Mereo BioPharma, Merus, Millennium Pharmaceuticals, MSD, Nerviano Medical Sciences, Nurix Therapeautics Inc, Oncologie, Oxford Vacmedix, Pfizer, Plexxikon Inc., QED Therapeutics, Inc., Relay Therapeutics, Repare Therapeutics, Ribon Therapeutics, Roche, Sapience, Seagen, Servier, Stemline, Synthon Biopharmaceuticals, Taiho, Tesaro, Turning Point Therapeutics, Inc, PMVPharma, Takeda

This study was funded by Repare Therapeutics, Inc.

Elisa Fontana

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

FBXW7mut prevalence1CRC - 13.1% Esophageal - 7.1% Gastric - 10.2%

CCNE1amp prevalence1CRC - 0.5 % Esophageal - 7.1% Gastric - 6.4%

LUNRE AND IRI SYNERGIZE TO ENHANCE DNA DAMAGE AND ANTI-TUMOR ACTIVITY

CCNE1amp and deleterious FBXW7mut present in ~20% of GI cancers are associated with poor prognoses1-3 and have no matched targeted therapies

Lunre, a well-tolerated,first-in-class PKMYT1i, is synthetically lethal with CCNE1amp or deleterious FBXW7mut 4,5

Lunre abrogates iri-induced CDK1 phosphorylation causing premature entry into mitosis with extensive DNA damage, enabling synergistic anti-tumor activity

			CCNE1 amp
FBXW7mut
		Cyclin E	Dysregulated
				CDK2	G1/S checkpoint
	G1
Lunre		Cell		S
	M	Cycle
PKMYT1	CDK1				Iri
			Amplified DNA damage
	Cyclin B
				and replication stress

% positive tissue

40

35

30

25

20

15

10

5

Target engagement

- pCDK1 (Thr14) IHC

% strong positive cells

Vehicle Lunre Iri Lunre + Iri

35

30

25

20

15

DNA damage

- gH2AX IHC

Tumor volume (mm3)

VehicleLunre Iri Lunre + Iri

Anti-tumor activity

1500					Vehicle
				Lunre 10 mg/kg BID
1250					Iri 15 mg/kg QW
1000					Lunre + Iri
750
500
250
0
0				5	10		15	20
						Time (days)

Target engagement - pCDK1 (Thr14)

Pre-treatmentOn-treatment

DNA damage- gH2AX IHC

Pre-treatmentOn-treatment

DLD FBXW7-/-tumor-bearing animals (CB-17 SCID, n=7 per group) were treated with single agents lunre (10 mg/kg, BID, PO daily), Iri (15 mg/kg, IP, QW), or the combination and assessed for anti-tumor activity and tumor PD biomarker modulation via evaluation of pCDK-Thr14 and γH2AX by IHC in tumor samples tissue samples collected on day 2 (26 hours after treatment initiation, n=3 animals per treatment group). Paired pre- and on-treatment biopsies were collected on the MINOTAUR study those collected within the window achieving exposure above IC90 were evaluable for target engagement and showed declines in pCDK-Thr14 levels. DNA damage induction confirms pathway engagement. amp, amplification; BID, twice daily; CCNE1, cyclin E1; CDC25, cell division cycle-25; CDK, cyclin-dependent kinase; CHK1, checkpoint kinase 1; CRC, colorectal cancer; FBXW7, F-box and WD repeat domain containing 7; g, gamma; GI, gastrointestinal; H, histone; IHC, immunohistochemistry; iri, irinotecan; lunre, lunresertib; mut, mutated; p, phosphorylated; Ph, phase; PKMYT1, protein kinase, membrane-associated tyrosine/threonine; SCID, severe combined immunodeficiency; Thr, threonine; QW, once weekly.

MINOTAUR: STUDY DESIGN AND DEMOGRAPHICS

(PKMYT1 INhibitor and FOLFIRI TreAtment of solid TUmoRs)

Key inclusion criteria	Design and objectives
• Locally advanced or metastatic	Lunre (dose escalation) + FOLFIRI
GI or other solid tumors

Demographics

	CRC	Other	Total
	tumorsc
Parameter, n (%)	(N=18)	(N=38)
(N=20)
Sex
Male	12 (66.7)	9 (45.0)	21 (55.3)

• Measurable disease by RECIST v1.1
• Local NGS report (tissue or plasma-based)
• CCNE1amplificationa or deleterious FBXW7alterations (centrally reviewedb)
• Prior iri permitted

• Primary:
• • Safety and tolerability
  • RP2D and schedule
• Secondary and exploratory:
• • Pharmacokinetics
  • Preliminary antitumor activity
  • Pharmacodynamics
  • ctDNA monitoring

Age (years)		(33-75) 57.5 (31-78) 55.5
Median (range)	55.0	(31-78)
≥65 years	5 (27.8)	7 (35.0)	12	(31.6)
ECOG status
0	8 (44.4)	10 (50.0)	18	(47.4)
1	10	(55.6)	10 (50.0)	20	(52.6)
Prior LoT
0-2	7 (38.9)	14 (70.0)	21	(55.3)
3+	11	(61.1)	6 (30.0)	17	(44.7)
Prior iri	13	(72.2)	5 (25.0)	18	(47.4)
Prior platinum	17	(94.9)	20 (100)	37	(97.4)
RAS/BRAF	4 (22.2)	13 (65)	17	(44.7)
WTd
RASmut e	14	(77.8)	7 (35)	21	(55.3)
BRAFmut	0 (0)	0 (0)	0 (0)

Study is ongoing, closed to enrollment: NCT05147350

Enrollment gene	18 (100.0)	8 (40.0)	26 (68.4)
FBXW7
CCNE1	0 (0)	12 (60.0)	12 (31.6)

aCopy number ≥6. bNGS report centrally reviewed and annotated by Precision Oncology Decision Support (PODS) Group at MDACC. cOther tumor types include anal (n=2), bile duct (n=3), esophageal (n=4), gastric (n=5), jejunal (n=1), pancreatic (n=3), and neuroendocrine (originating from the intestinal tract; n=2). dIncludes WT RAS and RAF. eIncludes single nucleotide variants and/or amplifications in KRAS and NRAS. ANC, absolute neutrophil count; CCNE1, cyclin E1; CRC, colorectal; ctDNA, circulating tumor DNA; ECOG, Eastern Cooperative Oncology Group; FBXW7, F-box and WD repeat domain containing 7; FOLFIRI, folinic acid, fluorouracil, and irinotecan hydrochloride; iri, irinotecan; GI, gastrointestinal; LoT, lines of therapy; mut, mutation; NGS, next-generation sequencing; pts, patients; RECIST, response evaluation criteria in solid tumors; RP2D, recommended phase II dose; WT, wild-type.

SAFETY PROFILE CONSISTENT WITH FOLFIRI ALONE

RP2D established at 60mg BID, continuous daily dosing

• Lunre 40-240mg continuous and 160-240mg 3 days on/4 days off were evaluated
• No safety-related treatment discontinuation or Gr3+ TRAEs at RP2D

Safety profile consistent with FOLFIRI alonea,6,7

• Neutropenia was the most common Gr3+ hematologic TRAE
• • Similar rate to FOLFIRI alone (30% vs 31.6%)a,6,7
  • Reversible and preventable with FOLFIRI interruption and/or dose modifications

	All patients
	N=38
TRAEs in ≥ 15% of	All Grades	Gr3+b
patients, n (%)
Nausea/Vomiting	21 (55.3)	1	(2.6)
Neutropenia	16 (42.1)	12	(31.6)
Diarrhea	15 (39.5)	2	(5.3)
Mucosal inflammation	15 (39.5)	2	(5.3)
Fatigue	13 (34.2)	0 (0)
Rashc	12 (31.6)	0 (0)
Alopecia	8 (21.1)	1	(2.6)
Leukopenia	8 (21.1)	5 (13.2)
Anemia	7 (18.4)	2	(5.3)
PPE syndrome	7 (18.4)	1	(2.6)
Stomatitis	7 (18.4)	3	(7.9)
Taste disorder	6 (15.8)	0 (0)

aData extracted from the control arm of the randomized phase III VELOUR study. bGrade 4 TRAEs: neutropenia in 3 (7.9%) patients. cRash terms include maculo-popular, pruritis, rash, skin exfoliation, erythema, dermatitis contact, eczema, flushing, rash erythematous, and rash pruritic. BID, twice daily; d, day; FOLFIRI, folinic acid, fluorouracil, and irinotecan hydrochloride; gr, grade; lunre, lunresertib; PPE, palmar-plantar erythrodyxaesthesia;

RP2D, recommended phase II dose; TRAE, treatment-related adverse event.

PROLONGED CLINICAL BENEFIT AND ROBUST ANTI-TUMOR ACTIVITY OBSERVED, INCLUDING IN PATIENTS WITH PRIOR IRI

CRC

CBRa: 7 (46.7%)	DOT >9 mo in CRC
Iri naïve: 2/5 (40%)
	Iri-experienced: 2/10 (20%)

	80	ORRb: 18.2% (95% CI: 7-35.5)
	60
change from BL tumor size (%)
40
20
0
−20
−40
Best in
−60
	−80

Other tumors

			100	ctDNA MRRc: 14/23 (61%)
	PR, confirmed	mVAFR	50
CBRa: 10 (55.6%)	PR, unconfirmed
Enrollment gene	Treatment ongoing	0
FBXW7	First PD	Best	−50
CCNE1	Prior iri
RP2D (60 mg BID)
	−100

0	4	8	12	16	20	24	28	32	36	40	44	48	52	56	60	64	68	72
									Time on treatment (weeks)
		Tumor type:			Anal			Bile duct			Colorectal			Esophageal		Gastric		Jejunal			Neuroendocrine			Pancreatic

aCBR was defined as the best overall response of CR or PR according to RECIST 1.1 criteria or duration of treatment ≥16 weeks without (denoted by dashed line). bORR was defined as the best response of confirmed CR or PR, unconfirmed CR or PR, or tumor marker response according to RECIST v1.1 criteria. cctDNA MR was defined as a ≥50% decline in ctDNA (denoted by dashed line). For DOT and tumor reduction data as of 6June24 and represent the efficacy evaluable population (≥1 post-baseline tumor assessment; n=33). ctDNA MR data as of 07May2024 using the Tempus xF+ liquid biopsy panel. Patients with no variants detected at baseline were deemed as non-monitorable for this analysis (n=7). BID, twice daily; BL, baseline; CBR, clinical benefit rate; CCNE1, cyclin E1; PR, partial response; CRC, colorectal cancer; DOT, duration of treatment; FBXW7, F-box and WD repeat domain-containing 7; iri, irinotecan; mo, months; MRR, molecular response rate; mVAFR, mean variant allele frequency rate; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; RP2D, recommended phase II dose.

PROLONGED TUMOR RESPONSE IN PATIENT WITH ANAL CARCINOMA

Case description:

• 59-year-oldfemale patient with anal carcinoma with FBXW7 mutation, high cyclin E
• History of 3 prior treatments; no prior iri

Study treatment: Lunre: 120mg BID 3 days on/4 days off and

iri: 180mg/m2; 5FU 2400mg/m2; LV 400mg/m2

• Duration of treatment: 9 months
• Response:
• • PR (confirmed), initially at 6 weeks
  • Best target lesion decrease from baseline: -65.2%
  • Molecular Response at 4 weeks: -98%

Porta Hepatis LN

Tumor assessmenta

Baseline	6 weeks
24 mm	11 mm

ctDNA dynamicsb

Gene alteration:

ARID1A p.R1721*

ATR p.R2547Q

CDK12 p.P1313A

ERBB2 p.E207K

FBXW7 p.R479P

FBXW7 p.R83K

MTOR p.R491L

RET p.E235Q

ROS1 p.Q925*

aRepresentative CT scans from screening (baseline) and 6 weeks on study. Bar represents 150mm. bctDNA analysis of allele frequency over time. 5-fluorouracil; BID, twice daily; d, days; CT, computed tomography; ctDNA, circulating tumor DNA; FBXW7, F-box and WD repeat domain-containing 7; FOLFIRI, folinic acid, fluorouracil, and irinotecan hydrochloride; iri, irinotecan; LN, lymphnode; lunre, lunresertib; LV, leucovorin; PR, partial response.

PROLONGED STABLE DISEASE IN PATIENT WITH CRC AND PRIOR IRI

Case description: 67-year-old male patient with CRC with KRAS and FBXW7 mutations

Prior therapies:

• Neoadjuvant CAPOX, primary and liver resection, adjuvant CAPOX - PD within 5 months
• FOLFIRI x 5 cycles with PD
• Trifluridine/tipiracil x 3 cycles with PD

Study treatment: Lunre: 240mg QD continuous and iri: 180mg/m2; LV 400mg/m2; 5FU infusion 2400mg/m2

• Duration of treatment: 46 weeks
• Response:
• • SD with decrease from baseline: -1.3%
  • Molecular Response at 2 weeks: -74%

aRepresentative CT scans from screening (baseline) and 6 weeks post treatment. Red line indicates tumor and bar represents 150mm. bctDNA analysis of allele frequency over time. 5FU, 5-fluorouracil; CAPOX, capecitabine and oxaliplatin; CRC, colorectal cancer; CT, computed tomography; ctDNA, circulating tumor DNA; FBXW7, F-box and WD repeat domain-containing 7; FOLFIRI, folinic acid, fluorouracil, and irinotecan hydrochloride; iri, irinotecan; lunre; lunresertib; LV, leucovorin; PD, progressive disease; QD, once weekly; SD, stable disease.

Liver metastasis Lung metastasis RLL Segment

Tumor assessmenta

Baseline	6 weeks
20 mm	16 mm

72 mm

76 mm

ctDNA dynamicsb

Gene alteration:	p.A1492fs
APC
APC	p.R876*
BRCA1	p.V1532I
ERBB2	p.T105I
KRAS	p.G12D
TERT	p.K570T

CONCLUSIONS

In the first evaluation of this novel combination, standard FOLFIRI and daily lunre were well tolerated

• The hematologic safety profile was consistent with that reported for FOLFIRI alone
• Low-grade,reversible rash was consistent with lunre monotherapy experience

Preliminary RP2D was established as 60mg BID continuous daily lunre plus standard FOLFIRI, with no Gr3+ TRAEs or TRAEs leading to discontinuation observed at RP2D

Promising efficacy in a heavily pretreated CCNE1amp and FBXW7mut population known to be associated with a poor prognosis

• 6 partial responses, regardless of prior iri exposure (ORR: 18.2%)
• Patients with CRC had prolonged clinical benefit with 40% of iri-naïve patients receiving treatment >9 months

This promising targeted treatment combination in high-risk GI tumors that harbor CCNE1amp or FBXW7mut warrants further exploration in a randomized phase II study

ACKNOWLEDGEMENTS

The authors would like to thank the patients, their families, and all investigators involved in the MINOTAUR (RP- 6306-03) study and the participating MINOTAUR site study coordinators for their contributions. We would also like to thank the members of the Repare Clinical Study Team:

• Biljana Bazdar-Vinovrski, Samuel Bonilla, Adrian J. Fretland, Stephanie Guerrera, Michelle Hahn, Esha Jain, Susan May, Leena Rasal, Adam Remick, Victoria Rimkunas, Ian M. Silverman, Ellen Skalski, Danielle Vasconcelos, and Marisa Wainszelbaum
• Sara Fournier and Marc Hyer for the preclinical data

Thank you to Dr. Rachel Woodford from the Sarah Cannon Research Institute UK for exceptional care of the patient with CRC and providing the scans shown in this presentation.

This study was funded by Repare Therapeutics Inc.

Elisa Fontana

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