Replimune : IGNYTE Oral Presentation at ASCO 2024

EFFICACY AND SAFETY OF RP1 COMBINED WITH NIVOLUMAB IN PATIENTS WITH ANTI-PD-1-FAILED MELANOMA FROM THE IGNYTE CLINICAL TRIAL

Michael K. Wong, Joseph J. Sacco, Caroline Robert, Judith Michels, Tawnya L. Bowles, Gino K. In, Katy K. Tsai, Céleste Lebbé, Caroline Gaudy-Marqueste, Eva Muñoz-Couselo, Mark R. Middleton, Adel Samson, Dirk Schadendorf, Georgia M. Beasley, Jiaxin Niu, Bartosz Chmielowski, Trisha M. Wise-Draper, Junhong Zhu, Marcus Viana, Mohammed M. Milhem

Dr. Michael K. Wong, MD, PhD, FRCPC

The University of Texas MD Anderson Cancer Center, Houston, TX, USA

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Key takeaways

Clinical relevance

• Treatment of melanoma patients after progression on an anti-PD-1 containing regimen remains a considerable unmet need

m

IGNYTE data analysis by investigator review

• Efficacy
• • RP1 combined with nivolumab provides deep and durable responses in patients with advanced melanoma who had confirmed disease progression, while on prior anti-PD-1 therapy for at least 8 weeks, including in combination with anti-CTLA-4
  • The ORR was 33%, with a median duration of response of >36 months (N=156)
• Safety
• • The treatment showed a favorable safety profile with generally 'on target' and transient grade 1-2 side effects indicative of systemic immune activation

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Background

• There are limited options for melanoma patients who have progressed on anti-PD-1 therapy1 (including on adjuvant

anti-PD-1 therapy)

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• Further single agent anti-PD-1 for patients having confirmed PD on prior anti-PD-1 gives a response rate of 6-7%1,2
• For patients who have not received anti-CTLA-4 therapy, ipilimumab or nivolumab + ipilimumab or relatlimab are potential options3, but toxicity is high4-5
• Adding anti-LAG3 to anti-PD-1 has not demonstrated meaningful efficacy in the anti-PD-1-failed setting6
• For targeted therapy-naïve patients with BRAF mutant tumors, BRAF-targeted therapy responses are generally

transient7

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• T-VEC+ pembrolizumab in patients who progressed on prior anti-PD-1 therapy has limited activity outside of the

adjuvant setting, with no responses seen in patients with visceral disease8-9

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• TIL therapy gives response rates of ~30%, but comes with toxicity (nearly all patients have grade 4 toxicity)10

CTLA-4, cytotoxic T-lymphocyte antigen 4; LAG3, lymphocyte-activation gene 3; PD-1, programmed cell death protein 1; TIL, tumor infiltrating lymphocyte

1. Mooradian MJ, et al. Oncology. 2019;33(4):141-8. 2. Beaver JA, et al. Lancet Oncol. 2018;19(2):229-39. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Melanoma: Cutaneous. Version 2.2024. 4. Pires da Silva I, et al. Lancet Oncol. 2021;22(6):836-47. 5. VanderWalde AM, et al. Presented at the American Association of Cancer Research Annual Meeting 2022. New Orleans. 6. Ascierto PA, et al. J Clin Oncol. 2023;41(15)2724-35. 7. Dixon-Douglas JR, et al. Curr Oncol Rep. 2022;24(8):1071-9. 8. Gastman B, et al. J Clin Oncol. 2022;40(16_suppl):9518. 9. Hu-Lieskovan S, et al. Cancer Res. 2023;83(7_suppl):3275. 10. US Food and Drug Administration. BLA clinical review and evaluation - AMTAGVI. BLA 125773. Updated February 6, 2024. Accessed May 31, 2024].https://www.fda.gov/media/176951/download.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

IGNYTE Study design (Anti-PD-1 failed melanoma cohort)

28 days	First dose	2 weeks	RP1+nivolumaba	2 weeks	2 weeks	Nivolumab
28 days	RP1 1×106	2 weeks	2 weeks Nivolumab
Screening		1×107 pfu/mL,	240 mg		480 mg (Q4W)
	pfu/mL		240 mg
Anti-PD-1-failed
cutaneous melanoma							100-day
cohort
						safety
(140 pts; 16 pts treated	Cycle 1		Cycles 2-8	Cycle 9		Cycles 10-30b
		follow-up
in prior cohorts: Total
156)

3-yearfollow-up from last patient enrolled

Tumor response assessment: Radiographic imaging (CT) at baseline and every 8 weeks from first dose and every 12 weeks after confirmation of response

Primary objectives

• To assess the safety and efficacy (by independent central review [mRECIST]) of RP1 in combination with nivolumab

Secondary objective

• ORR by investigator review (mRECIST)
• To assess the efficacy of RP1 in combination with nivolumab as determined by DOR, CR rate, DCR, PFS, by central & investigator review, 1-year and 2-year OS

Key eligibility

Advanced melanoma having confirmed progression while onprior anti-PD-1 therapyc; at

least 1 measurable and injectable lesion (≥1 cm LD), including deep/visceral; adequate organ function; no prior treatment with oncolytic therapy; ECOG performance status 0-1

Criteria for prior anti-PD-1-failure

≥8 weeks of prior anti-PD-1,confirmed progression while onanti-PD-1;anti-PD-1 must be the last therapy before the clinical trial. Patients on prior adjuvant therapy must

have progressed while onprior adjuvant treatment (progression can be confirmed by biopsy)

Primary analysis to be conducted when all patients have ≥ 12 months follow up

aDosing with nivolumab begins at dose 2 of RP1 (C2D15). bOption to reinitiate RP1 for 8 cycles if criteria are met.

c. Non-neurological solid tumors CR, complete response; CT, computed tomography; DCR, disease control rate; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; LD, longest diameter; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death protein 1; PFS, progression-free survival; pfu, plaque-forming unit; Q4W, every 4 weeks; RECIST, Response Evaluation Criteria in Solid Tumors.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Baseline clinical characteristics

• A 'real world' anti-PD-1 failed melanoma population was enrolled
• • Good representation of each of the sub-groups of patients who progress on prior anti-PD-1 therapy

	Patients, n (%)	All patients
		(N = 156)
	Age (median [range])	62 (21-91)
	Sex
	Female	52 (33.3)
	Male	104 (66.7)
	Stage
	IIIb/IIIc/IVM1a	75 (48.1)
	IVM1b/c/d	81 (51.9)
	Prior therapy
	Anti-PD-1 only as adjuvant therapy	39 (25.0)
	Anti-PD-1 not as adjuvant therapy	117 (75.0)
	Anti-PD-1 & anti-CTLA-4	74 (47.4)
	Received BRAF-directed therapy	17 (10.9)

	Patients, n (%)	All patients	​
		(N = 156)	​
	Other disease characteristics
	Primary resistance to prior anti-PD-1a	105 (67.3)	​
	Secondary resistance to prior anti-PD-1b,c	51 (32.7)​
	BRAF wt	103 (66.0)	​
	BRAF mutant	53	(34.0)​
	LDH ≤ULN	105 (67.3)	​
	LDH >ULN	50	(32.1)​
	LDH unknown	1	(0.6)	​

The median follow up for all patients on study is 15.4 months (range 0.5-55.5)

Data cutoff: March 8th 2024. aPrimary resistance: Progressed within 6 months of starting the immediate prior course of anti-PD-1 therapy; bSecondary resistance: Progressed after 6 months of treatment on the immediate prior course of anti-PD-1 therapy; cIncludes 2 pt unknown resistance status. CTLA-4, cytotoxic T-lymphocyte antigen 4; LDH, lactate dehydrogenase; PD-1, programmed cell death protein 1; ULN, upper limit of normal; wt, wild-type.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Efficacy

• The data presented today is the investigator assessed data with all patients having at least 12 months follow up
• • Centrally reviewed, primary endpoint data, will be presented separately once available

BOR

1. (%)
   CR PR SD

PD

ORR

			All patients enrolled in IGNYTE
All patients	Prior single-	Prior anti-PD-	Stage IIIb-IVM1a	Stage IVM1b-d	1o resistance to	2o resistance to
(n = 156)	agent anti-PD-1	1/CTLA-4	(n = 75)	(n = 81)	anti-PD-1	anti-PD-1
	(n = 82)	Exposure				(n = 105)	(n = 51)b
		(n = 74)a
23 (14.7)	18 (22.0)	5	(6.8)	18 (24.0)	5	(6.2)	18 (17.1)	5	(9.8)
28 (17.9)	13 (15.9)	15	(20.3)	13 (17.3)	15	(18.5)	18 (17.1)	10	(19.6)
34 (21.8)	18 (22.0)	16	(21.6)	19 (25.3)	15	(18.5)	17 (16.2)	17	(33.3)
63 (40.4)	31 (37.8)	32	(43.2)	24 (32.0)	39	(48.1)	47 (44.8)	16 (31.4)
51 (32.7c)	31 (37.8)	20 (27.0)	31 (41.3)	20 (24.7)	36 (34.3)	15 (29.4)

aEight patients were treated with sequential anti-CTLA-4 and anti-PD-1 (ORR for prior combined anti-CTLA-4/anti-PD-1 was 25.8%). bIncludes one patient with unknown resistance status. cORR for the 140 registration intended cohort was 32.1%

• Approximately 1 in 3 patients achieved an objective response (32.7%)
• Consistent ORR across subgroups, including:

1. 27% ORR in patients who had prior anti-PD-1 & anti-CTLA-4

1. 34% ORR in patients who are primary resistant to their prior anti-PD-1 therapy

Data cutoff: March 8th 2024. BOR, best overall response; CR, complete response; CTLA-4, cytotoxic T-lymphocyte antigen 4; PD-1, programmed cell death protein 1; PD, progressive disease; PR, partial response; ORR, objective response rate; SD, stable disease.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Responses are Systemic

Change in Size of Individual Injected and Non-injected Lesions

RP1 Injected

RP1 Non-injected

first 28 responders from the study

• All lesions were measured, not only target lesions

• Each line represents

an individual lesion

• 70.4% of responding patients had non-injected lesions
• • Responders include patients with minority of lesions injected
• Injected and non-injected lesions responded with similar duration and kinetics
• Depth of response independent of whether injected

Responses in non-injected lesions

demonstrate systemic benefit

Includes both target and non-target lesions for RECIST assessment, measured from CT/MRI scans for radiologically assessable lesions (responders from the first 75 patients enrolled into the registration intended cohort). 58/75 patients had at ≥ 1 non-injected lesion, of whom 15 achieved a response based on those lesions only (excludes possible response in injected lesions); ORR of 25.9% on the basis of non-injected lesions only. First presented at ASCO 2023.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Duration of Response

• Responses are durable, with a median DOR by Kaplan-Meier estimate of 36.6 months

Probability (%)

# at risk
>6 months	>12 months	>18 months	>24 months
100%	84.2%	74.9%	65.2%

The median follow up for responders is 27.9 months (range 10.5-55.5)

Data cutoff: March 8th 2024. Duration of response defined as time from baseline to end of response for responders. DOR, duration of response.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Duration of Benefit

• A substantial proportion of patients achieved durable clinical benefit, including those with SD, with a 55% disease control rate overall

• 65% of responses are ongoing at the time of this analysis

Patients with at least one post baseline assessment

Data cutoff: March 8th 2024. The target lesion response is shown for patients with at least one post-baseline assessment. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC

Patient examples

Patient 1121-2011: Stage IVM1c,progressed on prior nivolumab (adjuvant) and pembrolizumab (1L); CR

Injected

Non-injected

Patient 1156-2008: Stage IVM1b, BRAF- mutant, progressed on prior nivolumab (1L); PR

Injected Non-injected

Responses seen in non-injected distant & visceral tumors

RP1 injected

Non-injected

1L, first line; CR, complete response; PR, partial response

PRESENTED BY: Dr. Michael K. Wong, MD, PhD, FRCPC