Slide 1: Vusolimogene oderparepvec-wtpg (TUDRIQEV) with Nivolumab for Advanced Cutaneous Melanoma
CC-1 Vusolimogene oderparepvec-wtpg (TUDRIQEV ) in Combination with Nivolumab for the Treatment of Adults with Unresectable Advanced Cutaneous Melanoma July 30, 2026 United States Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee
Slide 2: Introduction
CC-2 Introduction Kari Jeschke, MA Senior Vice President, Regulatory Affairs, Replimune, Inc.
Slide 3: Melanoma Community Support for Urgent Access to RP1
CC-3 Melanoma Community Support for Urgent Access to RP1
Slide 4: Proposed Indication Statement
CC-4 TUDRIQEV is indicated in combination with nivolumab for the treatment of adults with unresectable advanced cutaneous melanoma who experienced disease progression with an anti-programmed death receptor-1 (PD-1) based regimen Proposed Indication Statement
Slide 5: Favorable Benefit-Risk for Accelerated Approval
CC-5 Favorable Benefit-Risk for Accelerated Approval IGNYTE-3 randomized confirmatory trial ongoing with OS data expected in 2030 UNMET NEED: SERIOUS, LIFE-THREATENING DISEASE EFFICACY Adequate and Well-controlled Trial Supporting Evidence IGNYTE ORR: 33.6% (95% CI: 25.8, 42) DoR: 24.8 months (95% C
Slide 6: Melanoma Approvals Since Initiation of IGNYTE Study
CC-6 Melanoma Approvals Since Initiation of IGNYTE Study 1. NCCN Guidelines Version 2.2026 Melanoma: Cutaneous. MELSYS 2 of 10. 2. Ascierto PA, et al. J Clin Oncol. 2023 May 20;41(15):2724-35. 3. AMTAGVI USPI. 2024 Iovance Biotherapeutics, Inc. Recent FDA Approvals Year Basis of Approval Relevance t
Slide 7: Ongoing Collaboration with FDA through 2025
CC-13 Ongoing Collaboration with FDA through 2025 2021 2022 2023 2024 2025 Key alignments with FDA: • Potential flexibility on single trial, pending compelling evidence (2021) • Enroll real-world population (2021) • RECIST 1.1 (2023) • Analysis of all injected and non-injected lesions (2023) • Liter
Slide 8: Initial FDA Clinical Review: Basis for Approval
CC-14 Initial FDA Clinical Review: Basis for Approval FDA BLA Clinical Review and Evaluation, July 15 2025 (obtained by Replimune through Freedom of Information Act) “…The reviewers acknowledge that the clinical benefit of VO in combination with nivolumab is based on results from a single arm trial
Slide 9: Initial FDA Clinical Review: Recommended RP1 for Approval
CC-15 Initial FDA Clinical Review: Recommended RP1 for Approval FDA BLA Clinical Review and Evaluation, July 15 2025 (obtained by Replimune through Freedom of Information Act) “…Based on the IGNYTE trial results, a comprehensive literature review, the life-threatening condition of the intended patie
Slide 10: Regulatory Topics
CC-16 Regulatory Topics
Slide 11: Relevance of MOA to Response Assessment
CC-17 Relevance of MOA to Response Assessment LOCAL IMMUNE EFFECT SYSTEMIC IMMUNE EFFECT • Direct oncolytic virus-mediated tumor lysis attracts antigen-presenting cells • Antigen-presenting cells internalize tumor antigens, leading to T cell activation • Activated T cells traffic systemically, drivi
Slide 12: RECIST 1.1: Replimune vs. FDA Response Rate Analysis
CC-18 RECIST 1.1: Replimune vs. FDA Response Rate Analysis *If corrected for denominator = 25% (FDA sensitivity analysis) FDA ANALYSIS N=22 N=0 ORR 15.7%*, n/N=22/140 REPLIMUNE ANALYSIS N=22 N=25 ORR 33.6%, n/N=47/140 NON-INJECTED TARGET LESION ALL TARGET LESIONS INJECTED Patients with all target le
Slide 13: Replimune Position: Response Assessment
CC-19 Replimune Position: Response Assessment FDA Issues from briefing document FDA Issue Replimune Position Application of RECIST 1.1 confounds interpretation of efficacy results “RECIST 1.1 specifies that tumor lesions subjected to loco-regional therapies are generally not considered measurable fo
Slide 14: Replimune Position: Response Assessment
CC-20 Replimune Position: Response Assessment 1. FDA Type C meeting September 2023 FDA Issues from briefing document; BOR, best overall response; IRC, independent review committee FDA Issue Replimune Position Other confounding factors: Patient-by-patient analysis confirms appropriate response assess
Slide 15: Replimune Position: Contribution of Effect
CC-21 Replimune Position: Contribution of Effect FDA Issues from briefing document 1. NCCN, SITC, Ribas FDA Issue Replimune Position “Objective response data from the single-arm IGNYTE study is not of sufficient magnitude to overcome concerns about the contribution of effect, particularly in the abs
Slide 16: What You Will Hear Today
CC-22 What You Will Hear Today Dual mechanism of action Kevin Harrington, MD, PhD, FRCP, FRCR, FRSB Professor of Biological Cancer Therapies Institute of Cancer Research Mechanism of Action Michael Wong, MD, PhD, FRCPc Clinician, IGNYTE Study Advisory Board Former Physician in Chief, Roswell Park Ca
Slide 17: Additional Experts
CC-23 Additional Experts RECIST/ itRECIST Greg Goldmacher Chief Scientific & Medical Officer, Perceptive Inc. Melanoma Oncologist Nikhil Khushalani Vice Chair for the Department of Cutaneous Oncology, Moffitt Cancer Center Melanoma Oncologist Yana Najjar Associate Professor of Medicine and Director
Slide 18: RP1 Mechanism of Action and Biological Plausibility
CC-24 RP1 Mechanism of Action and Biological Plausibility Kevin Harrington, MD, PhD, FRCP, FRCR, FRSB Professor of Biological Cancer Therapies Institute of Cancer Research
Slide 19: Dual MOA Drives Local and Systemic Antitumor Immune Responses
CC-25 Dual MOA Drives Local and Systemic Antitumor Immune Responses 1. Thomas S, et al. J Immunother Cancer. 2019;7(1):214. RP1 is an HSV-1 based oncolytic viral immunotherapy that expresses GM-CSF and a fusogenic glycoprotein GALV-GP-R1 1LOCAL IMMUNE EFFECT 2 SYSTEMIC IMMUNE EFFECT Oncolytic Immuno
Slide 20: RP1 Combined with Anti-PD-1 Enhances Systemic Anti-tumor Activity
CC-26 RP1 Combined with Anti-PD-1 Enhances Systemic Anti-tumor Activity mRP1=mouse RP1 Thomas et al. JITC 2019 Injected Tumor Un-injected Tumor Tumor Diameter (mm) Vehicle Anti-PD1 0/10 regress 0/10 regress 0/10 regress 0/10 regress 20 15 10 5 0 0 5 10 15 20 25 30 35 40 20 15 10 5 0 0 5 10 15 20 25
Slide 21: Mechanisms of Resistance to Anti-PD-1
CC-27 • Lack of T cell, PD-L1 expression and IFN gamma are known to be the resistance mechanisms of anti-PD-1 treatment1 • Patients who have drug holiday before progression on anti-PD-1: retreatment may be effective – Tumor microenvironment may still be immunologically active/sensitive – Memory CD8+
Slide 22: RP1+Nivolumab Increases CD8+ T Cells and PD-L1 Levels
CC-28 RP1+Nivolumab Increases CD8+ T Cells and PD-L1 Levels in IGNYTE Patients 1. Data on file Additional analysis confirmed responding lesions exhibit significantly higher CD8+ and PD-L1 at Day 43 vs. screening (compared to lesions that do not respond)1 1. Data on file Patient 2 (Responder) SCREENI
Slide 23: RP1 + Nivolumab Reprograms the Tumor Microenvironment
CC-29 RP1 + Nivolumab Reprograms the Tumor Microenvironment (TME) in IGNYTE Melanoma Patients P Value by Mann-Whitney U Test (Wilcoxon rank-sum test). D, day; DAPI, 4′,6-diamidino-2-phenylindole; FOXP3, forkhead box P3; nivo, nivolumab; PD-1, programmed cell death protein 1; PD-L1, programmed death-
Slide 24: Melanoma: Unmet Need and Treatment Paradigm
CC-30 Melanoma: Unmet Need and Treatment Paradigm Michael Wong, MD, PhD, FRCPc Clinician, IGNYTE Study Advisory Board Former Physician in Chief, Roswell Park Cancer Center
Slide 25: Significant Unmet Need Exists for Advanced Melanoma
CC-31 • In the US, 110,000 new melanoma cases with ~8,500 related deaths projected in 20261 • 50% of advanced melanoma patients progress in the first 12 months2,3 • Real-world 5-year OS among patients with distant metastatic disease is only 35%1 Significant Unmet Need Exists for Advanced Melanoma 1.
Slide 26: Limited Options Post ICI Progression in Advanced Melanoma
CC-32 Limited Options Post Immune Checkpoint Inhibitor (ICI) Progression in Advanced Melanoma Neoadjuvant/ Adjuvant/ First line • Pembrolizumab (Keytruda) • Nivolumab (Opdivo) • Ipilimumab (Yervoy) • Ipilimumab + Nivolumab • Relatlimab/Nivolumab (Opdualag) Monotherapy Combinations
Slide 27: Limited Options Post ICI Progression in Advanced Melanoma
CC-33 Limited Options Post Immune Checkpoint Inhibitor (ICI) Progression in Advanced Melanoma Neoadjuvant/ Adjuvant/ First line • Pembrolizumab (Keytruda) • Nivolumab (Opdivo) • Ipilimumab (Yervoy) • Ipilimumab + Nivolumab • Relatlimab/Nivolumab (Opdualag) Monotherapy Combinations Progression on Ant
Slide 28: Lifileucel (AMTAGVI) is the Only FDA Approved Agent for Anti-PD-1 Failed Melanoma
CC-34 Lifileucel (AMTAGVI) is the Only FDA Approved Agent for Anti-PD-1 Failed Melanoma AMTAGVI (lifileucel) [package insert]; initial approval 2024 Lifileucel (AMTAGVI) Efficacy (ORR) • 31.5% (4.1% CR) • (n=73, primary efficacy data set) Safety (Gr3+) • 7.5% treatment-related mortality (n=160) Cons
Slide 29: NCCN Recommendations: PD-1 Retreatment Unlikely to Show Benefit
CC-35 NCCN Recommendations: PD-1 Retreatment Unlikely to Show Benefit “if a patient experienced progression of melanoma during or shortly after a systemic therapy, rechallenge with the same therapy or a therapy of the same class is unlikely to yield a response and is not recommended.” -NCCN Guidelin
Slide 30: Options Following Progression on Monotherapy Anti-PD-1
CC-36 Options Following Progression on Monotherapy Anti-PD-1 Progression 1. VanderWalde et al 2023 Nat Med. 2023 Sep;29(9):2278-85; 2. Ascierto et al RELATIVITY-020 trial. J Clin Oncol. 2023 May 20;41(15):2724-35. On progression 28% ORR1 57% Grade 3+ toxicity 9-12% ORR2 ~15% Grade 3+ toxicity Anti-P
Slide 31: Options Following Progression on Combination ICI
CC-37 Options Following Progression on Combination Immune Checkpoint Inhibitor (ICI) 1. Ascierto et al RELATIVITY-020 trial. J Clin Oncol. 2023 May 20;41(15):2724-35; 2. Menzies et al 2022 N Engl J Med. 2022;386(17):1668-9 Ipilimumab + Anti-PD-1 Relatlimab + Nivolumab 9-12% ORR1 ~15% Grade 3+ toxici
Slide 32: Summary
CC-38 • Based on the RELATIVITY-020 study a 9-12% ORR is a reasonable benchmark for the IGNYTE study data • Limited existing options have significant toxicity and/or modest response rates • Unmet need remains significant for patients who have failed anti-PD-1 based treatments Summary
Slide 33: IGNYTE Study: Anti-PD-1 Failed Cutaneous Melanoma
CC-39 IGNYTE Study: Anti-PD-1 Failed Cutaneous Melanoma Kostas Xynos, MD, PhD, MBA Chief Medical Officer, Replimune, Inc.
Slide 34: IGNYTE Phase 2 Study Design: Anti-PD-1 Failed Cutaneous Melanoma Cohort
CC-40 IGNYTE Phase 2 Study Design: Anti–PD-1 Failed Cutaneous Melanoma Cohort CRR, complete response rate; DCR, disease control rate; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death protein-1; PFS, p
Slide 35: Strict Criteria to Ensure Patients Definitively Failed Anti-PD-1 Therapy
CC-41 Strict Criteria to Ensure Patients who are Enrolled Definitively Failed Anti–PD-1 Therapy 1. FDA clinical review, July 15, 2025 • Minimum exposure requirement: ≥8 weeks; 96% of patients received ≥12 weeks • Anti–PD-1 therapy required as the immediate prior line of treatment • Confirmed progres
Slide 36: Baseline Clinical Characteristics: A Real-World Population
CC-42 Baseline Clinical Characteristics: A Real-World Population Data cutoff: October 15, 2024. a Primary resistance: immediate prior anti-PD-1 exposure ≥6 weeks and best response of PD or SD for <6 months. b Secondary resistance: immediate prior anti-PD-1 exposure ≥6 months and best response of CR,
Slide 37: Efficacy
CC-43 Efficacy
Slide 38: Clinically Meaningful Responses Observed in Anti-PD-1-Refractory Melanoma
CC-44 Clinically Meaningful Responses Observed in Anti-PD-1–Refractory Melanoma Population (IGNYTE Study) 0 10 20 30 40 50 Overall Response Rate (ORR) Complete Response (CR) Partial Response (PR) Stable Disease (SD) Percent (%) 33.6% 16.4% 17.1% 21.4% n=47 n=23 n=24 n=30 Data Cutoff: October 15, 202
Slide 39: Only 5-7% ORR Expected with Further Anti-PD-1 Monotherapy
CC-45 Only 5-7% ORR Expected with Further Anti-PD-1 Monotherapy Following Definitive Progression Ribas A, et al. Lancet Oncol. 2018;19(5):e219; Kluger HM, et al. J Immunother Cancer. 2020;8(1):e000398. 0 10 20 30 40 50 RP1 + Nivo (IGNYTE) SITC Monotherapy Guidelines (Kluger 2020) PD-1 Monotherapy (R
Slide 40: RELATIVITY-020 is a Reasonable Benchmark for Magnitude of Effect
CC-46 RELATIVITY-020 is a Reasonable Benchmark for Magnitude of Effect Ascierto PA, et al. J Clin Oncol. 2023;41(15)2724-35. ≤5% 0 10 20 30 40 50 RP1 + Nivolumab (IGNYTE) Nivolumab + Relatlimab (RELATIVITY-020*) Percent (%) >20% increase 33.6% 9-12% Similar study design • Prospective study with broa
Slide 41: Meaningful Responses Across Clinically Relevant Subgroups
CC-47 RP1+ Nivolumab Delivers Meaningful Responses Across Clinically Relevant Subgroups Data cutoff: October 15, 2024 Centrally reviewed RECIST 1.1 responses; all patients have ≥12 months follow-up All patients 140 33.6 (25.8, 42.0) Agent Single-agent anti-PD-1 75 40.0 (28.9, 52.0) Anti–PD-1/CTLA-4
Slide 42: Durable Response Supports Systemic Benefit
CC-48 ORR (95% CI) was 33.6% (25.8%, 42.0%), and the median DOR (95% CI) was 24.8 months (14.8, NE) Durable Response Supports Systemic Benefit Cutoff: March 8, 2026. CI, confidence interval; DOR, duration of response; nivo, nivolumab; NE, not estimable; ORR, objective response rate; RECIST 1.1, Resp
Slide 43: 3-Year Overall Survival Among All Patients
CC-49 3-Year Overall Survival Among All Patients Data cutoff: March 8, 2026. CI, confidence interval; nivo, nivolumab; OS, overall survival. RP1 + nivo Censored + Probability of OS 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66
Slide 44: Clinical Safety Data
Clinical Safety Data cCc-50
Slide 45: Overview of Safety for RP1 in Combination with Nivolumab
CC-51 Overview of Safety for RP1 in Combination with Nivolumab *Includes reports of disease progression=8, death=1, head injury=1, multiple organ disfunction=1, myocardial infarction=1. Patients with: N=140 n (%) Any TEAE 137 (97.9) Any SAE 50 (35.7) Any TEAE with outcome of death* 12 (8.6) Any TEAE
Slide 46: Adverse Events Occurring in >10% of Patients
CC-52 Adverse Events Occurring in >10% of Patients (Excluding Laboratory-Related Adverse Events) – IGNYTE Study (N=140) * A composite that includes multiple related terms Data cutoff: October 15, 2024 None of the common adverse events were Grade 4 or 5 0.7 0.7 1.4 1.4 1.4 1.4 2.1 1.4 11.4 12.1 12.9
Slide 47: Fatal Events Considered Possibly Related by FDA: Pooled Safety Analysis
CC-53 Fatal Events Considered Possibly Related by FDA: Pooled Safety Analysis (N=335) Data cutoff: October 15, 2024 MCC, Merkel cell carcinoma; CSCC, cutaneous squamous cell carcinoma; NMSC, non-melanoma skin cancer Related to RP1/Nivolumab Patient ID Age/Sex Cohort (Malignancy) Preferred Term Inves
Slide 48: Assessment of Topics of Interest
CC-54 Assessment of Topics of Interest • Contribution of Effect • Response Assessment
Slide 49: Patients Serving as Their Own Control Supports Contribution of Effect
CC-55 Patients Serving as Their Own Control Analysis Supports the Contribution of Effect (IGNYTE Study) Replimune data on file. ORR analysis includes non-adjuvant patients only (cannot assess prior response to adjuvant treatment) n=104 for all patients and n=31 for responders. Patient Population Tim
Slide 50: Durability Supports Systemic Impact in IGNYTE Study
CC-56 Durability Supports Systemic Impact in IGNYTE Study *If corrected for denominator = 25% (FDA sensitivity analysis) NE, not evaluable NR, not reached Responder (n/N) ORR (95% CI) DOR, months (95% CI) Patients who had all target lesions injected 25/51 49.0 (34.8, 63.4) NR (25.6, NE) FDA ANALYSIS
Slide 51: Patient Example With Injected Only Disease
CC-57 Patient Example With Injected Only Disease Baseline NOV 2021 MAR 2022 FEB 2024 Liver INJECTED Response Assessment Disease Background: • 68 yo M, Stage IVM1c Prior line of therapy: • Pembrolizumab (adjuvant) Confirmed BOR per RECIST 1.1 by IRC = PR DOR = 45.7mo Injected
Slide 52: Response in All Lesions Measured is Consistent with RECIST 1.1
CC-58 Response in All Lesions Measured is Consistent with RECIST 1.1 ORR 33.6% *Only target lesions Best Response Category Response Based on Injected Measured Lesions Only n (%) Response Based on Non-injected Measured Lesions Only n (%) CR 16 (14.8) 13 (12.0) PR 18 (16.7) 18 (16.7) SD 33 (30.6) 28 (
Slide 53: Patient Level Analysis Supports Systemic Effect
CC-59 Patient Level Analysis Supports Systemic Effect (Responders, All Measured Lesions) Data cutoff: October 15, 2024 a. Patient had a CR as a radical resection of all 3 lesions on the skin of the left foot confirmed full regression; b. The sum of diameters of 4 target lesions met the criteria for
Slide 54: Deep Responses Across Tumor Burden Spectrum
CC-60 Deep Responses Across Tumor Burden Spectrum Cutoff: 8 March 2024 All Measured Lesions Baseline (mm) Patients with Adjuvant Therapy: + Combined Sum of Diameter 0 -100 -80 -60 -40 -20 300 200 220 240 260 280 180 80 100 120 140 160 60 20 40 Patients + + + + + + + + + + + + + + + Tumor Burden at B
Slide 55: Summary
CC-61 Summary
Slide 56: Favorable Benefit-Risk for Accelerated Approval
CC-62 Favorable Benefit-Risk for Accelerated Approval IGNYTE-3 randomized confirmatory trial ongoing with OS data expected in 2030 UNMET NEED: SERIOUS, LIFE-THREATENING DISEASE EFFICACY Adequate and Well-controlled Trial Supporting Evidence IGNYTE ORR: 33.6% (95% CI: 25.8, 42) DoR: 24.8 months (95%
Slide 57: Clinical Perspective and Case Studies
CC-63 Mohammed Milhem, MBBS Professor of Internal Medicine Former Division Chair and Holden Chair for Experimental Therapeutics Division of Hematology and Oncology, University of Iowa Clinical Perspective and Case Studies
Slide 58: Clinical Reality Today
CC-64 • Patients whose disease progresses after PD-1 therapy have: – Limited treatment options – Modest response rates – TILs treatment present logistical and safety challenges • What we need: – New treatment options that can benefit patients whose disease has progressed on prior PD-1 therapy – Inje
Slide 59: RP1+Nivolumab Provides an Important Option for Difficult to Treat Patients
CC-65 • Three patient examples – Adjuvant Failed – Failed Multiple Lines – Non-injected Visceral Responses RP1+Nivolumab Provides an Important Option for Difficult to Treat Patients
Slide 60: Patient Example: Adjuvant Failed
CC-66 Patient Example: Adjuvant Failed Left Posterolateral Back NON-INJECTED Left Axillary Lymph Node INJECTED Left Axilla NON-INJECTED BASELINE 6 MONTHS (PR) 29 MONTHS (CR) Disease Background: • 50 yo F, Stage IIIC Prior lines of therapy: • Pembrolizumab • Elevated LDH at baseline Confirmed BOR per
Slide 61: Patient Example: Failed Multiple Lines
CC-67 Patient Example: Failed Multiple Lines Multiple sites of disease at baseline including chest, abdomen, and pelvis BASELINE 9 MONTHS BASELINE 9 MONTHS Disease Background: • 74 yo F, Stage IVM1b Prior lines of therapy: • Atezolizumab+ cobimetinib • Atezolizumab • Ipilimumab • SX682 (CXCR-inhibit
Slide 62: Patient Example: Non-injected Visceral Responses
CC-68 Patient Example: Non-injected Visceral Responses BASELINE 9 MONTHS Disease Background: • 62 yo F, Stage IVM1c Prior lines of therapy: • Nivolumab (adjuvant) • Pembrolizumab (adv/met) • Elevated LDH at baseline Confirmed BOR per by IRC = PR Injected Non-injected
Slide 63: RP1 Needed for Patients Now
CC-69 • Urgent unmet need remains • RP1 has a positive clinical benefit risk – Compelling efficacy – Favorable safety profile • Innovative modalities require creative and pragmatic approaches to advance the field RP1 Needed for Patients Now
Slide 64: Vusolimogene oderparepvec-wtpg (TUDRIQEV) with Nivolumab for Advanced Cutaneous Melanoma
CC-70 Vusolimogene oderparepvec-wtpg (TUDRIQEV ) in combination with nivolumab for the treatment of adults with unresectable advanced cutaneous melanoma July 30, 2026 United States Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee