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Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. R.Garcia - Carbonero VIRAGE trial: randomized Phase IIb, open - label, study of Nab - Paclitaxel and Gemcitabine with/without intravenous VCN - 01 in Patients with Metastatic Pancreatic Cancer ( mPDAC ) Rocio Garcia - Carbonero * , Roberto Pazo Cid, Teresa Macarulla, Berta Laquente , Alana Nguyen, Carmen Guill n, Andr s Mu oz, Edward J Kim, Mireya Cazorla, Tara Seery, Miriam Lobo de Mena, Chris Nevala - Plagemann, Vivek Sharma, Eva Mart nez de Castro, Charles Le, Mike Kaleko, Mary Ann Shallcross, Carmen Blasco, Manel Cascallo, Manuel Hidalgo . *Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Spain
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Declaration of Interests R. Garcia - Carbonero Rocio Garcia - Carbonero Consultant or Advisory Role: AAA/Novartis, Advanz Pharma, Astellas, Bayer, BMS, Boerhinger , Crinetics , Esteve, GSK, Hutchmed , Ipsen, ITM, MSD, Novocure , PharmaMar, Pierre Fabre, Sanofi, Servier, Takeda Research Funding: MSD Scientific Societies: Chair of ENETS, ESMO Faculty Coordinator for NETs
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Background: VCN - 01 R. Garcia - Carbonero VCN - 01 ( zabilugene almadenorepvec ) is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB 1 pathway and express hyaluronidase (PH 20 ) to degrade tumor stroma and facilitate chemotherapy penetrance and antitumor immune response . VCN - 01 nab - paclitaxel gemcitabine T - Cells Neoantigen Cancer Associated Fibroblast Stroma STROMA degradation by PH20 facilitates solid tumor access of VCN - 01 and coadministered cancer therapies SELECTIVE replication at very high levels lyses tumor cells directly without harming healthy tissues IMMUNOGENIC actions of VCN - 01 turn "cold" tumors "hot" and elicit an anti - tumor immune response SYSTEMIC administration delivers VCN - 01 to primary tumor and metastases and detargets the liver Acceptable safety profile and encouraging activity when combined with gemcitabine/nab - paclitaxel in a Phase 1 study ( Garcia - Carbonero et al . J Immunother Cancer 10 : e 003255 , 2022 ) .
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. VIRAGE - Design R. Garcia - Carbonero VIRAGE is a multicenter, open - label, randomized trial for direct comparison of up to 2 doses of VCN - 01 with gem/nab - paclitaxel (SoC) to SoC alone in patients with metastatic pancreatic adenocarcinoma ( mPDAC ) 92 patients to be enrolled with 57 total deaths required for analysis of OS with 80% power to detect a hazard ratio (HR) of 0.51 - 0.65 for OS with 2 - sided alpha 0.1. P - values are displayed as 2 - sided statistical analysis using the log - rank test. ARM 1 IV gemcitabine (125 mg/m 2 ) IV nab - paclitaxel (1000 mg/m 2 ) D1, D8 & D15 of each 28 days cycle (SoC) ARM 2 2 doses of IV VCN - 01 ( 1 x 10 13 vp ) one week before : cycle 1 of SoC cycle 4 of SoC Patients with histologically or cytologically confirmed newly - diagnosed mPDAC No prior systemic therapy ECOG: 0 - 1 Stratification factors: x Geographical area (USA vs EU) x ECOG (0 vs 1) R 1:1 n=46 n=46 Primary Objectives x Overall Survival (OS). x Safety and tolerability Secondary x PFS / TTP x ORR x DCR x 1 - year OS and PFS rates x Duration of Response ( DoR ). x Changes in CA 19.9 Treatment until disease progression, unacceptable toxicity or consent withdrawal
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. VIRAGE - CONSORT R. Garcia - Carbonero Groups for analysis: x Modified Intent - to - Treat ( mITT ) / Safety population All randomized patients who received any dose of the assigned treatment, including ARM II patients who received VCN - 01 but not SoC x Full Analysis Set (FAS) - evaluating the VCN - 01 + SoC combination: All randomized patients who received one dose of SoC (ARM I) or a complete dose of VCN - 01 and at least one dose of SoC (ARM II). ARM II patients who received VCN - 01 but not SoC were replaced per protocol x Preplanned Subgroup Analysis Set - evaluating potential effects of second VCN - 01 dose All patients who started the 4th cycle of SoC (ARM I) or all patients who received a second dose of VCN - 01 and started the 4th cycle of SoC (ARM II)
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. VIRAGE - Demographics R. Garcia - Carbonero FAS mITT VCN - 01 + SoC (n=48) SoC (n=48) VCN - 01 + SoC (n=53) SoC (n=48) 48 48 53 48 n 66.0 (41 - 86) 68.5 (52 - 85) 66.0 (41 - 86) 68.5 (52 - 85) Median Age in years (range) 18 (37.5) 10 (20.8) 21 (39.6) 10 (20.8) n (%) <65 years 30 (62.5) 38 (79.2) 32 (60.4) 38 (79.2) n (%) 65 years 23 (47.9) 22 (45.8) 26 (49.1) 22 (45.8) n (%) Male Gender 25 (52.1) 26 (54.2) 27 (50.9) 26 (54.2) n (%) Female 23.70 25.65 23.70 25.65 Median Body Mass Index (kg/m 2 ) 19 (39.6) 17 (35.4) 21 (39.6) 17 (35.4) n (%) 0 ECOG at randomization 29 (60.4) 31 (64.6) 32 (60.4) 31 (64.6) n (%) 1 31 (64.6) 40 (83.3) 31 (58.5) 40 (83.3) Yes Liver metastases at baseline 17 (35.4) 8 (16.7) 22 (41.5) 8 (16.7) No 37 (77.1) 38 (79.2) 41 (77.4) 38 (79.2) 1 or 2 Number of metastatic sites 11 (22.9) 10 (20.8) 12 (22.6) 10 (20.8) 3 18 (37.5) 20 (41.7) 19 (35.4) 20 (41.7) Head Primary tumor location 30 (62.5) 28 (58.3) 34 (64.4) 28 (58.3) Body and tail 39 (81.2) 40 (83.3) 41 (77.4) 40 (83.3) > 37 UI/ml Ca 19,9 at baseline 9 (18.8) 8 (16.7) 12 (22.6) 8 (16.7) 37 UI/ml
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Safety : Treatment Emergent AEs ( 10% patients) R. Garcia - Carbonero VCN - 01 + SoC (N=53) n(%) SoC (N=48) n (% ) Preferred Term SOC % Grade 3 (n) % All grades (n) % Grade 3 (n) % All grades (n) 11,3% 6 52,8% 28 14,6% 7 47,9% 23 Anaemia Blood and lymphatic system disorders 33,9% 18 50,9% 27 14,6% 7 37,5% 18 Neutropenia 5,7% 3 43,4% 23 6,3% 3 35,4% 17 Thrombocytopenia 3,8% 2 49,1% 26 2,1% 1 27,1% 13 Abdominal pain Gastrointestinal disorders 34,0% 18 27,1% 13 Constipation 3,8% 2 52,9% 27 6,3% 3 45,9% 22 Diarrhoea 3,8% 2 60,4% 32 27,1% 13 Nausea 1,9% 1 43,4% 24 2,1% 1 20,9% 10 Vomiting 15,1% 8 90,6% 48 14,6% 7 75,0% 36 Asthenia/ Fatigue General disorders and administration site conditions 22,6% 12 2,1% 1 Chills 13,2% 7 17,0% 9 2,1% 1 Influenza like illness 43,4% 23 31,3% 15 Oedema 3,8% 2 77,4% 41 25,0% 12 Pyrexia 20,8% 11 50,9% 27 10,4% 5 20,8% 10 Transaminases increased Investigations 1,9% 1 11,3% 7 4,2% 2 PA increased 7,5% 4 15,0% 8 2,1% 1 GGT increased 1 49,1% 27 2,1% 1 41,7% 20 Decreased appetite Metabolism and nutrition disorders 13,2% 7 6,3% 3 Hypomagnesaemia 3,8% 2 2,1% 1 10,4% 5 Hyponatraemia 13,2% 7 6,3% 3 Arthralgia Musculoskeletal and connective tissue disorders 7,5% 4 12,5% 6 Back pain 13,2% 7 2,1% 1 Musculoskeletal pain 15,1% 8 2,1% 1 Myalgia 26,4% 14 18,8% 9 Dysgeusia Nervous system disorders 9,4% 5 10,4% 5 Headache 9,4% 5 58,5% 31 4,2% 2 43,8% 21 Neurotoxicity 3,8% 2 11,3% 6 6,3% 3 Insomnia Psychiatric disorders 1,9% 1 11,3% 6 4,2% 2 Cough Respiratory, thoracic and mediastinal disorders 11,3% 6 6,3% 3 Dyspnoea 11,3% 6 8,3% 4 Epistaxis 30,2% 16 50,0% 14 Alopecia Skin and subcutaneous tissue disorders 15,1% 8 2,1% 1 Rash 1,9% 1 11,3% 7 2,1% 1 Hypotension Vascular disorders Two TEAE lead to death ( 1 in each Arm), but none of them were related to VCN - 01 or SoC
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Safety : VCN - 01 - related TEAEs ( 5% patients) R. Garcia - Carbonero VCN - 01 Dose 2 (N=36) VCN - 01 Dose 1 (N=53) Preferred Term % Grade 3 (n) % All grades (n) % Grade 3 (n) % All grades (n) - - 52.7% 19 1.9% 1 58.5% 31 Pyrexia 2.8% 1 11.1% 4 1.9% 1 32.1% 17 Asthenia / Fatigue - - 11.1% 4 15.1% 8 30.2% 16 Transaminases increased - - 16.6% 6 - - 30.2% 16 Nausea - - 25.0% 9 - - 26.4% 14 Vomiting - - 2.7% 1 13.2% 7 16.9% 9 Influenza like illness - - 2.7% 1 1.9% 1 13.2% 7 Platelet count decreased/Thrombocytopenia - - 2.7% 1 - - 13.2% 7 Decreased appetite - - 5.5% 3 - - 13.2% 7 Diarrhea - - 19.4% 7 - - 9.4% 5 Chills - - 2.7% 1 5.7% 3 7.5% 4 Lymphocyte count decreased - - - - 5.7% 3 5.7% 4 Gamma - glutamyl transferase increased - - - - 1.9% 1 5.7% 3 Anemia - - 5.5% 2 - - 5.7% 3 Cytokine release syndrome - - - - 3.8% 2 3.8% 2 Treatment - induced liver injury
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Duration of Response ( DoR ) SoC VCN - 01 + SoC Response Rate, DoR & PFS R. Garcia - Carbonero DCR % ORR (n) PD SD PR CR 34 ( 70.8% ) 15 ( 31.3% ) 14 19 15 0 SoC (n=48) 37 (77.1%) 19 (39.6% ) 11 18 18 1 VCN - 01 (n=48) 0.512 0.314 p - value HR (95% CI) Median (95% CI) Events / Total Treatment Arm Ref. 5.4 (2.0 - 6.8) 11 / 15 SoC 0.22 (0.08 - 0.62) 11.2 (7.4 - NE) 7 / 19 VCN - 01 + SoC Logrank P - value: 0.0035 Progression Free Survival (PFS) Response Rate (ORR) VCN - 01+SoC (n=48) SoC (n=48) VCN - 01+SoC (n=53) SoC (n=48) 7.0 (4.8 - 11.2) 4.6 (3.5 - 6.5) 5.6 (3.8 - 10.4) 4.6 (3.5 - 6.5) Median (95% CI) months 0.55 (0.34 - 0.88) Ref. 0.63 (0.4 - 1.0) Ref. HR (95% CI) 0.012 0.048 (Cox) p - value 0.011 0.047 (Log - rank) Based on CT scan evaluation by sites; + Censor mITT SoC VCN - 01 + SoC FAS SoC VCN - 01 + SoC mITT FAS
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. SoC VCN - 01 + SoC SoC VCN - 01 + SoC Primary Endpoint - Overall Survival R. Garcia - Carbonero VCN - 01+SoC (n=48) SoC (n=48) 10.8 (7.4 - 15.8) 8.6 (6.9 - 11.6) Median (95% CI) months 0.57 (0.34 - 0.96) Ref. HR (95% CI) 0.034 (Cox) p - value 0.055 (Log - rank) + Censor VCN - 01+SoC (n=53) SoC (n=48) 10.6 (6.6 - 14.8) 8.6 (6.9 - 11.6) Median (95% CI) months 0.69 (0.42 - 1.12) Ref. HR (95% CI) 0.136 (Cox) p - value 0.196 (Log - rank) + Censor mITT FAS The prespecified OS primary study endpoint was met
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Preplanned Subgroup Analysis All patients who started the 4th cycle of SoC (+ 2 doses of VCN - 01 in Arm II) R. Garcia - Carbonero VCN - 01+SoC (n=34) SoC (n=29) VCN - 01+SoC (n=34) SoC (n=29) 14.8 (10.6 - NE) 11.6 (8.6 - 12.8) 11.2 (7.3 - 16.6) 7.4 (5.7 - 8.4) Median (95% CI) months 0.44 (0.21 - 0.92) Ref. 0.48 (0.25 - 0.91) Ref. HR (95% CI) 0.029 0.025 (Cox) p - value 0.046 0.017 (Log - rank) Based on CT scan evaluation by sites; + Censor PFS OS C5+ 4 Cycle 3 Cycle 2 Cycle 1 Cycle TREATMENT ARM I: SoC ARM II: SoC+VCN - 01 | 120 | 113 | 106 | 99 | 92 | 85 | 78 | 71 | 64 | 57 | 50 | 43 | 36 | 29 | 22 | 15 | 8 | 1 Day SoC VCN - 01 + SoC OS SoC VCN - 01 + SoC PFS Arm I Arm II
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Results - Biologic Data R. Garcia - Carbonero 0 100 200 300 400 500 600 160 640 2,560 10,240 40,960 163,840 Days (since 1st VCN-01 dose) N a b T i t e r ( 1 / x ) VCN - 01 genomes in patients blood NAbs titers in patients sera* *NAb's titers: levels of neutralizing antibodies against VCN - 01 Sustained VCN - 01 genomes levels indicated persistent replication and confirmed the bioactivity of the 2 nd dose despite the presence of neutralizing antibodies ( NAbs )
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Conclusions R. Garcia - Carbonero VCN - 01 at 1E13 vp /dose combined with gemcitabine/nab - paclitaxel was safe and well tolerated VCN - 01 - related serious adverse events were transient and resolved, the most common being flu - like symptoms, transaminase increase and drug - induced liver injury. VCN - 01 significantly improved OS (primary endpoint) in combination with Gem - Abraxane as compared to Gem - Abraxane alone in patients with chemona ve metastatic pancreatic adenocarcinoma. Survival benefit was greater among pts who received 2 VCN - 01 doses and with longer follow - up PFS was also significantly improved with the addition of VCN - 01 to SoC. ORR was numerically higher among pts treated with VCN - 01 and chemotherapy, and the duration of response was doubled as compared to patients treated only with chemotherapy. These encouraging data support further evaluation of this combination in a larger, blinded clinical trial with additional VCN - 01 doses
Content of this presentation is copyright and responsibility of the author. Permission is required for re - use. Thank you!!! We want to thank all patients, their families, investigators and their study team who participated in VIRAGE trial. R.Garcia - Carbonero