Phase 1b KEYNOTE-2 (STORM): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients Hardev S. Pandha 1, Kevin J. Harrington 2, Christy Ralph 3, Alan Melcher 2, Brendan Curti 4, Rachel Sanborn 4, Charles Rudin 5, Jonathan Rosenberg 5, Sumati Gupta 6, Wallace Akerly 6, Emmett Schmidt 7, David Kaufman 7, Mark Grose 8, Bronwyn Davies 8, Roberta Karpathy 8, Darren Shafren 8 1
I have the following financial relationships to disclose: Consultant: Abbvie, BMS, Celgene, G1 Therapeutics, Novartis Scientific advisory board: Harpoon Therapeutics I will discuss the following off label use and/or investigational use in my presentation: CVA21 2
Cytoplasmic replication of CVA21 in non-muscle invasive bladder cancer 3
Implant human SK-Mel 28 Treatment CAVATAK or saline Sacrifice mice and excise tumor Day Day 14 3h 6h 24h 72h x Tumor gene profiling SCID Balb/C CAVATAK or saline IV (tail vein) Excise tumor for viral and cellular gene profiling 4
γ Saline Tumor gene expression CVA-21 Tumor CVA21 replication 15 Saline-CXCL1 15 CAVATAK-CXCL1 TCID 5 equivalent/mg tumor 1 7 1 6 1 5 1 4 1 3 1 2 1 1 CXCL1 Normalised gene-fold changes 12 9 6 3 2. 3h 6h 24h 72h Time post-saline administration (h) Saline-PD-L1 Normalised gene-fold changes 12 9 6 3 2. 3h 6h 24h 72h Hours post-cavatak administration CAVATAK-PD-L1 1 2 4 6 8 Time post-cavatak administration (h) PD-L1 Normalised gene-fold changes 1.5 1..5 Normalised gene-fold changes 1.5 1..5. 3h 6h 24h 72h Time post-saline administration (h). 3h 6h 24h 72h Time post-cavatak administration (h) 5
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Tail vein injection 3LL-hICAM-1 cells Treatment iv CVA21 or saline + ip anti-pd-1 or control mab Observation: Sacrifice 2% weight loss or labored breathing Day 7 1 13 16 3LL-hICAM-1 cells (i.v tail vein) CVA21 anti-pd-1 mab * 3LL-ICAM-1 cells are murine NSCLC 3LL cells stably transfected to express human ICAM-1 to allow CAVATAK binding and cell infection 7
Kaplan-Meier Survival analysis* Control Ab + Saline Control Ab + CVA21 Control Ab + Saline anti-m-pd-1 + Saline anti-m-pd-1 + Saline anti-m-pd-1 + CVA21 1 1 1 Percent survival 5 Percent survival 5 Percent survival 5 P = NS 5 1 15 2 25 Days ** P =.33 1 2 3 Days *P =.21 1 2 3 Days *n=1, sacrifice 2% weight loss or labored breathing 8
Part A / CVA21 Part B / CVA21 + pembrolizumab (Monotherapy) (Combination) Advanced melanoma, prostate, NSCLC or bladder cancer, sero-negative CVA21 days 1,3,5,22,43,64,85,16,127,148 Cohort 1 1 x1 8 TCID 5 n=3 Cohort 2 3 x 1 8 TCID 5 n=3 Cohort 3 1 x 1 9 TCID 5 Mandatory lesion biopsy (Day 8) Melanoma, NSCLC, Bladder And Prostate cancer n=3 each No DLT s CVA21 days 1,3,5,8,29,5,71,92,113,134,155 + pembrolizumab (2mg) every 3 weeks starting Day 8 Cohort Expansion NSCLC (~n=4) CVA21 (1 x1 9 TCID 5 ) + pembrolizumab Cohort 1 (n= 3) NSCLC or bladder cancer CVA21 (1 x1 8 TCID 5 ) + pembrolizumab Cohort 2 (n = 3) NSCLC or bladder cancer CVA21 (3 x1 8 TCID 5 ) + pembrolizumab Cohort 3 (n = 3) NSCLC or bladder cancer CVA21 (1 x1 9 TCID 5 ) + pembrolizumab Cohort Expansion Bladder CA (~n=4) CVA21 (1 x1 9 TCID 5 ) + pembrolizumab 9
Part A: Histologically-confirmed (1) NSCLC, (2) bladder cancer, (3) castrate-resistant prostate cancer (CRPC) which are metastatic, or (4) Stage IIIC or Stage IV melanoma. Part B: Histologically or cytologically-confirmed advanced (1) NSCLC, (2) urothelial carcinoma. Part A: All subjects in Cohort 3 or P2D cohort must have a lesion accessible for FNA or core biopsy or open biopsy on Day 8 of the first treatment cycle. Part B: All subjects in Cohort 3 or P2D cohort must have either archival tissue available or a lesion accessible for mandatory core biopsy or open biopsy prior to treatment. Day 15 biopsy is requested but optional ECOG Performance Scale -1 Part B (Part A: -2). Life expectancy >3 months. Measureable disease based on RECIST 1.1. 1
Primary Objectives Part A To determine if CVA21 given intravenously is capable of tracking to malignant tumors. To establish a safe dose schedule of CVA21 for subsequent Phase 2 clinical trials. To describe the safety profile for intravenously-administered CVA21. Part B To assess and describe the safety profile of intravenous CVA21 and intravenous pembrolizumab in solid tumors of metastatic bladder cancer and NSCLC. To assess efficacy of the combination of CVA21 and intravenous pembrolizumab. in solid tumors of metastatic bladder cancer and NSCLC. 11
N=18 Related to CVA21 n (%) Grade 1 Grade 2 Grade 3 Grade 4-5 Total Fatigue 3 (17%) 2 (11%) 5 (28%) Pyrexia 4 (22%) 1 (6%) 5 (28%) Flu-like illness 2 (11%) 1 (6%) 3 (17%) Lethargy 3 (17%) 3 (17%) Headache 1 (6%) 1 (6%) Abdominal distension 1 (6%) 1 (6%) Diarrhea 1 (6%) 1 (6%) Nasopharyngitis 1 (6%) 1 (6%) Arthralgia 1 (6%) 1 (6%) Myalgia 1 (6%) 1 (6%) Dry skin 1 (6%) 1 (6%) 12
1 8 AUC 48 hours post-infusion (CVA21 RNA copies/ml serum) 1 7 1 6 1 5 Cohort 1: Cohort 2: Cohort 3: 1 8 TCID 5 3x1 8 TCID 5 1 9 TCID 5 *Area under the curve (AUC) exposure over 48hr following the first infusion of CVA21 13
1 6 1 5 1 4 1 3 Prostate cancer Melanoma NSCLC Bladder cancer CVA21 RNA copies/mg tumour RNA 1-5 1-6 3-5 2-5 3-6 2-7 1-1 3-12 1-11 1-9 Patient Number Limit of detection (15 copies/mg RNA) Bone Bone Lymph Node Abdominal Wall Soft tissue, chest Chest Wall Lung iliac node Thigh Liver *Day 8 biopsy from Cohort 3 patients administered three infusions of 1 9 TCID 5 of CVA21 14
Control Anti-enteroviral protein Pt 2-5 (IVM1c) Nucleus Cytoplasmic CVA21 viral proteins Pt 3-6 (IVM1c) *Day 8 biopsy from Cohort 3 patients administered three infusions of 1 9 TCID 5 of CVA21 15
Best percentage change in the target lesions sum of diameters relative to baseline 1 75 5 25-25 -5 Melanoma Castrate-resistant prostate cancer NSCLC Metastatic bladder cancer PD SD PR *irrecist criteria: Preliminary data, investigator assessed + First response assessment at Day 42 16
17 3-1 NSCLC 3-2 Melanoma 2-1 Bladder CVA21 RNA copies/ml serum 2 15 1 5 Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 8 6 4 2 Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 2 15 1 5 Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 6 4 2 1-1 Prostate Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 6 4 2 2-3 NSCLC Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 3 2 1 2-2 Bladder Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 4 3 2 1 1-9 Bladder Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 8 6 4 2 1-6 Prostate Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 CVA21 RNA copies/ml serum 5 4 3 2 1 3-6 Melanoma Secondary viral replication Post -infusion viral load 48h post-infusion #1 48h post-infusion #2 72h post-infusion #3 17
Single IV dose (Phase 1) Multi IV dose (KEYNOTE 2) Anti-CAVATAK neutralising antibody titre 65536 16384 496 124 256 64 16 4 CVA21 infusion Pt 24 Pt15 Pt26 Pt16 1.5 1 2 4 8 16 32 64 Pos/Neg Cut-off Anti-CAVATAK neutralising antibody titre 65536 16384 496 124 256 64 16 4 3-1 3-2 2-1 2-2 2-3 1-1 1 CVA21 infusions 1.5 1 2 4 8 16 32 64 Days post-cavatak infusion Days post-cavatak infusion 18
Enrolment complete IV delivery of CVA21 was generally well tolerated no grade 3 or 4 related AE s with a median of 6 CVA21 infusions per patient no dose-limiting toxicities CVA21 tumor targeting in patients with melanoma, NSCLC and bladder cancer patients in Cohort 3 was confirmed detection of CVA21 viral RNA in tumor biopsies at study day 8 viral replication by IHC in melanoma tumor biopsies Of the 15 patients from Cohorts 1-3 eligible for investigator best overall response assessment, 1 PR, 1 SD and 4 PD were observed Serum viral loads suggest potential secondary viral replication events 19
IV CVA21 days 1,3,5,8,29,5,71,92,113,134,155 + IV pembrolizumab (2mg) every 3 weeks starting Day 8 Cohort 1 (n= 3) NSCLC or bladder cancer CVA21 (1 x1 8 TCID 5 ) + pembrolizumab Cohort 2 (n = 3) NSCLC or bladder cancer CVA21 (3 x1 8 TCID 5 ) + pembrolizumab Recruitment complete Recruitment complete Cohort 3 (n= 3) NSCLC or bladder cancer CVA21 (1 x1 9 TCID 5 ) + pembrolizumab Recruitment complete No DLT s Cohort Expansion NSCLC (~n=4 +/- prior checkpoint) CVA21 (1 x1 9 TCID 5 ) + pembrolizumab Cohort Expansion Bladder CA (~n=4 +/- prior checkpoint) CVA21 (1 x1 9 TCID 5 ) + pembrolizumab 2
N=1 Related to CVA21 n(%) Related to Pembrolizumab n(%) Grade 1 Grade 2 Grade 3 Grade 4-5 Grade 1 Grade 2 Grade 3 Grade 4-5 No DLT s reported Fatigue 3 (3%) 2 (2%) Nausea 2 (2%) 1 (1%) 1 (1%) Pyrexia 3 (3%) 1 (1%) Myalgia 2 (2%) Headache 2 (2%) Hypotension 1 (1%) 1 (1%) Diarrhea 1 (1%) 1 (1%) Dizziness 2 (2%) Vomiting 1 (1%) 1 (1%) Constipation 1 (1%) Chills 1 (1%) Hyponatremia 1 (1%) Flu-like illness 1 (1%) Malaise 1 (1%) 21
Cohort CVA21 Dose (TCID5) 1 1 x 1 8 2 3 x 1 8 Patient No. Tumor Type 121 NSCLC 67 M 151 Bladder 73 M Age Gender Prior Therapy Response (Day)* surgery (2), chemotherapy (5), radiotherapy surgery (11), chemotherapy (2), radiotherapy (2) CVA21 Doses Pembrolizumab Doses PD (Day 114) 8 5 PD (Day 118) 9 6 152 Bladder 58 M surgery (3), chemotherapy (2) PD (Day 83) 7 4 153 NSCLC 62 M 154 Bladder 68 F surgery, chemotherapy (2), radiotherapy surgery (4), chemotherapy (2), immunotherapy (BCG, atezolizumab), other 122 NSCLC 76 F chemotherapy (2), radiotherapy 132 Bladder 8 M 3 1 x 1 9 123 NSCLC 66 M surgery (13), radiotherapy, chemotherapy (5), immunotherapy (BCG, atezolizumab) chemotherapy (2), radiotherapy (2), immunotherapy (anti-b7h3, anti- PDL1, ipilimumab, nivolumab) PD (Day 92) ** 7 4 Withdrawn due to unrelated grade 3 sepsis (Day 19) Withdrew consent (Day 25) 4 1 3 1 PD (Day 29) 4 2 ongoing (Day 44) 5 2 155 NSCLC 81 M chemotherapy, immunotherapy (nivolumab) ongoing (Day 21) 4 1 156 Bladder 61 M chemotherapy, surgery (2) ongoing (Day 15) 4 1 *First response assessment at Day 92; **Clinical progression only 22
Reciprocal Log 1 anti-cva21 neutralising antibody titer 2 2 Part A: CVA21 2 15 2 1 2 5 Pos/Neg cut-off 2.5 1 2 4 8 16 32 64 Reciprocal Log 1 anti-cva21 neutralising antibody titer 2 2 2 15 2 1 2 5 Part B: CVA21+ pembrolizumab + pembrolizumab Pos/Neg cut-off 2.5 1 2 4 8 16 32 64 Study Days Study Days 23
Enrollment in Part A (monotherapy) is complete with no DLTs observed Successful systemic CVA21 tumor targeting and findings of potential secondary CVA21 replication (Part A) Evidence of tumor stabilization and response (Part A) At present, the combination of intravenous CVA21 and pembrolizumab (Part B) has been generally well-tolerated in heavily pre-treated patients with or without prior immune checkpoint therapy Enrollment in Part B (combination) Cohorts 1,2 and 3 complete. Expansion cohort currently recruiting One grade 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab Comparable host anti-cva21 immune responses in the presence or absence of pembrolizumab Intravenous delivery of CVA21 is able to target metastatic lesions with the potential to upregulate PD-L1 expression during the viral replication process 24
The investigators, patients, and study staff who are contributing to this study; Viralytics R&D and clinical teams Support for this study was provided by Viralytics Ltd. Merck & Co. 25