Agenus Inc. · NASDAQ:AGEN
Agenus — Investor Day (November 2022)
131 slides from Agenus's investor day presentation, Nov 12, 2022
Slide 1: SITC R&D Day
SITC R&D Day November 12, 2022
Slide 2: Forward-Looking Statements
FORWARD-LOOKING STATEMENTS This presentation contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding Agenus’, MiNK’s, and SaponiQx’s clinical development and regulatory plans (including the scope of any r
Slide 3: Innovation and Speed for Cancer Cures: The Road Taken, The Data
INNOVATION AND SPEED FOR CANCER CURES • Drug Development for Global Access. Next-Gen products - unprecedented data - Dr. Todd Yancey • The Path to Get to Curative Therapies for Patients with Advanced Cancers - Dr. Mike Atkins • Cancers’ Pathway; How to Block it - Dr. Larry Norton THE ROAD TAKEN • No
Slide 4: Innovation and Speed for Cancer Cures
INNOVATION AND SPEED FOR CANCER CURES
Slide 5: Agenus Portfolio Designed to Reach Untapped I-O Market
AGENUS PORTFOLIO DESIGNED TO REACH UNTAPPED I-O MARKET Hot Current I-O market FDA approved I-O agents $47B Limited development TUMOR Warm trials are very long and costly Cold Early/Low Late/High STAGE OF DISEASE / # PRIOR TREATMENTS 5 Source: Evaluate Pharma 2022 global revenue estimates, Agenus ana
Slide 6: Agenus Portfolio Designed to Reach Untapped I-O Market
AGENUS PORTFOLIO DESIGNED TO REACH UNTAPPED I-O MARKET Hot TUMOR Warm Cold Early/Low Late/High STAGE OF DISEASE / # PRIOR TREATMENTS 6 Source: Evaluate Pharma 2022 global revenue estimates, Agenus analysis
Slide 7: Drug Development for Global Access, Next-Gen Products, Unprecedented Data
DRUG DEVELOPMENT FOR GLOBAL ACCESS, NEXT-GEN PRODUCTS, UNPRECEDENTED DATA Todd Yancey, MD Senior Global Clinical Development, Medical Affairs and Commercial Advisor
Slide 8: The Path to Get to Curative Therapies for Patients with Advanced Cancers
THE PATH TO GET TO CURATIVE THERAPIES FOR PATIENTS WITH ADVANCED CANCERS Michael B. Atkins, M.D. Deputy Director Lombardi Comprehensive Cancer Center Georgetown-Lombardi Comprehensive Cancer Center William M. Scholl Professor and Vice-Chair Department of Oncology Georgetown University Medical Center
Slide 9: Cancer Immunotherapy – a journey from the Wilderness toward the Promised Land
November 12, 2022 Cancer Immunotherapy – a journey from the Wilderness toward the Promised Land Michael B. Atkins, M.D. Deputy Director Lombardi Comprehensive Cancer Center Georgetown-Lombardi Comprehensive Cancer Center William M. Scholl Professor and Vice-Chair Department of Oncology Georgetown Un
Slide 10: Cancer Immunotherapy Principles
Cancer Immunotherapy Principles • All “successful” cancers must solve the challenges of overcoming defenses erected by host immune systems • “Treating the immune system so that it can treat the cancer” Jedd Wolchok • Because the activated immune system can target many tumor antigens simultaneously,
Slide 11: HD IL-2 Therapy: Durable Responses/Cures
HD IL-2 Therapy: Durable Responses/Cures • HD IL-2 produces durable responses in ~10% of patients with advanced melanoma or RCC Few relapses in patients responding for over 2.5 years (likely cured) FDA approval in 1992 (RCC) and 1997 (melanoma) Metastatic Melanoma (N = 270) Metastatic RCC (N = 2
Slide 12: High Dose IL-2 Therapy
High Dose IL-2 Therapy 1985
Slide 13: High Dose IL-2 Therapy
High Dose IL-2 Therapy 1985 2000+ A case study for what is wrong with cancer clinical development • Uncontrolled • No target • No target population • Toxic • Inpatient • No correlates Proof of Principle
Slide 14: Efforts to Improve IL-2 Therapy: Lessons Learned
Efforts to Improve IL-2 Therapy: Lessons Learned • Lower dose IL-2 • CRs only seen with HD IL-2 (McDermott et al JCO 2005) • Dissociation of toxicity from Efficacy • Toxicity and efficacy elimination with steroid (Mier et al 1990) • Efficacy, but no toxicity reduction with sTNFR or sIL-1R (Du Bois J
Slide 15: Vitiligo and hypothyroidism following HD IL-2 Rx
Vitiligo and hypothyroidism following HD IL-2 Rx Treated May 1986 – Alive today without disease Atkins et62,1988. Atkins et al NEJM 318:1557 al NEJM, 1988
Slide 16: E3695: Concurrent Biochemotherapy vs CVD – Final Result
E3695: Concurrent Biochemotherapy (BCT) vs CVD – Final Result p= p=0.696 0.731 Atkins et aletJCO Atkins al J 2008 Clin Oncol 2008
Slide 17: Tumor-Infiltrating Lymphocytes + IL-2 in Metastatic Melanoma: OS
Tumor-Infiltrating Lymphocytes + IL-2 in Metastatic Melanoma: OS 1.0 0.9 CR (n=20) 0.8 Proportion Surviving What is keeping these 0.7 cells from killing the 0.6 tumor in vivo? 0.5 0.4 0.3 PR (n=32) 0.2 0.1 NR (n=41) 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Survival Time (Mos) Robbins
Slide 18: Biologic Rationale for Combined PD-1 and CTLA-4 Blockade
Biologic Rationale for Combined PD-1 and CTLA-4 Blockade APC – T-cell Interaction Tumor Microenvironment Activation (cytokine secretion, lysis, proliferation, migration to tumor) MHC TCR TCR MHC +++ +++ Dendritic B7 CD28 T cell T cell Tumor cell cell +++ PD-1 PD-L1 B7 CTLA-4 --- --- anti-PD-1 anti-C
Slide 19: Ipilimumab Shows OS Plateau at 3 Years
Analysis From Phase II and Phase III Trials of Ipilimumab Show OS Plateau at 3 Years Schadendorf D, et al. J Clin Oncol. 2015 [Epub ahead of print]. 1.0 0.9 0.8 Median OS: 11.4 mos (95% CI: 10.7-12.1) Proportion Alive 0.7 3-yr OS rate: 22% (95% CI: 20% to 24%) 0.6 0.5 0.4 0.3 0.2 Ipilimumab 0.1 Cens
Slide 20: KEYNOTE-006 Results: Final Analysis
KEYNOTE-006 Results: Final Analysis • ORR, PFS, and OS superiority of pembrolizumab over ipilimumab Arm Events, n HR (95% CI) P Pembro Q2W 122 0.68 (0.53-0.87) 0.00085 100 Pembro Q3W 119 0.68 (0.53-0.86) 0.00083 90 Ipi 142 — — Overall Survival, % 80 70 60 NR (22.1-NR) 50 NR (23.5-NR) 40 16.0 (13.5-2
Slide 21: CheckMate-067: Melanoma 6.5-year follow-up Data
CheckMate-067: Melanoma 6.5-year follow-up Data Progression-free Survival Overall Survival Wolchok et al JCO 2021
Slide 22: CM 214: Nivo/Ipi in RCC
CM 214:Nivo/Ipi in RCC 1.0 1.0 0.9 0.9 ITT: HR 0.72 (0.61–0.86) 0.8 0.8 77% P = 0.0002 0.7 0.7 64% OS (probability) 0.6 0.6 56% PFS (probability) 43% 67% nivo/ipi 0.5 0.5 36% 34% 56% 0.4 0.4 44% nivo/ipi 47% 0.3 0.3 0.2 sunitinib 0.2 28% sunitinib 0.1 22% 0.1 0.0 0.0 0 3 6 9 12 15 18 21 24 27 30 33
Slide 23: Checkpoint Inhibitor Lessons
Checkpoint Inhibitor Lessens • Relation of irAEs and benefit • Stopping therapy-creating TFS • Activity in patients with brain metastases • Sequencing with standard therapies • Mixed Combination Issues
Slide 24: Advanced Melanoma Patients Treated with ICIs
Advanced Melanoma Patients Treated with ICIs Georgetown-Lombardi IO Database Lev-Ari et al- SMR 2021
Slide 25: Combination I/O Achieves Treatment Free Survival
Combination I/0 Achieves “Many” Patients’ Preferred Outcome- Treatment Free Survival or “TFS” Treatment ends Benefit persists Gibney et al JITC 2021 EA-6192 (PET-Stop)
Slide 26: TFS and Survival States Over 60-Month Follow-Up Period
TFS and Survival States Over 60-Month Follow-Up Period A) NIVO + IPI Percent of patients B) NIVO C) IPI Percent of patients Percent of patients NIVO + IPI NIVO IPI Percent Percent Percent 60-mo 60-mo Difference (95% CI): 60-mo Difference (95% CI): of of of Survival State mean mean NIVO + IPI vs NIVO
Slide 27: TFS = Travel Full Survival
TFS = Travel Full Survival
Slide 28: Survival in Pts with asymptomatic CNS Disease
Survival in Pts with asymptomatic CNS Disease Intracranial PFS OS 100 100 INV assessed 90 BICR assessed 90 80 80 74% 72% 70 70 54% (INV) 54% (INV) 60 52% (BICR) 52% (BICR) 60 PFS (%) OS (%) 50 50 40 40 30 30 20 20 10 10 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 0 3 6 9 12 15 18 21
Slide 29: Overall Survival (OS): Step 1 +/- Step 2
Overall Survival (OS): Step 1 +/- Step 2 Nivo/Ipi +/- Dab/Tram: 38/133 died, 2-yr OS rate 72% (95% CI:62%, 79%) 20%, (95% RCI: 3%-38%), Z-stat= 3.157 >2.743 Dab/Tram +/- Nivo/Ipi: 62/132 died, 3-yr OS Rate 2-yr OS rate 52% (95% CI: 42%, 60%) IO +/-TT 66.2% (56.0,74.6) TT +/- TT 42.8% (32.9, 52.4) Lo
Slide 30: Triplet Therapy: BRAF/MEK+anti-PD-(L)1
Triplet Therapy: BRAF/MEK+anti-PD-(L)1 • KEYNOTE-022, IMspire150, COMBI-i NIVO/IPI 5-yr PFS rate in BRAF-mutant melanoma 38 % No tail on PFS Curve !!! Chmielowski B. Poster presented at: ESMO; September 19-21, 2020. Presentation 4816. 30
Slide 31: KN-426: IO+VEGFR-TKI in RCC
KN-426: IO+VEGFR-TKI in RCC Events, Median (95% CI), 100 n mo 90 Pembro + Axi 264 15.4 80 (12.7-18.9) 60% Sunitinib 281 11.1 70 48% (9.1-12.5) PFS, % 60 38% 50 27% HR 0.71 (95% CI 0.60-0.84) 40 P < 0.0001a 30 20 10 0 0 6 12 18 24 30 36 42 No. at risk Months 432 300 234 180 109 37 2 0 429 248 159 112
Slide 32: IO-Non IO Combinations: Cautions
IO-Non IO Combinations: Cautions • IO is different than tumor-directed therapy, because of its ability to produce Treatment-free survival (TFS)/”Cure” • Combinations that improve median PFS or median OS without producing TFS, may sacrifice the potential of IO while contributing toxicity, inconvenien
Slide 33: Principal IO Endpoints
Principal IO Endpoints • Landmark PFS/OS • Complete (near complete) Response Rate • Response Duration • Time to initiation of subsequent therapy • Treatment Free Survival/ “Cure” • Overall Quality of Life/Overall Value
Slide 34: Our goal should not be simply to turn cancer into a chronic disease
Our goal should not be simply to turn cancer into a chronic disease… We should strive to make cancer a curable disease Using agents/combinations that maximize the anti- tumor immune response (raise the plateau and enable TFS) is critical to achieving that goal
Slide 35: Acknowledgements
Acknowledgements Other • Ryan Sullivan Georgetown-LCCC • Jen Wargo Geoff Gibney • Craig Slingluff • DFHCC • • Nicholas Acquavella • Ben Izar • David McDermott • Suthee Rapisuwon • Bartozc Chmielowski • James Mier • Waddah Al-Refaie • HCRN GU Team • Rupal Bhatt • Aaron Rozenbom • Brian Rini • Mario S
Slide 36: Special Acknowledgements
Special Acknowledgements
Slide 37: Cancers Pathway; How to Block It
CANCERS PATHWAY; HOW TO BLOCK IT Larry Norton, MD Memorial Sloan Kettering Cancer Center Senior Vice President, Office of the President, Medical Director, Evelyn H. Lauder Breast Center
Slide 38: Why is it so hard to cure cancer in the clinic?
Why is it so hard to cure cancer in the clinic?
Slide 39: Why is it so hard to cure cancer in the clinic?
Why is it so hard to cure cancer in the clinic? What can we do about this?
Slide 40: It is rather easy to cure cancer in the laboratory
It is rather easy to cure cancer in the laboratory Exponential Growth
Slide 41: It is rather easy to cure cancer in the laboratory
It is rather easy to cure cancer in the laboratory Anti-Mitotic Therapy Exponential Growth
Slide 42: But clinical cancers do not grow exponentially!
But clinical cancers do not grow exponentially!
Slide 43: But clinical cancers do not grow exponentially!
But clinical cancers do not grow exponentially! Exponential Growth Gompertzian Growth
Slide 44: But clinical cancers do not grow exponentially!
But clinical cancers do not grow exponentially! Exponential Growth Benjamin Gompertz Gompertzian 1779-1865 Growth
Slide 45: But clinical cancers do not grow exponentially!
But clinical cancers do not grow exponentially! Exponential Growth Gompertzian Growth Norton L et al., Nature, 1976
Slide 46: Chemotherapy based on Gompertzian kinetics improves cure rates
Chemotherapy based on Gompertzian kinetics improves cure rates Breast Recurrence Cancer Reduced Mortality Reduced No Increase All Cause in Death Mortality without Reduced Recurrence 26 Randomized Trials, 37,298 Patients: EBCTCG, Lancet, 2019
Slide 47: Tumor growth and cancer cell metastases are linked
Tumor growth and cancer cell metastases are linked MDA MB 231 Parental 4175 1834 SPARC IL13RA2 MMP1 ERG COX2 CXCL1 MMP2 ID1 RARRES3 EFEMP1 MANT2 LY6E
Slide 48: Tumor growth and cancer cell metastases are linked
Tumor growth and cancer cell metastases are linked MDA MB 231 Parental 4175 1834 SPARC IL13RA2 MMP1 ERG COX2 CXCL1 MMP2 ID1 RARRES3 EFEMP1 MANT2 LY6E Norton and Massague, Nature Med, 2006
Slide 49: Tumor growth and cancer cell mobility (seeding) are linked
Tumor growth and cancer cell mobility (seeding) are linked Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J. Cell, 2009
Slide 50: Tumor growth and cancer cell mobility (seeding) are linked
Tumor growth and cancer cell mobility (seeding) are linked Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J. Cell, 2009
Slide 51: Breast cancer seeds create their own microenvironment by recruitment
Breast cancer seeds create their own microenvironment by recruitment Angiogenesis Leukocytes Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J. Cell, 2009
Slide 52: Comen E, Norton L, Massagué. Nature Rev Clin Oncol, 2011
Comen E, Norton L, Massagué. Nature Rev Clin Oncol, 2011
Slide 53: So, the growth of human cancers has two components
So, the growth of human cancers has two components:
Slide 54: Mitosis and Geometry
So, the growth of human cancers has two components: Mitosis (the division of the cancer cells) Geometry (the relationship of the cancer to its microenvironment)
Slide 55: Gompertzian cancers are not cured by the same anti-mitotic therapy
Gompertzian cancers are not cured by the same anti-mitotic therapy that cures exponential cancers in the laboratory
Slide 56: Gompertzian cancers are not cured by the same anti-mitotic therapy
Gompertzian cancers are not cured by the same anti-mitotic therapy that cures exponential cancers in the laboratory Anti-Mitotic Therapy Exponential Growth Gompertzian Growth
Slide 57: Gompertzian cancers are not cured by the same anti-mitotic therapy
Gompertzian cancers are not cured by the same anti-mitotic therapy that cures exponential cancers in the laboratory Anti-Mitotic Therapy Exponential Growth Gompertzian Growth
Slide 58: Immunotherapy added to antimitotic therapy can cure
…but immunotherapy added to antimitotic therapy can cure! Anti-Mitotic Therapy Exponential Growth Anti-Mitotic Therapy plus Immunotherapy Gompertzian Growth
Slide 59: Therapy that Addresses the Tumor Microenvironment
Therapy that Anti-Mitotic Therapy Addresses the Tumor Microenvironment (Immunotherapy) Comen E, Norton L, Massagué. Nature Rev Clin Oncol, 2011
Slide 60: What can we do about this?
Why is it so hard to cure cancer in the clinic? What can we do about this?
Slide 61: Human cancers are Gompertzian. What can we do about this?
Why is it so hard to cure cancer in the clinic? Human cancers are Gompertzian. What can we do about this?
Slide 62: Expand the activity of highly effective immunotherapy to cold cancers
Why is it so hard to cure cancer in the clinic? Human cancers are Gompertzian. What can we do about this? Expand the activity of highly effective immunotherapy to currently “cold” cancers.
Slide 63: Thank You!
Why is it so hard to cure cancer in the clinic? Human cancers are Gompertzian. What can we do about this? Expand the activity of highly effective immunotherapy to currently “cold” cancers. Thank You!
Slide 64: The Road Taken
ROADTAKEN 1 2enus THE ROAD TAKEN
Slide 65: Novel Medicines, Accessible Combinations, with Integrated Platforms
NOVEL MEDICINES, ACCESSIBLE COMBINATIONS, WITH INTEGRATED PLATFORMS Jennifer Buell, Ph.D. President & CEO, MiNK Therapeutics
Slide 66: Clinical Stage Pipeline
CLINICAL STAGE PIPELINE Diverse portfolio targeting multiple aspects of the cancer immunity cycle Mechanism/target Product Candidate Partner Phase 1 Phase 2 PD-1 +/- CTLA-4 Balstilimab +/- Zalifrelimab Greater China Cervical (2nd line) Majority / Fc-enhanced CTLA-4 + PD-1 Botensilimab +/- Balstilima
Slide 67: Agenus Highlights
AGENUS HIGHLIGHTS Agenus is a clinical-stage immuno-oncology (I-O) company advancing a deep pipeline of checkpoint inhibitors, immune activators, and tumor microenvironment conditioning agents, including a novel innate and adaptive immune activator (botensilimab) Botensilimab Robust Portfolio Track
Slide 68: Integrated Capabilities for Differentiation & Speed
INTEGRATED CAPABILITIES FOR DIFFERENTIATION & SPEED Commercial and cGMP Manufacturing Clinical Operations Reduces timelines & costs, improves flexibility Enables rapid, high quality clinical enrollment • Berkeley, CA • 2 in-house CROs with suite of capabilities – medical writing, stats/data manageme
Slide 69: The Data
ROADTAKEN 1 2enus THE DATA
Slide 70: Agenus Portfolio for Curative Therapies
AGENUS PORTFOLIO FOR CURATIVE THERAPIES Steven O’Day, MD Chief Medical Officer
Slide 71: Botensilimab/Balstilimab Efficacy in Combination Patients
BOTENSILIMAB/BALSTILIMAB EFFICACY IN COMBINATION PATIENTS (N=125) 130 Best Percent Change From Baseline (%) 120 110 100 90 80 70 60 50 40 30 20 20% Tumor 10 Growth 0 -10 -20 -30 30% Tumor -40 -50 Reduction -60 -70 -80 -90 -1000 -1100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 0 6 1
Slide 72: Treating the Most Difficult Cancers - Botensilimab
TREATING THE MOST DIFFICULT CANCERS - BOTENSILIMAB Breelyn Wilky, MD University of Colorado Cancer Center Director of Sarcoma Medical Oncology Deputy Associate Director for Clinical Research
Slide 73: A Look Back…
A Look Back… Perspectives on immunotherapy in sarcoma PRESENTATION TITLE
Slide 74: Sarcomas: Over 100 different cancers!
Sarcomas: Over 100 different cancers! Head to toe… Young to old… Benign to aggressive… High-grade undifferentiated sarcomas – mesenchymal stem cells PRESENTATION TITLE Damerell et al, Signal Transduct Target Ther, 2021
Slide 75: Sarcomas: Customizing treatment approaches by subtype and genetic drivers
Sarcomas: Customizing treatment approaches by subtype and genetic drivers Drug RR (%) PFS OS The “Others” (median, (median, Limited activity of cytotoxics months) months) and targeted therapies Doxorubicin 18.3 6.8 19.7 Common “adult” subtypes Liposomal doxorubicin 10 2.1 10.6 • High grade pleomorph
Slide 76: Sarcomas and immune surveillance?
Sarcomas and immune surveillance? • Coley’s Toxins • Occasional cures of oligometastatic sarcomas by resection • Variability in progression of disease PRESENTATION TITLE
Slide 77: Angiosarcoma - my first immunotherapy super-responder
Angiosarcoma - my first immunotherapy super-responder • Treated with AGEN1884 (anti-CTLA4) on Phase 1 trial at dose level 1 – 0.1 mg/kg every 3 weeks x 18 months • Radiographic complete response since March 2017, path CR confirmed February 2018 – remains cured! • Remarkable responses in cutaneous an
Slide 78: Alveolar soft part sarcoma – the real success story!
Alveolar soft part sarcoma – the real success story! Axitinib plus pembrolizumab PRESENTATION TITLE Wilky et al, Lancet Oncol 2019
Slide 79: Alveolar soft part sarcoma – the real success story!
Alveolar soft part sarcoma – the real success story! Therapy N RR mPFS Reference (95% CI) (months, 95% CI) OSCAR, Nivolumab (ASPS only) 14 7.1% 6.0 Kawai et al, CTOS (0.2-33.9) (3.7-9.3) 2020 Hindi et al (retrospective) 21 47.6% 10.9 Hindi et al, CTOS (Not reported) (9.9-11.9) 2020 Durvalumab/Tremel
Slide 80: Selected PD1/PD-L1 combination trials in sarcomas
Selected PD1/PD-L1 combination trials in sarcomas CTLA-4 Study Agents ORR mPFS Subtypes (RR) Macrophages Pembrolizumab1 18% 4.5 mo UPS 23%2, LPS 10% Microenvironment Ipilimumab/Nivolumab3,4 16% 4.1 mo UPS 28.6%4, LPS 14.3% Chemo Cyclophosphamide/Pembro5 2% 1.4 mo 1 PR mSFT Axitinib/Pembro6 25% 4.7 m
Slide 81: Only ~20% of common soft tissue sarcomas have robust immune expression
Only ~20% of common soft tissue sarcomas have robust immune expression Petitprez et al, Nature TITLE PRESENTATION 2020
Slide 82: Fundamental questions for immunotherapy in sarcomas…
Fundamental questions for immunotherapy in sarcomas… 1. Why are we stuck at 20% ceiling despite trying numerous combinations to target evasion mechanisms? 2. Who benefits and how should we enrich future studies for responders? • Subtypes? • Presence of tertiary lymphoid structures? • Other emerging
Slide 83: SITC Data Recap
SITC Data Recap Botensilimab/balstilimab in “cold” and I-O refractory metastatic solid tumors PRESENTATION TITLE
Slide 84: All combination patients (N=125)
All combination patients (N=125) 1300 1200 1100 EFFICACY 1000 900 800 Best Percent Change 700 ORR, %* 20% (95% CI, 13-28%) From Baseline (%) 600 500 400 300 200 20% Tumor BOR, n (%) 100 00 Growth -100 -200 CR 3 (2) -300 30% Tumor -400 -500 Reduction PR 22 (18) -600 -700 -800 -900 SD 58 (46) -1000 -1
Slide 85: MSS CRC (n=59)
MSS CRC (n=59) 100 90 EFFICACY 80 70 60 ORR, %* 22% (95% CI, 12-35%) Best Percent Change 50 From Baseline (%) 40 30 20 ∞ 20% Tumor BOR, n (%) 10 + 0 Growth -10 +§ CR 1 (2) -20 -30 + 30% Tumor -40 + PR 12 (20) -50 + Reduction -60 + + + -70 -80 + SD 30 (51) -90 + -100 -110 PD 16 (27) 0 6 12 18 24 30 3
Slide 86: Recurrent platinum refractory/resistant ovarian (n=19)
Recurrent platinum refractory/resistant ovarian (n=19) 130 120 110 EFFICACY 100 Histology 90 80 High grade serous Best Percent Change 70 From Baseline (%) 60 50 Clear cell ORR, %* 26% (95% CI, 9-51%) 40 Carcinosarcoma 30 20 10 Endometrioid/clear cell 20% Tumor 0 Growth BOR, n (%) -10 -20 -30 -40 30%
Slide 87: Sarcoma (n=12)
Sarcoma (n=12) 130 120 110 EFFICACY 100 Subtype 90 80 Cutaneous Angiosarcoma 70 42% (95% CI, 15- Best Percent Change From Baseline (%) 60 Leiomyosarcoma 50 ORR, %* 40 Liposarcoma 72%) 30 Pleomorphic 20 20% Tumor 10 Visceral Angiosarcoma 0 Growth BOR, n (%) -10 -20 -30 30% Tumor -40 -50 Reduction CR
Slide 88: Anti-PD-(L)1 NSCLC (n=4)
Anti-PD-(L)1 NSCLC (n=4) 110 100 90 EFFICACY 80 70 Best Percent Change 60 From Baseline (%) 50 ORR, % 50% (95% CI, 7-93%) 40 30 20 20% Tumor 10 0 Growth BOR, n (%) -10 -20 -30 30% Tumor -40 CR 0 (0) Reduction + -50 -60 -70 PR 2 (50) -80 -90 0 6 12 18 24 30 36 42 48 54 60 66 SD 1 (25) Weeks on Study
Slide 89: Investigator-Sponsored Trials
Investigator-Sponsored Trials 1) Doxorubicin/zalifrelimab/balstilimab 2) Doxorubicin/botensilimab/balstilimab PRESENTATION TITLE
Slide 90: Doxorubicin/zalifrelimab/balstilimab
Doxorubicin/zalifrelimab/balstilimab ICI priming prior to chemo start Drug Schedule 4 cycles CTLA-4 Balstilimab 300 mg flat q3weeks up to 2 years Zalifrelimab 1 mg/kg q6weeks x 4 Doxorubicin 75 mg/m2 (bolus/zinecard) q3weeks x 6, starts at C2 Cycle 1 Cycle 2, 4, 6 Cycle 3, 5, 7 Cycle 8+ Cycle 10 Dox
Slide 91: Doxorubicin/botensilimab/balstilimab
Doxorubicin/botensilimab/balstilimab NCT04028063, PI: Wilky PRESENTATION TITLE
Slide 92: Acknowledgements
Acknowledgements Wilky Lab: Cristiam Moreno Tellez, MD Kyle Powers, BS Lindsey Kemp, BS M. Jane Underdown, MD (Ped Heme-Onc) Nick Therrien, BS (MS candidate) Davila Lab: Eduardo Davila, PhD Allison Christians, MS Joseph Magno, PhD Candidate Dexiang Gao/Junxiao Hu HIMSR Core Facility Clinical Researc
Slide 93: Thank You
THANK YOU Email: breelyn.wilky@CUAnschutz.edu. Twitter: @breelynwilkyMD PRESENTATION TITLE
Slide 94: Botensilimab – A Transformative Treatment for CRC
BOTENSILIMAB – A TRANSFORMATIVE TREATMENT FOR CRC Joseph Grossman, MD Vice President, Exploratory Medicine
Slide 95: Currently Approved Treatments and Experimental Immunotherapies Offer Limited Efficacy in 2L+ MSS CRC
CURRENTLY APPROVED TREATMENTS AND EXPERIMENTAL IMMUNOTHERAPIES OFFER LIMITED EFFICACY IN 2L+ MSS CRC 100 Investigational • ~95% of metastatic Standard of Care colorectal cancer is 80 microsatellite stable (MSS CRC) mPFS ~2 months Percent (%) 60 mOS ~6 months • Limited efficacy with regorafenib and T
Slide 96: Spider Plot (N=59)
SPIDER PLOT (N=59) Efficacy 100 ORR, %* 22% (95% CI, 12-35%) 90 80 70 BOR, n (%) 60 CR 1 (2) Best Percent Change 50 From Baseline (%) 40 30 20 ∞ PR 12 (20) 10 + SD 30 (51) 0 -10 +§ -20 -30 + PD 16 (27) -40 + -50 + + + -60 -70 + DCR (CR + PR + SD), % 73% (95% CI, 60-84%) -80 + -90 + -100 Median DOR,
Slide 97: Waterfall Plot (N=59)
WATERFALL PLOT (N=59) Efficacy ORR, %* 22% (95% CI, 12-35%) 100 90 BOR, n (%) 80 70 60 CR 1 (2) 50 Best Percent Change in 40 PR 12 (20) Target Lesions (%) 30 20% Tumor ∞ 20 + Growth SD 30 (51) 10 0 -10 PD 16 (27) -20 + 30% -30 § Tumor DCR (CR + PR + SD), % 73% (95% CI, 60-84%) -40 -50 Reduction ++ -
Slide 98: The Path to Botensilimab Approval
THE PATH TO BOTENSILIMAB APPROVAL Dr. Patricia Carlos Chief of Regulatory, Quality and Safety
Slide 99: The Road Taken
ROADTAKEN | 9 e€Nus
Slide 100: The Path to Approval
THE PATH TO APPROVAL 100
Slide 101: How Can We Deliver Botensilimab Plus Balstilimab to Patients as Fast as Possible
HOW CAN WE DELIVER BOTENSILIMAB PLUS BALSTILIMAB TO PATIENTS AS FAST AS POSSIBLE • Early and often engagement strategy with global regulators • Expedited approval mechanisms for patients with limited treatment options for serious disease • Comprehensive approach to Safety, Efficacy and Optimal Dosin
Slide 102: First Filing
FIRST FILING • Anticipate that first filing will be in MSS CRC in 2024 • Planning for multiple supplemental filings in years to follow 102
Slide 103: The Future of Cancer Immunotherapy
THE FUTURE OF CANCER IMMUNOTHERAPY Dr. Alexander M.M. Eggermont Professor Clincal&Translational Immunotherapy University Medical Center Utrecht Chief Scientific Officer Princess Maxima Center for Pediatric Oncology Utrecht, Netherlands Board Comprehensive Cancer Center Munich Emeritus Professor, Sur
Slide 104: Immunotherapy Revolution: Lessons from Melanoma
Immunotherapy Revolution: Lessons from Melanoma: From Advanced to Adjuvant to NEO-Adjuvant Agenus R&D, Boston, November 2022 Dr. Alexander M.M. Eggermont Professor Clincal&Translational Immunotherapy University Medical Center Utrecht Chief Scientific Officer Princess Maxima Center for Pediatric Onco
Slide 105: Short List of Statements
Short List of Statements 1) Anti-PD1 is a core necessity as it protects CTL function at tumor site 2) Anti-CTLA4 is core necessity to prime Tcells and Provide Tcell clone diversity 3) Anti-CTLA4 is here to stay 4) Anti-LAG3 prolongs CTL function but has less Tcell clone diversity power 5) The anti-P
Slide 106: Checkmate-67 NIVO + IPI: 5 Year Overall Survival
CheckMate 067 Checkmate-67 NIVO + IPI: 5 Year Overall Survival NIVO+IPI NIVO IPI 100 (n = 314) (n = 316) (n = 315) • Improved OS with NIVO+IPI and 90 NIVO vs IPI over 5 years Median OS, mo (95% CI) NR (38.2‒NR) 36.9 (28.2‒58.7) 19.9 (16.8‒24.6) 80 HR (95% CI) vs IPI 0.52 (0.42‒0.64) 0.63 (0.52‒0.76)
Slide 107: Dreamseq Overall Survival (OS): Step 1 +/- Step 2
Dreamseq Overall Survival (OS): Step 1 +/- Step 2 Nivo/Ipi +/- Dab/Tram: 38/133 died, 2-yr OS rate 72% (95% CI:62%, 79%) 20%, (95% RCI: 3%-38%), Z-stat= 3.157 >2.743 Dab/Tram +/- Nivo/Ipi: 62/132 died, 2-yr OS rate 52% (95% CI: 42%, 60%) Log-rank p-value = 0.0095 PRESENTED BY: Michael B. Atkins, MD
Slide 108: Soooo hard to break the anti-PD1 ceiling: Recent Failures
Soooo hard to break the anti-PD1 ceiling RECENT FAILURES Agonistic mAbs CD137, ICOS-1, STING,………. Anti-IDO drug Epcadostat ECHO-301/KN-252: Pembrolizumab + Epcadostat vs Pembrolizumab IT(intratumoral) Treatments: Oncolytic Virus TVEC and TLR Tilsolimod MASTERKEY-265 : Pembrolizumab+TVEC vs Pembroliz
Slide 109: Immune System Blocked at Multiple Levels
IMMUNE SYSTEM BLOCKED AT MULTIPLE LEVELS • 1) CTL PRIMING e.g. CTLA4 ……….. - Unblock: anti-CTLA4 • 2) CTL EFFECTOR Function e.g. PD-1 / PDL-1……… - Unblock: anti-PD1/anti-PDL1 • 3) MACROPHAGES in Tumor Infiltrate (TAM) e.g. Macrophages; MDSC - anti-FcγRII Mabs: avoid anti-PD1 neutralization - F
Slide 110: The Old and New Era: Adjuvant Therapy of Stage III Melanoma
THE OLD AND NEW ERA Approved drugs for the adjuvant therapy of stage III melanoma Old Era (1996‒2011) • High-Dose Interferon (IFN)-α2b (US, EU), Low-Dose IFN-α2a (EU), pegylated IFN-α2b (US)1 New Era (2015‒2018) HR Stage FDA/EMA Ipilimumab (US)2,3,4 HRRFS(Ipilimumab vs. Placebo)=0.75 III (2015) Nivo
Slide 111: IPI + NIVO vs NIVO vs PBO in Resected Stage IV
The importance of Anti-CTLA4 also in combination adjuvant IPI 3mg/q3wk + NIVO 1mg vs NIVO vs PBO in RESECTED STAGE IV
Slide 112: Checkmate 915: IPI 1mg/q6wk + Nivo vs Nivo
Checkmate 915: IPI 1mg/q6wk + Nivo vs Nivo RFS in ITT population NIVO + IPI NIVO (n = 920) (n = 924) 100 Events, n 327 347 90 Median, mo (95% CI) NR NR 80 HR (97.295% CI)a 0.92 (0.77–1.09) 70 64.6% Pb 0.269 RFS (%) 60 50 63.2% 40 30 20 10 NIVO + IPI NIVO 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 No. a
Slide 113: Neoadjuvant Immunotherapy Revolution
NEOADJUVANT IMMUNOTHERAPY REVOLUTION More Cures / Shorter TXs / Less Surgery - Palpable/Macroscopic Stage III Melanoma - Resectable Stage IV Melanoma - MSI ColoRectal Cancer - Locally advanced CSCC (face/head/neck) - T3 Bladder Cancer - Multiple other trials (Lung, H&N,GEJ,TNB,GBM)
Slide 114: The Concept of Neoadjuvant Immunotherapy
The Concept of Neoadjuvant Immunotherapy Versluis, Long, and Blank, Nat Med 2020
Slide 115: Neoadjuvant is Superior to Adjuvant Immunotherapy
Neoadjuvant is Superior to Adjuvant Immunotherapy OpACIN (Phase 1) SWOG S1801 (Phase 2) Blank et al., Nat Med 2018 Patel et al., LBA6 ESMO 2022
Slide 116: OpACIN-neo: RFS After 2.5 Years FU
OpACIN-neo (2 cycles Ipi1/Nivo3): RFS After 2.5 Years FU and Pathologic Response Predicts Outcome1 • OpACIN-neo: after a median follow-up of 24.6 months, only 1/64 (2%) patient with pathologic response has relapsed * 85.5% * 96.9% 96.9% 100 83.6% 100 Relapse-Free Survival, % Relapse-Free Survival, %
Slide 117: Pooled Analysis: Neoadjuvant Therapy in Stage III Melanoma
Pooled Analysis: Neoadjuvant Therapy in Stage III Melanoma RFS by Pathological Response : SUPERIORITY IMMUNOTHERAPY IMMUNOTHERAPY Anti-PD1 pCR = 20% Targeted Therapy Anti-PD1 + Anti-CTLA4 pCR = 43% Dabrafenib + Trametinib pCR = 47% pCR pPR pCR pPR Med f/u 19.3 mo Med f/u 25.9 mo @ProfGLongMIA Alexan
Slide 118: ASCO 2020: PRADO
ASCO 2020: PRADO (The First 99 Patients)1 NEOADJUVANT IPI+NIVO REDUCE TLND RATES: LESS SURGERY Personalized Response-Driven Adjuvant Therapy After Combination of Ipilimumab and Nivolumab in Stage IIIB/C Melanoma pCR or pathological near No pnCR CLND Follow-up CT Q12W Follow-upc (0%-10% vital Stage I
Slide 119: Neoadjuvant Immunotherapy Will Be #1 Topic in the Next 5 Years
NEOADJUVANT IMMUNOTHERAPY WILL BE #1 TOPIC IN THE NEXT 5 YEARS: More Cures—Less Surgery! MELANOMA palpable lymph nodes • Nivolumab 3 + ipilimumab 1: 70% pathologic CR! • No more TLND in >50% of patients with palpable nodes in 5 years • S1801 Neoadjuvant-Adjuvant Pembrolizumab in Stage III: New Stand
Slide 120: NICHE 1: Chalabi, Haanen, NKI Amsterdam
NICHE 1: Chalabi, ----- Haanen, NKI Amsterdam 1 2 0
Slide 121: NICHE: No More Rectum Resections!
NICHE 2 (107 T3T4 pts): Chalabi et al. : NO MORE RECTUM RESECTIONS ! 1 2 1 THIS IS NEW STANDARD OF CARE: NO RCT PLEASE (Eggermont)
Slide 122: Locally advanced CSCC: Neoadjuvant Cemiplimab
70 Locally advanced CSCC : NEOADJUVANT CEMIPLIMAB Gross et al. (NEJM 2022) • Neoadjuvant cemiplimab is highly active in resectable CSCC • 63.3% combined pathologic response rate (pCR + MPR) by ICPR • 68.4% ORR by RECIST 1.1 • Most classified partial response (PR) • Imaging underestimated pathologic
Slide 123: Neoadjuvant Immunotherapy Will Be #1 Topic in the Next 5 Years
NEOADJUVANT IMMUNOTHERAPY WILL BE #1 TOPIC IN THE NEXT 5 YEARS: More Cures—Less Surgery! MELANOMA palpable lymph nodes • Nivolumab 3 + ipilimumab 1: 70% pathologic CR! • No more TLND in >50% of patients with palpable nodes in 5 years: NEW BEST PRACTICE • S1801 Neoadjuvant-Adjuvant Pembrolizumab in S
Slide 124: NSCLC: Neoadjuvant Nivo+Chemo vs Chemo
NSCLC: NEOADJUVANT Nivo+Chemo vs Chemo Checkmate-816 FDA APPOVAL 3/2022 - 37% Reduction Relapses: RFS (HR, 0.63; P =.0052) - mRFS Nivo+chemo 31.6 mts vs 20.8 mts for chemo - pCR rate combi vs mono: 24% vs 2% (P <.0001) - IA for OS : HR 0.57 (95% CI, 0.38-0.87)
Slide 125: Impact of Only 1 Dose Neo-Adjuvant Anti-PD1 for Recurrent GBM
Impact of Only 1 Dose Neo-Adjuvant Anti-PD1 for Recurrent GBM Median PFS: 72.5 – 99.5 days Median OS: 228.5 days – 417 days HR: 0.43; P2 =0.03 HR: 0.39; P2 = 0.04
Slide 126: Predictions: Approved and To Be Approved (Neo) Adjuvant Tx
PREDICTIONS APPROVED and TO BE Approved (NEO) ADJUVANT TX 1) MELANOMA 8) CRC dMMR / MSI 2) RCC 9) MERKEL 3) BLADDER 10) cSCC 4) LUNG 11) TNBC 5) ESOPHAGEAL / GEJ 12) H&N ? 6) GEJ /GASTRIC 13) GBM ? 7) HCC
Slide 127: Thank You
S12 . ccc MUNCHEN ZU Ss UMC Utrecht ( Qasr: CANCER CENTER pediatric oncology Thank You
Slide 128: Agenus Portfolio Can Reach Untapped I-O Market
AGENUS PORTFOLIO CAN REACH UNTAPPED I-O MARKET Hot Current I-O market FDA approved I-O agents $47B Limited development TUMOR Warm trials are very long and costly Cold Early/Low Late/High STAGE OF DISEASE / # PRIOR TREATMENTS 128 Source: Evaluate Pharma 2022 global revenue estimates, Agenus analysis
Slide 129: Reflections - Moderation Led by Dr. Alexander M.M. Eggermont
REFLECTIONS - MODERATION LED BY DR. ALEXANDER M.M. EGGERMONT
Slide 130: Agenus Next: Questions & Answers and Conclusions
AGENUS NEXT: QUESTIONS & ANSWERS AND CONCLUSIONS Todd Yancey, MD Senior Global Clinical Development, Medical Affairs and Commercial Advisor
Slide 131: SITC R&D Day
SITC R&D Day November 12, 2022