A Phase 1 Dose Escalation Study of PRS-343, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-positive Malignancies Authors: Sarina Piha-Paul1, Johanna Bendell2, Anthony Tolcher3, Sara Hurvitz4, Anuradha Krishnamurthy5, Anthony El-Khoueiry6, Amita Patnaik7, Rachna Shroff8, Anne Noonan9, Paula Pohlmann10, Noah Hahn11, Marc Matrana12, Markus Zettl13, Kayti Aviano13, Lynn Mar13, Patrick Jolicoeur13, Shane Olwill13, Ingmar Bruns13, Geoffrey Ku14 1The University of Texas MD Anderson Cancer Center, Texas, USA 8University of Arizona Cancer Center, Arizona, USA 2Sarah Cannon Research Institute/Tennessee Oncology, LLC, Tennessee, 9The Ohio State University, Department of Internal Medicine, USA Division of Medical Oncology, Ohio, USA 3NEXT Oncology, Texas, USA 10Georgetown University Lombardi Comprehensive Cancer Center, 4University of California Los Angeles Jonsson Comprehensive Washington DC, USA Cancer Center, California, USA 11Sydney Kimmel Cancer Center at Johns Hopkins, Maryland, USA 5University of Pittsburgh Medical Center, Pennsylvania, USA 12Ochsner Cancer Institute, Louisiana, USA 6 Keck School of Medicine of USC, Norris Comprehensive 13Pieris Pharmaceuticals, Inc., Massachusetts, USA Cancer Center, California, USA 14Memorial Sloan Kettering Cancer Center, New York, USA 1 7START San Antonio, Texas, USA
Disclosure Information Arog Pharmaceuticals – Research Support AstraZeneca – Research Support, Consulting Bristol-Myer Squibb – Research Support, Consulting GEOFFREY KU Daiichi Sankyo – Research Support Reports relationships Eli Lilly – Consulting with the following: Merck – Research Support, Consulting Pieris Pharmaceuticals – Research Support, Consulting Zymeworks – Research Support 2
PRS-343, a HER2 4-1BB Bispecific, Drives 4-1BB Agonism in the Tumor Microenvironment in HER2 Positive Solid Tumors CLINICALLY-RELEVANT HER2-targeting moiety of the drug 4-1BB cross-linking ameliorates BIOMARKERS localizes to the tumor microenvironment T-cell exhaustion and is critical and facilitates 4-1BB cross-linking for T-cell expansion 4-1BB Pathway Activation Soluble 4-1BB HER2 targeting HER2 Antibody PD-L1 PRS-343 Atezolizumab PRS-343 T-cell 4-1BB Co-Stimulation targeting PD-1 Proliferation Anticalin® Blockade of CD8+ and CD8+/Ki67+ Proteins Checkpoint 4-1BB Inhibition 3
Study Design: Monotherapy and Combination with Atezolizumab Dose Levels Primary Objectives Secondary Objectives • Characterize • Assess potential Dose Levels in safety profile Monotherapy Dose Combination with of PRS-343 and in immunogenicity Dose Levels (mg/kg) 1200mg Atezolizumab combination with fixed dose and PD effects of 1 0.0005 atezolizumab • Characterize PK profile 2 0.0015 • Identify MTD and/or RP2D 3 0.005 • Investigate dosing 4 0.015 of PRS-343 alone and in schedule 5 1 0.05 combination with 6 2 0.15 • Investigate efficacy 7 3 0.5 atezolizumab 8 4 1 9 5 2.5 10 6 5 8 Schedule 1: Q3W dosing on day 1; 21-day cycle 11 7 ACTIVE 11 (b) 8 Schedule 2 (b): Q2W dosing on days 1, 15; 28-day cycle SCHEDULES 11 (c) 8 Schedule 3 (c): Q1W dosing on days 1, 8, 15; 21-day cycle 12 (b) 12 In combination with atezolizumab: Q3W dosing on day 1; 21-day 13 (b) 18 Obinutuzumab cycle 8 + 11(b) Data cut-off: 27-Jul-20 4
Key Enrollment Criteria: Monotherapy and Combination with Atezolizumab Inclusion Criteria Exclusion Criteria • Diagnosis of HER2+ advanced/metastatic solid tumor • Ejection fraction below the lower limit of malignancy that has progressed on standard therapy normal with trastuzumab and/or pertuzumab or for which no standard therapy is available • Systemic steroid therapy or any other form • HER2+ solid tumors documented by ASCO, CAP or of immunosuppressive therapy within seven institutional guidelines (monotherapy); HER2+ status days prior to registration documented by clinical pathology report • Known, symptomatic, unstable or (combination) progressing CNS primary malignancies • Patients with breast, gastric and GEJ cancer must • Radiation therapy within 21 days prior to have received at least one prior HER2-targeted registration (limited field radiation to non- therapy for advanced / metastatic disease visceral structures is allowed, e.g., limb • Measurable disease per RECIST v1.1 bone metastasis) • ECOG 0 or 1 (monotherapy); ECOG 0-2 (combination) • Adequate liver, renal, cardiac and bone marrow function 5
Baseline Characteristics Monotherapy and Combination with Atezolizumab All Subjects (n = 74, 41) In Combination with In Combination with Characteristic Monotherapy; n (%) Primary Cancer Type Monotherapy; n (%) Atezolizumab; n (%) Atezolizumab; n (%) Age, Median (range) 63 (24–92) 59 (26-87) Gastroesophageal 27 (36%) 7 (17%) Gender F 44 (59%) 23 (56%) Breast 16 (22%) 12 (29%) M 30 (41%) 18 (44%) Colorectal 10 (14%) 5 (12%) ECOG PS 0 19 (26%) 12 (29%) Gynecological 9 (12%) 4 (10%) 1 55 (74%) 18 (44%) Prior Therapy Lines Biliary Tract 7 ( 9 %) 6 (15%) 1 9 (12%) 5 (12%) Non-Small Cell Lung - 4 (10%) 2 10 (14%) 7 (17%) 3 15 (21%) 6 (15%) Bladder 2 ( 3 %) 1 ( 2 %) 4 11 (15%) 6 (15%) 5+ 28 (38%) 17 (41%) Pancreatic 1 ( 1 %) 1 ( 2 %) Median no. of anti-HER2 Other – Cancer Treatments 1 ( 1 %) 1 ( 2 %) of Unknown Origin Breast 7 3-4 Other – Salivary Duct 1 - Gastric 3 1 ( 1 %) Data cut-off: 27-Jul-20 6
Monotherapy A Phase 1, Open-label, Dose Escalation Study of PRS-343 in Patients with HER2-Positive Advanced or Metastatic Solid Tumors 7
Treatment-Related Adverse Events for Monotherapy All Subjects Monotherapy Occurred in > 1 Patient n = 145 (%) % Grade 3 Infusion Related Reaction 27 (19%) 3 (2%) Fatigue 11 (8%) 1 (1%) Nausea 11 (8%) Vomiting 8 (6%) Chills 8 (6%) Abdominal pain Anemia 2 (1%) 1 (1%) Anorexia Arthalgia 2 (1%) Asthenia 2 (1%) Cough 2 (1%) Decreased appetite 2 (1%) Diarrhea 6 (4%) Dizziness 2 (1%) Dry mouth Dyspnoea 3 (2%) Fever Flushing 5 (3%) 2 (1%) Lightheadness Lymphocyte count decreased Neutrophil count decreased Non-cardiac chest pain 4 (3%) Paraesthesia 3 (2%) 1 (1%) Peripheral sensory neuropathy Pruritis 3 (3%) Rash 2 (1%) One TRAE above Grade 3: Grade 4 Infusion Related Reaction in cohort 10 (5mg/kg PRS-343, Q3W). Data cut-off: 27-Jul-20 8
Summary of Responses at Active Dose Range of PRS-343 in Monotherapy Based on clinical data, serum concentration of > 20 µg/ml defines active dose range (beginning at Cohort 9) Cohort 13b 12b 11c Obi 11b 11 10 9 Total 18 mg/kg, 12 mg/kg, 8 mg/kg, 8 mg/Kg, 8 mg/kg, 8 mg/kg, 5 mg/kg, 2.5 mg/kg, Best Response Q2W Q2W QW Q2W Q2W Q3W Q3W Q3W Evaluable Patients 3 2 4 2 7 4 6 5 33 CR 1 - - - - - - 1 PR - - - 3 - - - 3 SD - - 1 1 3 3 3 2 13 ORR 33% 0% 0% 0% 43% 0% 0% 0% 12% DCR 33% 0% 25% 50% 86% 75% 50% 40% 52% Data cut-off: 27-Jul-20 9
Increase in CD8+ T Cells and Circulating Soluble 4-1BB Support 4-1BB Engagement by PRS-343 Biopsy Biopsy Pre-dose PRS-343 PRS-343 Post-dose (Cycle 1 Day 1) (Cycle 2 Day 1) (Cycle 2 Days 2-8) 10/25 patients 21/43 patients * evaluated evaluated 30000 6 * Unpaired 2 tailed t- SD≥C6 test 20000 5 P<0,05 PR CR 10000 4 PD 6000 3 4000 tumor area 2 2000 s41BB [pg/ml]s41BB Serum Tumor 2 0 /mm 1 C1 C3 C4 C1 C3 C4 Fold induction CD8+ Tcells 0 Time (Cycles) Non-Active Dose Active Dose Non-Active Dose Active Dose Cohorts 1-8 Cohorts 9-13b Cohorts 1-8 Cohorts 9-13b 10
Gastric Cancer Patient (107-012) with PR Patient Profile, Treatment History and Treatment Outcome Patient Profile Oncology Treatment History Duration • Cohort 11b | 8 mg/kg every two weeks Trastuzumab, Pembrolizumab • 80-year old woman; initial diagnosis in June 2017 July 2017 – June 2018 + Capecitabine/oxaliplatin • Stage IV gastric adenocarcinoma Nivolumab with IDO1 inhibitor • Metastases to liver, lymph node and adrenal glands Aug 2018 – Jan 2019 • HER2 IHC 3+; PD-L1 positive (CPS=3) (investigational drug) • NGS: ERBB2 amplification, TP53 mutation, alteration of CDK12 and SF3B1 Lesion Size (mm) Lesions Lesion Site Baseline C2 Post-treatment C3 Post-treatment C4 Post-treatment C6 Post-treatment Target 1 Liver 14 12 10 9 8 Target 2 Liver 20 16 10 8 9 Target 3 Pancreas 19 16 14 14 14 % Change from Baseline -17% -36% -42% -42% Non-target 1 Lung Present Present Present Present Present Non-target 2 Stomach Present Present Present Present Absent Non-target 3 Stomach Present Present Present Present Absent 11 Data cut: 24-Jan-2020
CD8+ T Cell Numbers in the Tumor and Circulating s4-1BB Increase Post-Treatment in responding Gastric Cancer Patient (107-012) treatment - Baseline C4 Post CD8Ki67 fold change: 5.8 CD8 fold change: 5.7 2000 1.9 x CD8 pre [n/mm2]: 38 CD8 pre [n/mm2]: 16 3 increase ) 2 100 1500 250 90 80 2 ) 200 2 70 1000 60 150 50 s41BB 1 s41BB [pg/ml] s41BB (n/mm 40 500 Tumor 100 30 Serum 20 Fold Change Predose to 50 0 0 CD8 +Ki67+ T cells 10 Baseline 2 4 8 15 Pre C2 0 0 CD8 + T cells (n/mm T + CD8 Timepoint (days) C1 d8 Pre Post Pre Post C1 day 2 C1 predose 12
Rectal Cancer Patient (103-021) with CR Patient Profile, Treatment History and RECIST Oncology Treatment History Duration Monotherapy: Rectal Cancer Patient with Confirmed CR Capecitabine + XRT Apr-May 2017 • Cohort 13b | 18 mg/kg Q2W • FoundationOne Her2 Neoadjuvant Folfox May-Sep 2017 • 59-year-old male; initial amplification; in-house Resection Dec 2017 diagnosis March 2017 testing IHC 3+ Folfiri/Avastin Mar-Jul 2018 • Stage 4 rectal adenocarcinoma • MSS, TMB low (2 mt/Mb) 5FU/Avastin maintenance Aug 2018-May 2019 cancer; metastasized to heart and lung Irinotecan/Avastin May-Nov 2019 SBRT Nov 2019 Lesion Size (mm) Lesions Lesion Site Baseline C2 Post-treatment C4 Post-treatment C6 Post-treatment Target 1 Lung 22 13 0 0 % Change -41% -100% -100% from Baseline Non-target 1 - Present Present Absent Absent Data cut-off: 27-Jul-20 13
CD8+ T Cell Numbers in the Tumor and Circulating s4-1BB Increase Post-Treatment in CR Rectal Cancer Patient (103-021) treatment treatment - - Baseline C6 Post C2 Post 2 8.2 x CD8 fold change: 2.3 CD8 pre [n/mm ]: 238 6 6000 increase ) 2 700 600 4 4000 500 400 s41B B 2 2000 s41BB [pg/ml] 300 Serum Tumor 200 Baseline Change to Fold BLQ 0 0 100 Baseline 2 3 4 8 15 P re C 2 CD8 + T cells (n/mm T + CD8 0 Timepoint (days) C1 day 2 Pre Post C1 predose C2 predose 14
Combination Therapy with Atezolizumab A Phase 1B, Open-label, Dose Escalation Study of PRS-343 in Combination With Atezolizumab in Patients with Specific HER2-Positive Advanced or Metastatic Solid Tumors 15
PRS-343 + Atezolizumab Duration of Exposure C2D21 C6D21 C10D21 C14D21 C18D21 C22D21 C24D21 Ovarian 102-122 Cohort 7 (8mg/kg) Bladder 111-111 BCA 102-120 Cohort 6 (5mg/kg) NSCLC 113-104 Cohort 5 (2.5mg/kg) Ovarian 112-106 Lung 107-104 Cohort 4 (1mg/kg) Gallbladder 107-103 CUP 102-115 Rectal 113-102 Partial Response BCA 108-105 Gastric Cancer 102-123 Stable Disease Rectal 102-121 GEJ 112-107 Disease BCA 102-116 Progression NSCLC 111-110 Death GEJ 102-114 X Esophageal 114-101 On Treatment Rectal 112-101 BCA 108-101 Discontinued (AE) BCA 112-102 Discontinued NSCLC 107-109 GYN 111-112 (Clinical GYN 108-106 Progression) Pancreatic 113-101 Discontinued CHOL 108-102 CRC 111-107 (Patient and/or BCA 102-113 Physician decision) *BCA 102-112 Rectal 102-111 Discontinued GEJ 102-109 (Disease Gallbladder 107-107 Progression) Cholangiocarcinoma 107-105 BCA 102-105 BCA 111-106 * Scan and EOT Gallbladder 102-104 on same day; RECIST response is presented DAYS ON TREATMENT | Data Cut: 18-AUG-2020 16
Treatment-Related Adverse Events for Combination with Atezolizumab All Subjects Combination with Atezolizumab Occurred in > 1 Patient n = 148 (%) % Grade 3 Infusion Related Reaction 38 (26%) 3 (2%) Fatigue 12 (8%) Nausea 8 (5%) Vomiting 38 (26%) Chills Abdominal pain 2 (1%) Anemia 4 (3%) 2 (1%) Anorexia 2 (1%) Arthalgia 2 (1%) Asthenia Cough Decreased appetite Diarrhea 5 (3%) 1 (1%) Dizziness Dry mouth 3 (2%) Dyspnoea Fever 3 (2%) Flushing Lightheadness 2 (1%) Lymphocyte count decreased 3 (2%) 1 (1%) Neutrophil count decreased 3 (2%) 1 (1%) Non-cardiac chest pain Paraesthesia Peripheral sensory neuropathy 2 (1%) Pruritis 4 (3%) Rash Two TRAEs above Grade 3: Grade 4 AST increase, Grade 3 transaminitis, and eventually Grade 5 hepatic failure in cohort 7 (8mg/kg + 1200mg Data cut-off: 27-Jul-20 atezolizumab); Grade 4 hemolytic anemia (unrelated to PRS-343, related to atezolizumab) in cohort 7. 17
Soluble 4-1BB Increases in Active Dose Cohorts & Clinical Benefit is Associated with Tumoral Immune Cell Activation 4-1BB target engagement Soluble 4-1BB in serum CD8+ T cell Numbers CD8+ T cell Proliferation Tumor-localized activity IHC on tumor tissue Patients with prolonged clinical benefit show a trend of increased CD8+ T Substantial increase of s4-1BB is observed in active dose cell numbers, proliferation and elevated cytolytic function in tumor biopsies cohorts (4-7), suggesting PRS-343-mediated target engagement 18
Breast Cancer Patient (108-101) with PR Patient Profile, Treatment History and RECIST Oncology Treatment History Duration PRS-343+Atezolizumab: Breast Cancer Patient with PR Trastuzumab/Docetaxel/ Sep 2011-Jul 2013 • Cohort 6 | 5 mg/kg Q3W + • FISH HER2/CEP17 ratio 2.4, Tamoxifen/Carboplatin 1200mg atezolizumab HER2 copy number 4.8 Trastuzumab/Pertuzumab/Vinorelbine Aug 2013-Jan 2016 • 52-year-old male; Initial In-house testing IHC2+, FISH+ diagnosis July 2011 • PD-L1 low in pre-treatment and T-DM1/Fulvestrant Nov 2017-Mar 2018 high in post treatment biopsy • Stage 2 Invasive Ductal Capecitabine/Lapatinib Mar 2018 Breast Cancer Palbociclib/Arimidex Apr-May 2019 Lesion Size (mm) Lesions Lesion Site C2 Post- C4 Post- C6 Post- C8 Post- C12 Post- C16 Post- Baseline treatment treatment treatment treatment treatment treatment right pulmonary Target 1 16 18 15 13 13 6 5 ligament lymph node % Change +12.5% -6% -19% -19% -63% -69% from Baseline Non-target 1-4 - Present Present Present Present Present Present Present Data cut-off: 27-Jul-20 19
Tumoral and Circulating s4-1BB Increase Post- Treatment in PR Breast Cancer Patient (108-101) CD8+ T cell Numbers CD8+ T cell Proliferation Soluble 4-1BB 2 2 4000 1200 150 1000 + 2 3000 800 100 Ki67 Tcells / pg /ml] 600 + 2000 + 400 50 cells per mm2 per cells 1000 200 1BB [ Absolute numbers of numbers Absolute - tumor mm tumor CD8+Ki67+ T cells per mm per cells T CD8+Ki67+ Absolute numbers of CD8+ T CD8+ of Absolute numbers 0 0 s4 0 Abs.CD8 Abs.CD8 Pre Post cellsT tumor/ mm Pre Post C1 C3 C4 Pre treatment Pre treatment Post-treatment Post-treatment CD8+ T cell numbers, proliferation, cytolytic molecules and s4-1BB increase post-treatment, demonstrating 4-1BB arm activity of PRS-343 20
Conclusions Acceptable safety profile in all doses and schedules tested in monotherapy as well as in combination with atezolizumab Demonstrated durable anti-tumor activity in heavily pre-treated patient population across multiple tumor types, including those usually not responsive to immune therapy; novel and non-redundant MoA among HER2-targeting therapies Showed a clear increase in CD8+ T cell numbers and proliferative index in the tumor microenvironment of responders, soluble 4-1BB increase demonstrates activity of the 4-1BB arm of the molecule 2L HER2+ gastric/gastroesophageal cancer trial in combination with Paclitaxel and Ramucirumab in preparation 21
Acknowledgements Patients, their families and caregivers Investigators, as well as their site personnel Monotherapy Combination with Atezolizumab Study 0416 (NCT03330561 A Phase 1, Open-label, Dose Study 0818 (NCT03650348, A Phase 1B, Open-label, Escalation Study of PRS-343 in Patients with HER2-Positive Dose Escalation Study of PRS-343 in Combination With Advanced or Metastatic Solid Tumors) sponsored by Pieris Atezolizumab in Patients with Specific HER2-Positive • The University of Texas MD Anderson • University of Pittsburgh Medical Center – Advanced or Metastatic Solid Tumors) sponsored by Pieris, Cancer Center – S. Piha-Paul, B. Bruggman A. Krishnamurthy, B. Foster, A. Blasko atezolizumab kindly supplied by F. Hoffmann-La Roche Ltd • Sarah Cannon Research Institute, LLC – • University of Arizona Cancer Center – J. Bendell, J. Costin R. Shroff, D. Pennington • The University of Texas MD Anderson School of Medicine of USC, Norris Cancer Center – S. Piha-Paul, Comprehensive Cancer Center – A. • NEXT Oncology – A. Tolcher, K. Dotson • Georgetown University Hospital – B. Bruggman El-Khoueiry P. Pohlmann, S. Wagner • University of California Los Angeles Jonsson • NEXT Oncology – A. Tolcher, • The Ohio State University, Department Comprehensive Cancer Center – S. Hurvitz, • Sydney Kimmel Cancer Center at Johns K. Dotson of Internal Medicine – A. Noonan M. Rocha, R. Rubin Hopkins – N. Hahn, E. Lee • University of California Los Angeles • Ochsner Cancer Institute – • South Texas Accelerated Research • Memorial Sloan Kettering Cancer Center – Jonsson Comprehensive Cancer M. Matrana, S. Jerdonek Therapeutics – A. Patnaik, K. Rivas G. Ku, T. Shrivastav, P. Collins Center – J. Bendell, J. Costin • Memorial Sloan Kettering Cancer • University of Southern California, Keck Center – G. Ku, T. Shrivastav Pieris associates: Corinna Schlosser, Aizea Morales Kastresana 22