Phase 1 Dose Escalation Study of PRS-343, a HER2/4-1BB Bispecific Molecule, in Patients with HER2+ Malignancies Sarina Piha-Paul1, Johanna Bendell2, Anthony Tolcher3, Sara Hurvitz4, Amita Patnaik5, Anuradha Krishnamurthy6, Rachna Shroff7, Paula Pohlmann8, Noah Hahn9, Markus Zettl10, Jian Mei10, Kayti Aviano10, Manuela Duerr10, Rushdia Yusuf10, Louis A Matis10, Shane Olwill10, Ingmar Bruns10, Geoffrey Ku11 1The University of Texas MD Anderson Cancer Center, Texas, USA 5South Texas Accelerated Research Therapeutics, Texas, USA 10Pieris Pharmaceuticals, Inc., Massachusetts, USA 2Sarah Cannon Research Institute, LLC, Tennessee, USA 6University of Pittsburgh Medical Center, Pennsylvania, USA 11Memorial Sloan Kettering Cancer Center, New York, USA 3NEXT Oncology, Texas, USA 7University of Arizona Cancer Center, Arizona, USA 4University of California Los Angeles Jonsson Comprehensive Cancer Center, 8Georgetown University Hospital, Washington DC, USA California, USA 9Sydney Kimmel Cancer Center at Johns Hopkins, Maryland, USA
Disclosures • Arog Pharmaceuticals – research support • AstraZeneca – research support, consulting • Bristol-Myers 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 Study sponsored by Pieris Pharmaceuticals
PRS-343: A HER2 4-1BB Bispecific HER2- HER2-targeting moiety targeting of the drug localizes to the Antibody tumor microenvironment and HER2+ facilitates 4-1BB cross-linking Tumor Cell PRS-343 4-1BB cross-linking ameliorates T-cell exhaustion and is critical for T-cell 4-1BB- Tumor-specific targeting T Cell expansion Anticalin Proteins
Study Design Current Enrollment Primary Objectives Dose Level No. Patients Dose (mg/kg) • Characterize safety profile 1 1 0.0005 (Q3W) • Identify MTD or RP2D 2 1 0.0015 3 1 0.005 Secondary Objectives 4 2 0.015 5 20.05 • Characterize PK profile 6 50.15 • Investigate dosing schedule 7 70.5 • Assess potential immunogenicity and PD effects 8 61 • Investigate efficacy 9 62.5 10 95 11 78 Active Schedule 1: Schedule 2 : 11b 68 (Q2W) schedules Q3W dosing on Day 1 Q2W dosing on Days 1, 15 Total 53 Data cut-off: 23-Oct-19 for subjects up to Cohort 11b; additional cohorts enrolling
Key Enrollment Criteria Inclusion Criteria • Diagnosis of HER2+ advanced/metastatic solid tumor malignancy that has progressed on standard therapy or for which no standard therapy is available • HER2+ solid tumors documented by ASCO, CAP or institutional guidelines • Patients with breast, gastric and GEJ cancer must have received at least one prior HER2-targeted therapy for advanced / metastatic disease • Measurable disease per RECIST v1.1 • ECOG 0 or 1 • Adequate liver, renal, cardiac and bone marrow function Exclusion Criteria • Ejection fraction below the lower limit of normal with trastuzumab and/ or pertuzumab • Systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration • Known, symptomatic, unstable or progressing CNS primary malignancies • Radiation therapy within 21 days prior to registration (limited field radiation to non-visceral structures is allowed, e.g., limb bone metastasis)
Baseline Characteristics All Subjects (n = 53) Characteristic n (%) Primary Cancer Type n (%) Age, Median (range) 61 (29–92) Gastroesophageal 19 (36%) Gender F 33 (62%) Breast 14 (26%) M 20 (38%) Gynecological 6 (11%) ECOG PS 0 12 (23%) Colorectal 5 (9%) 1 41 (77%) Gallbladder/ Biliary 4 (8%) Prior Therapy Lines 1 6 (11%) Bladder 2 (4%) 25 (9%) 3 11 (21%) Pancreatic 1 (2%) 4 10 (19%) Other – Salivary Duct 1 (2%) 5+ 21 (40%) Median no. of anti-HER2 Treatments Other – Melanoma 1 (2%) Breast 4 Gastric 2 Data cut-off: 23-Oct-19
PRS-343 Clinical Pharmacology 1000 100 Preliminary PRS-343 0.015 mg/kg Pharmacology Profile 0.05 mg/kg 10 0.15 mg/kg 0.5 mg/kg 1 mg/kg • Preliminary PK: Mean terminal half-life 1 2.5 mg/kg of PRS-343 is approximately five days 5 mg/kg PRS-343 (µg/mL) serum conc 8 mg/kg (Q3W) 8 mg/kg (Q2W) 0.1 • 27.8% of patients are ADA+ with titers above 1:150 in cohorts covering active dose range (≥2.5 mg/kg) 0.01 0 200 400 600 Time (hours) Note: PRS-343 concentrations are below limit of quantification for dose levels < 0.015 mg/kg
Treatment-Related Adverse Events All Subjects Occurred in ≥ 1 Patient n = 111 | n (%) % Grade 3 Infusion Related Reaction 10 (9%) 2 (2%) Fatigue 10 (9%) 1 (1%) Chills 7 (6%) 0 Flushing 7 (6%) 3 (3%) Nausea 7 (6%) 0 Diarrhea 7 (6%) 0 Vomiting 6 (5%) 0 Non-Cardiac Chest Pain 5 (4%) 1 (1%) No Grade 4 or 5 Treatment-Related AEs
Summary of Responses at Active Dose Range of PRS-343 Based on clinical data, serum concentration of > 20 µg/ml defines active dose range (beginning at Cohort 9) Cohort 11b 11 10 9 Total Best Response 8 mg/kg, Q2W 8 mg/kg, Q3W 5 mg/kg, Q3W 2.5 mg/kg, Q3W Response Evaluable Patients 544518 PR 2- - - 2 SD 32128 PD -2338 ORR 40% 0% 0% 0% 11% DCR 100% 50% 25% 40% 55%
Best Response in Target Lesions Monotherapy Study Cohorts 1-11b 60% 40% Cohort 1 – 0.0005 mg/kg Cohort 2 – 0.0015 mg/kg Disease Progression 20% Cohort 5 – 0.5 mg/kg Cohort 6 – 1 mg/kg Cohort 7 – 0.5 mg/kg 0% Cohort 8 – 1 mg/kg Cohort 9 – 2.5 mg/kg -20% Cohort 10 – 5 mg/kg Best change from baseline (%) Best change from Partial Response Cohort 11 – 8 mg/kg -40% Cohort 11b – 8 mg/kg (Q2W) -60% 7 9 9 6 9 6 11 7 8 10 8 7 5 11b 9 11 10 8 10 8 11b 6 7 7 10 9 1 10 2 10 8 11b11b Cohort
Best Response in Target Lesions Monotherapy Study Cohorts 9-11b 60% 40% Cohort 9 – 2.5 mg/kg Cohort 10 – 5 mg/kg Disease Progression 20% Cohort 11 – 8 mg/kg Cohort 11b – 8 mg/kg (Q2W) 0% -20% Best change from baseline (%) Best change from Partial Response -40% -60% 9 9 9 11 10 10 11b 9 11 10 10 11b 9 10 10 11b 11b Cohort
Average Time on Treatment with PRS-343 Significantly Increases in Cohort 11b (8 mg/kg Q2W) Duration (Days) Number of Subjects = 28 Cohort 11b – 8 mg/kg (Q2W) Cohort 11 – 8 mg/kg Cohort 10 – 5 mg/kg Cohort 9 – 2.5 mg/kg Partial Response Stable Disease Disease Progression Death Discontinued On-Treatment 0 21 42 63 84 105 126 147 168 189 210
Increased CD8+ T Cell Numbers in Tumor Biopsies Post-Treatment Biopsy Biopsy Pre-dose PRS-343 PRS-343 Post-dose (Cycle 1 Day 1) (Cycle 2 Day 1) (Cycle 2 Days 2-8) Tumor Stroma Pronounced increase in CD8+ T cell 17 17 numbers is observed post-treatment in 16 16 patients receiving doses ≥ 2.5 mg/kg 6 6 5 5 tumor area tumor area 2 2 4 4 Patients benefiting from treatment (SD 3 3 > 120 days (blue) and PR (green) had 2 2 Fold induction CD8+ induction Fold Fold induction CD8+ induction Fold + T cells/mm T cells/mm 1 1 more pronounced increase in CD8 T 0 0 cell number in tumor vs. stroma Cohort 1-8 Cohort 9-11b Cohort 1-8 Cohort 9-11b
Gastric Cancer Patient with Confirmed PR Patient Profile, Treatment History and RECIST Patient Profile Oncology Treatment History Duration Best Response • Cohort 11b | 8 mg/kg every two weeks • 80-year old woman; initial diagnosis on June 2017 • Stage IV gastric adenocarcinoma Trastuzumab, Pembrolizumab + July 2017 – June 2018 Stable Disease • Metastases to liver, lymph node and adrenal glands Capecitabine/oxaliplatin • HER2 IHC 3+; PD-L1 positive (CPS=3) • NGS: ERBB2 amplification, TP53 mutation, alteration Nivolumab with IDO1 inhibitor Aug 2018 – Jan 2019 Stable Disease of CDK12 and SF3B1 (investigational drug) 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 9 Target 2 Liver 20 16 10 8 8 Target 3 Pancreas 19 16 14 14 14 % Change from Baseline -17% -36% -42% -42% PR, partial response; HER2, human epidermal growth factor receptor 2; PD-L1, Programmed Death Ligand 1; CPS, combined positive score; NGS, next-generation sequencing
Gastric Cancer Patient with Confirmed Partial Response Baseline Cycle 4
CD8+ T Cell Numbers Increase Post-Treatment in Responding Gastric Cancer Patient Tumor Stroma CD8 fold change: 5.7 CD8 pre [n/mm2]: 38 CD8 fold change: 4 CD8 pre [n/mm2]: 66 Pre-Treatment (CD8: Teal | Ki67: Red) Fold Change Fold Change Post-Treatment Post-Treatment Post-Treatment (CD8: Teal | Ki67: Red) CD8+ T cell numbers increase post-treatment. This is more pronounced in tumor tissue, consistent with the predicted MoA of PRS-343.
Conclusions: PRS-343 as Monotherapy Well-tolerated, with a good safety profile in all doses and schedules tested Demonstrated anti-tumor activity in heavily pre-treated patient population across multiple tumor types; treatment history indicative of 4-1BB-driven mechanism-of-action Showed a clear increase in CD8+ T cell numbers and proliferative index in the tumor microenvironment of responders Future studies are planned for continued development in defined HER2+ indications
Acknowledgements • Patients, their families and caregivers • Investigators, as well as their site personnel • The University of Texas MD Anderson Cancer Center – S. Piha-Paul, B. Bruggman • Sarah Cannon Research Institute, LLC – J. Bendell, J. Costin • NEXT Oncology – A. Tolcher, K. Dotson • University of California Los Angeles Jonsson Comprehensive Cancer Center – S. Hurvitz, M. Rocha, R. Rubin • South Texas Accelerated Research Therapeutics – A. Patnaik, K. Rivas • University of Pittsburgh Medical Center – A. Krishnamurthy, B. Foster, A. Blasko • University of Arizona Cancer Center – R. Shroff, D. Pennington • Georgetown University Hospital – P. Pohlmann, S. Wagner • Sydney Kimmel Cancer Center at Johns Hopkins – N. Hahn, E. Lee • Memorial Sloan Kettering Cancer Center – G. Ku, T. Shrivastav, P. Collins
Appendix
Adverse Events Unrelated to Treatment All Subjects Adverse Events Unrelated to Adverse Events Unrelated to n = 303 | n (%) n = 303 | n (%) Treatment Treatment Fatigue 14 (5%) Alanine aminotransferase increased 5 (2%) Abdominal pain 11 (4%) Blood bilirubin increased 5 (2%) Anemia 10 (3%) Headache 5 (2%) Constipation 9 (3%) Hyperglycemia 5 (2%) Decreased appetite 9 (3%) Pain 5 (2%) Dyspnea 9 (3%) Pruritus 5 (2%) Diarrhea 7 (2%) Vomiting 5 (2%) Dysphagia 6 (2%) Weight decreased 5 (2%) Nausea 6 (2%)