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Proffered Paper - Developmental therapeutics

525O - A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies

Date

20 Sep 2020

Session

Proffered Paper - Developmental therapeutics

Topics

Clinical Research

Tumour Site

Presenters

Geoffrey Ku

Citation

Annals of Oncology (2020) 31 (suppl_4): S462-S504. 10.1016/annonc/annonc271

Authors

G. Ku1, J.C. Bendell2, A.W. Tolcher3, S.A. Hurvitz4, A. Krishnamurthy5, A.B. El-Khoueiry6, A. Patnaik7, R.T. Shroff8, A. Noonan9, N.M. Hahn10, M. Matrana11, M. Zettl12, K. Aviano13, L. Mar13, P. Jolicoeur13, S. Olwill12, I. Bruns14, S. Piha-Paul15

Author affiliations

  • 1 Medical Oncology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 2 Medical Oncology, Sarah Cannon Research Institute, 37203 - Nashville/US
  • 3 Clinical Research Director, NEXT OncologyTM, 78229 - San Antonio/US
  • 4 Hematology/oncology Santa Monica, UCLA, 90404 - Santa Monica/US
  • 5 Division Of Hematology/ Oncology, University of Pittsburgh Hillman Cancer Center, 15232 - Pittsburgh/US
  • 6 Clinical Investigations Support Office, USC Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 7 Experimental Therapeutics, South Texas Accelerated Research Therapeutics, 78229 - San Antonio/US
  • 8 Medical Oncology, University of Arizona Cancer Center, Tucson/US
  • 9 Comprehensive Cancer Center, The Ohio State University, 43221 - Ohio/US
  • 10 Oncology And Urology, Greenberg Bladder Cancer Institute, Johns Hopkins University School of Medicine, 21287 - Baltimore/US
  • 11 Medical Oncology, Ochsner Medical Center, 70121 - New Orleans/US
  • 12 Translational Sciences, Pieris Pharmaceuticals, 85399 - Hallbergmoss/DE
  • 13 Clinical Development Department, PIERIS, 02109 - Boston/US
  • 14 Clinical Development Department, PIERIS, 10019 - New York/US
  • 15 Department Of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 - Houston/US
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Abstract 525O

Background

Anticalin® proteins are recombinant human proteins based on lipocalins. PRS-343, a first-in-class bispecific antibody-Anticalin fusion protein, targets HER2 and costimulatory immune receptor 4-1BB on T cells. Here, we report the results of a phase I trial in patients with HER2+ solid tumors.

Methods

PRS-343 was evaluated in sequential dose cohorts from 0.0005 to 18 mg/kg i.v. Doses were administered Q3W up to 8mg/kg, while doses at 8mg/kg were also given Q2W and Q1W and doses beyond 8mg/kg were administered Q2W. Primary study objectives included safety, tolerability and RP2D. Secondary objectives included ORR and DCR, PD response and PK profile. PD response (CD8+ T cell IHC) was assessed in tumor biopsies pre-/post-treatment.

Results

70 patients enrolled (median age 61 years, 59% female, 83% Caucasian, median of four lines of prior therapy) with GC/GEJ (n=25); BC (n=16); gynecological cancer (n=6); CRC (n=10); BTC (n=5); UC (n=2); melanoma, pancreatic and salivary duct cancer (n=1 each) were treated with PRS-343. Based on PK analyses and kinetics of the CD8+ T cell expansion post-treatment, the minimal active dose was considered to be 2.5 mg/kg. 33 patients treated at active dose levels were evaluable for response with an ORR and DCR of 12% and 52% (3% CR, 9% PR, 40% SD), respectively. All objective responses were observed on the Q2W schedule, at/above doses of 8mg/kg; ORR was 40% and DCR was 70% (10% CR, 30% PR). At active doses, we observed pronounced post-treatment expansion of CD8+ T cells while there was no increase at doses below 2.5mg/kg. This effect was more pronounced in patients with a confirmed PR or prolonged SD. PRS-343 was well tolerated and the most frequent TRAEs were mild to moderate infusion related reaction (25%), nausea (7%), arthralgia (5%), vomiting (4%), chills (4%), and fatigue (4%). No DLT was noted. We will also present results of a PRS-343/atezolizumab combination trial in HER2+ solid tumors.

Conclusions

PRS-343 is the first 4-1BB bispecific to demonstrate encouraging evidence of safety and clinical benefit with a correlative PD effect. Based on these data, a phase II trial in gastric/GEJ cancer has been planned in combination with ramucirumab and paclitaxel.

Clinical trial identification

NCT03330561.

Editorial acknowledgement

Legal entity responsible for the study

Pieris Pharmaceuticals.

Funding

Pieris Pharmaceuticals.

Disclosure

M. Zettl: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pieris Pharmaceuticals. K. Aviano: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pieris Pharmaceuticals. L. Mar: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pieris Pharmaceuticals. P. Jolicoeur: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pieris Pharmaceuticals. S. Olwill: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Pieris Pharmaceuticals. I. Bruns: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Pieris Pharmaceuticals. All other authors have declared no conflicts of interest.

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