Abstract Background: Hyaluronan (HA) accumulation in the tumor microenvironment increases tumor interstitial fluid pressure, promoting vascular collapse and limiting access of chemotherapy and immune cells to tumor sites. In animal models, HA-High tumors exhibit increased growth and metastasis, treatment resistance, and reduced survival. PEGPH20 is a PEGylated recombinant human hyaluronidase that enzymatically degrades tumor HA. Pembrolizumab (PEM) is a humanized monoclonal antibody targeting PD-1, demonstrating tolerability and activity in patients (pts) with non-small cell lung cancer (NSCLC). This study evaluates the safety and activity of PEGPH20 plus PEM in pts with NSCLC or gastric cancer. Methods: This Phase 1b study comprises dose escalation (up to 30 pts regardless of HA status) and cohort expansion (up to 51 pts with tumors accumulating high levels of HA). HA staining is performed using the VENTANA HA RxDX Assay, which indicates HA in the extracellular matrix. HA-High status (ie, patients who may achieve clinical benefit) was determined by Halozyme to be ≥50% staining based on clinical outcome data from a phase 2 study. For dose escalation, eligible pts (ECOG 0-1) had stage IIIB/IV NSCLC failing ≥1 prior platinum-based regimen or locally advanced or metastatic gastric adenocarcinoma failing ≥1 previous chemotherapy regimen. NSCLC pts known to be epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive must have received an EGFR inhibitor or ALK inhibitor, respectively. For cohort expansion, previously treated or untreated NSCLC is allowed; gastric cancer pts must have failed 1-2 prior treatments. PEGPH20 (1.6, 2.2, 2.6, 3.0, 4.0 µg/kg) is administered IV on D1, 8, 15 of each 21-day cycle followed by PEM 200 mg IV on D1, 4 to 6 hours after PEGPH20. Due to increased thromboembolic risk in gastric cancer, these pts receive prophylactic enoxaparin. Additional prophylaxis with piroxicam (possible musculoskeletal events) and proton pump inhibitors are given to all patients. The primary endpoint for dose escalation is the recommended Phase 2 dose for PEGPH20 in combination with PEM. The primary endpoint for cohort expansion is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival per RECIST and immune-related response criteria, pharmacokinetics, and adverse events. Exploratory endpoints include secondary efficacy endpoints by PD-LI status, plasma and tumor HA levels, and imaging parameters of tumor blood flow (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI]) and tumor metabolic activity (positron emission tomography/computed tomography [PET/CT] scans). ClinicalTrials.gov Identifier: NCT02563548. Citation Format: Lyudmila Bazhenova, Philip J. Gold, R. Donald Harvey, Alexander I. Spira, John Nemunaitis, Joaquina C. Baranda, Shirish Gadgeel. A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT032. doi:10.1158/1538-7445.AM2017-CT032