Phase II Study of Pegvorhyaluronidase Alfa (PEGPH20) and Pembrolizumab for Patients with Hyaluronan-High, Pretreated Metastatic Pancreatic Ductal Adenocarcinoma: PCRT16-001

TL;DR

A clinical trial tested a combination therapy for pancreatic cancer but found it not effective enough, though it was safe and showed some survival correlations with immune markers.

Contribution

The study is the first to evaluate PEGPH20 and pembrolizumab in HA-high metastatic pancreatic cancer and found safety and survival correlations with TCR clonality.

Findings

The treatment was safe but had limited efficacy with a median PFS of 1.5 months and stable disease in 29% of patients.

Higher baseline tumor T cell receptor clonality correlated with longer overall survival.

Prolonged survival was observed in patients who received subsequent chemotherapy after the trial.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a stroma-rich tumor which poses a barrier to anti-tumor immune surveillance. Stroma targeting with PEGPH20 improves infiltration of cytotoxic T-lymphocytes and delivery of PD1/PD-L1 antibodies in tumor models. This multicenter phase II study evaluated the efficacy, safety, and biomarkers of immune response and stroma modulation in patients with HA-high refractory PDA treated with PEGPH20 and pembrolizumab. Treatment was safe and conferred a median overall survival of 7.2 months in PDA patients pretreated with a median of two prior therapies. Nevertheless, with best response of stable disease in two of seven patients (29%) and PFS of only 1.5 months, this regimen was not deemed sufficiently effective in refractory HA-high PDA. Biomarker analysis noted a correlation between higher baseline tumor T cell receptor (TCR) clonality and longer overall survival.

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

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