ASCO GI 2022 | PCRT16-001: can PEGPH2O remodel the stroma to sensitize patients with HA-high PC to immunotherapy?
David Bing Zhen, MD, University of Washington Medicine, Seattle, WA, outlines the results of the Phase II study (NCT03634332) investigating PEGPH20 in combination with pembrolizumab for patients with hyaluronan (HA)-high refractory metastatic pancreatic adenocarcinoma (mPC). The accumulation of stromal HA is associated with a poor immune response and patient prognosis, protecting pancreatic cancer (PC) from immune surveillance. Preclinical data has demonstrated PEGPH20 increases infiltration of cytotoxic T-cells and potentially improves the delivery of PD-1 and PD-L1 antibodies, which have previously been shown to be ineffective in PC. Dr. Zhen explains that based on these findings, it was hypothesized stromal remodeling with PEGPH2O could sensitize patients with PC to immunotherapy. Patients received PEGPH20 once a week for 3 weeks and pembrolizumab was given on day 1 across a 28 day cycle. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS), safety, overall response rate (ORR) and rates of stable disease. Planned translational endpoints included amino phenotyping, T-cell receptor (TCR) clonality, circulating cytokines and circulating and tumor HA expression. 38 subjects were screened for HA expression, 8 of which has suitable HA expression and were enrolled onto the trial. Following treatment, an improvement in PFS compared to historical data was not detected. Most notably, however, the OS rate was reasonable compared to historical outcomes, demonstrating a median of 7.2 months. 4 patients had prolonged OS greater than 300 days with one patient exhibiting an OS rate of more than 538 days. 2 patients achieved stable disease and no ORRs were observed. The predominant reason for treatment discontinuation was disease progression. Additionally, the treatment adverse events were reasonable with the majority being grade 1. The translational analysis is still ongoing, however unique molecular alterations have been observed in the 2 patients that exhibited a prolonged OS greater than 300 days. A RET fusion was observed in 1 patient and FGFR amplifications in another. Importantly, due to the available targeted therapies, these mutations are potentially actionable and could be exploited to treat the tumor. The preliminary analysis showed no difference in CD8+ T-cell infiltration or PD-L1 expression with OS or ORR but further analysis is being conducted on TCR and cytokines. In conclusion, no improvement was observed with PEGPH20 and pembrolizumab combination. However, Dr. Zhen emphasizes that due to the encouraging OS results, this therapy may serve to prime future therapies, the conclusion of which will be based upon the translational analysis. This interview took place at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.
