Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer

Abstract

Survival rates for pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant tumor and one of the explanations for this is attributed to desmoplasia that impedes drug delivery. Based on this, stromal modifying agent such as Pegvorhyaluronidase alfa (PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high hyaluronic acid (HA) expressing tumors, the phase III HALO 301 study failed to miss it's primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the tumor stroma may be a physical barrier hampering drug delivery, it may also have protective effects in restraining tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted. Pancreatic cancer (PC) remains one of the deadliest cancers in the United States with very poor outcomes. In 2019, it is estimated that 56,770 Americans will be diagnosed with pancreatic cancer in the US and more than 45,750 will die of the disease. It is expected to become the second leading cause of cancer-related deaths by 2020 and currently has a 5-year overall survival rate of 8.5% for all stages combined. 1 PC is a relatively chemoresistant tumor with limited treatment options, which can include surgery if identified early in the disease process, radiation, chemotherapy, and some targeted therapies. Most patients present This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited.