Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer.

abstract CC BY

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.

expert opinion CC BY

Unfortunately, we now have two failed clinical trials for PEGPH20. It is of both academic and clinical importance to consider possible explanations for these failed trials. In SWOG 1313, the answer may lie more within the toxicity of the entire regimen. As a consequence, the overall treatment exposure in the experimental arm was inferior. The study group received half the number of cycles of chemotherapy and more dose reductions than the control group. This substantial imbalance in treatment exposure is likely the most relevant factor contributing to the very poor outcomes of the study group. Dosing of PEGPH20 could be another factor that contributed to the negative results of SWOG 1313. The recommended phase II dose (RP2D) schedule for PEGPH20 was q2 weeks, whereas in the positive HALO-202 trial it was administered weekly. Additionally, the lack of subject selection based on the HA high biomarker likely played a role. However, this was rectified in the HALO 301 study, which only included patients that had tumors with high-levels of HA expression. The phase II study showed promising results, especially in this subset of patients. The R2PD with the twice weekly dosing for PEGPH20 was also applied on this trial. Patients were also given enoxaparin to avoid the venous thromboembolism risk. Despite these corrections, HALO 301 now failed. Halozyme announced that although response rate was similar to the control arm, no significant difference was seen. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough? Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells, but additional intrinsic factors at play. The pancreatic cancer microenvironment is also filled with immunosuppressive cell types, such as myeloid derived suppressor cells (MDSCs) and regulatory T-cells (Tregs), which in turn alter the effector function of cytotoxic T-cells, leading to evasion of the immune system. It has also been shown that the amount of Tregs in the pancreatic microenvironment corresponds to the Tregs found peripherally, which could result in systemic chemotherapy resistance.14 The location of the cytotoxic T-cells also is problematic; they are located at the front of pancreatic cancer and not so much in the center where they can target malignant cells. Also, when they do cluster next to malignant cells they are unable to act upon them due to the dense stromal tissue.15 This has explained the poor response to immunotherapies in pancreatic cancer as well, along with the low mutational burden, and lack of significant neoantigens. Although preclinical studies have shown promise in the area of suppressing Tregs, clinical studies have not followed suit. The ECLIPSE trial, which depleted Tregs with cyclophosphamide and the GVAX vaccine has not shown any significant clinical outcomes.16 The epithelial to mesenchymal transition (EMT) is the conversion of epithelial cells into mesenchymal like cells in cell culture conditions, which is seen in the pancreatic tumor cell.20 However, the inhibition of this has been not proven to have an effect on pancreatic metastasis. Paradoxically, it does seem to affect chemoresistance of the pancreatic tumor cell. The theory behind this is the cell has seemed to have compensatory mechanisms to overcome the inhibition in terms of metastasis, but may suppress drug transporter and concentrating proteins, which could affect resistance to chemotherapies such as gemcitabine. Therefore, perhaps adding epithelial–mesenchymal transition (EMT) inhibitors to standard backbone chemotherapies is necessary to consider. 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. Sonic hedge hog (SHH) deficient tumors have reduced stromal content but surprisingly such tumors were more aggressive, exhibited undifferentiated histology, increased vascularity, and heightened proliferation.21 Another study investigating role of adjuvant gemcitabine compared to observation in resectable pancreatic cancer patients analyzed tissue samples of 162 patients. They found that dense stromal reaction was actually associated with improved disease free survival (DFS) and OS with median DFS and OS of 13.8 and 28 months in weak stroma (p=0.05) versus 10.1 and 20.2 months in strong stroma (p=0.047).22 Therefore, reversal of hypovascular stroma with stromal depleting and penetrating agents such as PEGPH20 may simply unleash the strain of aggressive cancer clones potentiating their metastatic capacity. In summary, the phylogenesis of pancreatic cancer is much more complex than originally thought. It may indeed be a combination of stromal modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.