PEGPH20: Future Directions in Pancreatic Adenocarcinoma
Insights From: Andrew Ko, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Andrew Ko, MD: The promising results of the randomized phase II HALO-202 trial prompted this large international phase III trial, HALO-301. It was fairly similar in design to the phase II trial in that it’s for patients with previously untreated metastatic pancreatic cancer, using gemcitabine/nab-paclitaxel as the backbone with or without the addition of PEGPH20. The study design is actually a 2:1 randomization, so you have a 2 out of 3 chance of being enrolled to the arm containing PEGPH20. Now, the one major difference, based on the results of the phase II study, is that the study is limited exclusively to patients whose tumors have high levels of hyaluronic acid, which is estimated to be somewhere in the 30% to 40% range in terms of all patients with metastatic pancreatic cancer. About 30% to 40% of them are expected to have levels of hyaluronic acid in their tumors that meet that threshold for being able to participate in the study.
In other words, they have that target to which PEGPH20 is acting upon, and so the study is really intended to enrich for patients who are most likely to benefit from the addition of PEGPH20. So, it’s a good study in terms of being a biomarker-selected trial, which we, at this point, lack in pancreatic cancer. Presently, the way we treat patients with pancreatic cancer is based primarily on clinical criteria and not based on any particular molecular biomarkers. So, this may turn out to be an important study, not just with what we hope will be positive results, but also because it may define a new biomarker that may be useful in terms of predicting the likelihood of success with a new agent like PEGPH20.
PEGPH20 has been looked at and is being looked at in combination with chemotherapy, as discussed. There’s certainly interest in combining PEGPH20 with other agents, particularly immunotherapy drugs like anti-PD-1 or PD-L1 inhibitors. Immunotherapy, in the realm of pancreatic cancer, has been a real challenge to date. We know that these immune checkpoint inhibitors, that have really transformed other types of cancers, by themselves have shown fairly minimal activity in pancreatic cancer. As noted, PEGPH20 does have an effect on the extracellular matrix, so the microenvironment of pancreatic cancer has shown to be actually a pretty crucial component of pancreatic cancer biology and may explain some of the resistance to chemotherapy and immunotherapy drugs. So, modifying this tumor microenvironment—which is generally, in pancreatic cancer, quite immunosuppressive—may lend itself to combination with immuno-oncology agents that may, if anything, allow for better infiltration of cytotoxic T cells and just may prime the tumor and the microenvironment to be more susceptible to the effects of immuno-oncology agents.
Right now, in pancreatic cancer, our mainstay of treatment has been chemotherapy. But certainly, we want to move beyond that in the field, whether to include agents like PEGPH20 that target the peritumoral stroma, the microenvironment; immuno-oncology agents, which alone don’t seem to be having a huge traction in pancreatic cancer; or molecularly targeted agents, which, to date, have not been super successful in this disease. So, I suspect some or all of these in combination with one another or with chemotherapy is going to be the way the field moves forward. I don’t think that chemotherapy is going to be supplanted at any time, but these agents may enhance the agents of chemotherapy, like PEGPH20, maybe sequenced before or after or used in various combinatorial ways that I hope will improve the outcomes for a greater proportion of patients with pancreatic cancer, as well as the ability to treat patients more smartly through biomarker selection such as hyaluronic acid. So, I’m hopeful that this phase III study will turn out to be positive because it will just be, I think, the next step in what hopefully will be a series of greater successes that move us beyond traditional chemotherapy.