Potentially Transformative Treatments Emerge in Pancreatic Cancer

Allyson Ocean, MD

Antistromal agents, vitamin D analogs, high-dose intravenous (IV) vitamin C, and immunotherapy agents are just a few therapeutic strategies currently being investigated in pancreatic cancer, explains Allyson Ocean, MD.

Targeting the tumor stroma led to encouraging data in a randomized phase II trial of patients with untreated metastatic pancreatic ductal adenocarcinoma who received nab-paclitaxel (Abraxane) and gemcitabine with or without PEGPH20 (pegvorhyaluronidase alfa).

The triplet was associated with significantly better progression-free survival (PFS) than nab-paclitaxel/gemcitabine alone (6.0 vs 5.3 months; HR, 0.73; 95% CI, 0.53-1.00; P = .048). When investigators stratified patients by hyaluronic acid (HA) expression, PFS in HA-high expressers was also improved with the triplet regimen versus the doublet (9.2 vs 5.2 months; HR, 0.51; 95% CI, 0.26-1.00; P = .048).

Ocean spoke to the development of these novel therapeutic regimens in the pancreatic cancer paradigm in a presentation at the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers.

OncLive: Please provide background of your lecture on the evolution of pancreatic cancer treatment.

In an interview during the meeting, Ocean, a medical oncologist and attending physician in gastrointestinal oncology at Weill Cornell Medicine/NewYork-Presbyterian Hospital, medical oncologist, The Jay Monahan Center for Gastrointestinal Health, associate professor of medicine, Weill Medical College of Cornell University, gave a glimpse of these emerging treatment strategies in pancreatic cancer.Ocean: Regarding therapies, I gave background on what exists today in terms of standard of care, metastatic disease, first-line therapy, second-line therapy, sequencing regimens, and the data that led to their approvals as standard regimens.

I also spoke about what’s on the horizon with regard to newer therapies in terms of categories. One of the categories targets the stroma, and a main reason why patients with pancreatic cancer progress, is because the therapies cannot penetrate these fibroblast-enriched stromata that are devoid of immune cells.

How will these therapies affect the patient population?

What are some of these emerging targeted agents?

I spoke about some emerging antistromal agents, including PEGPH20 and vitamin D analogs, and also touched on immunotherapy agents that are being tested now. I spoke about my own research at Weill Cornell Medicine involving high-dose IV vitamin C in KRAS-mutated cancers. I finished with some precision medicine topics in targeted therapies such as BRCA-mutated cancers and other targeted pathways that we can approach with newer therapies.If there is a drug that is successful at targeting the stroma, it’s going to affect all patients with pancreatic cancer. This is related to the ongoing phase III PEGPH20 clinical trial looking at PEGPH20 in combination with gemcitabine and nab-paclitaxel. That is showing more promise in tumors that are HA—positive. This population of patients, approximately 25% of the overall patient population, did better in the phase II studies with that combination.The first one I spoke about is in the vitamin D analog category. We know from the research of Ronald M. Evans, PhD, at the Salk Institute for Biological Studies, that the vitamin D receptor is very important in the stroma. The activation of the vitamin D receptor relates to the pancreatic stellate cell, which is responsible for the immune cross-talk and signaling that happens within pancreatic cancer in the stroma. Research has shown that inhibiting the vitamin D receptor with vitamin D analogs can turn the stellate cell into a less active cell. This can ultimately bring more immune cells into the stroma and allow for better penetration with chemotherapy.

In relation to the BRCA-mutated cancers, there are ongoing investigations using PARP inhibitors. These medicines are already approved for BRCA-mutated breast and ovarian cancers. Because the pathway is similar in pancreatic cancer, we hope to get positive data using PARP inhibitors in pancreatic cancer and also in combination with chemotherapy. Right now, they’re approved as single agents in those other diseases. They’re not approved in combination with chemotherapy, so that’s a promising ongoing area of research for BRCA-mutated cancers.

I also highlighted our research on high-dose IV vitamin C in KRAS-mutated cells. The use of high-dose IV vitamin C is being studied in both colon cancer and pancreatic cancer. The way that vitamin C targets the KRAS-mutated cell is through the Warburg effect, in which cells travel through a pathway where their energy metabolism is affected when they receive high-dose vitamin C. In a sense, it is a metabolic killing of the cell, forcing the cells into oxidative phosphorylation rather than [taking] the glycolytic pathway. The use of high-dose IV vitamin C in KRAS-mutated cancers is currently being studied in a pilot trial at Weill Cornell Medicine.

How are inherited versus noninherited genes factored into a physician’s treatment approach?

What is important to keep in mind regarding the progression of treatment in pancreatic cancer?

Stem cell inhibitors are also on trial. Napabucasin (BBI-608) is a stem cell inhibitor that’s being used in combination with gemcitabine and nab-paclitaxel in multiple cancers, including pancreatic cancer.When we find a family that carries an inherited predisposition to developing pancreatic cancer, sometimes we can use that to help the patient. If a patient carries the BRCA mutation, we might treat them with a platinum-based therapy because we know those cancers tend to respond better to platinum-based therapies, and we can use ongoing research about PARP inhibitors for these cancers.When you don’t treat pancreatic cancer on a daily basis, it’s easy to assume that the research is slow and lacking in effective therapies. However, we are making strides, and oncologists need to know that there are many ongoing clinical trials for patients. The number-one discussion you should have with your patients should be the potential of enrolling in clinical trials. Helping them find a clinical trial close to the institution where they are being treated is also important, so they can potentially receive a therapy that may improve the standard of care in pancreatic cancer.

Lastly, patients and oncologists should have hope in pancreatic cancer. We showed a series of videos of long-term pancreatic cancer survivors, specifically more than 3 years with metastatic disease, and of patients who have been cured of their disease. We want patients who are starting their journey to know that there are long-term survivors. Eventually, we plan to study these patients to find out what patterns exist in their tumor types and in their genetic makeup that enabled them to be cured of their disease for many years.

Hingorani SR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA). J Clin Oncol. 2017;35(15):4008. doi:10.1200/JCO.2017.35.15_suppl.4008.