Expert Hopes Novel Approaches Improve Outlook in Pancreatic Cancer

Ramesh K. Ramanathan, MD

Patients with pancreatic cancer are a difficult-to-treat population, as surgery continues to be the sole curative option. However, ongoing clinical trials are investigating combination treatments with standard chemotherapies to improve outcomes.

For example, the standard frontline regimen nab-paclitaxel (Abraxane) plus gemcitabine is being studied in combination with the monoclonal antibody vantictumab (OMP-18R5) in a phase Ib dose-escalation study for patients with previously untreated stage IV pancreatic cancer (NCT02005315). Safety and maximum-tolerated dose are the study’s primary outcome measures.

Additionally, a feasibility study is evaluating neoadjuvant gemcitabine/nab-paclitaxel plus hypofractionated, image-guided, intensity-modulated radiotherapy (HIGRT) in patients with resectable and borderline resectable pancreatic cancer (NCT02318095).

These trials, along with several others, are hoping to answer some of the key questions surrounding pancreatic cancer.

“Pancreatic cancer is increasingly a common problem,” said Ramesh K. Ramanathan, MD, vice chair of research in the Department of Hematology/Oncology at Mayo Clinic. “By 2020, it will be the second highest cause of cancer death in the United States, so it is becoming a bigger issue compared with other cancers.”

OncLive: What did you discuss during your lecture on pancreatic cancer at this State of the Science Summit?

In an interview during the 2017 OncLive® State of the Science Summit on Gastrointestinal Malignancies, Ramanathan, who lectured on these challenges and emerging agents, explained the hurdles oncologists are facing in the field of pancreatic cancer.Ramanathan: The treatment of pancreatic cancer has evolved over the last 5 years. We have 2 active regimens for first-line treatment. One is the FOLFIRINOX regimen, which came from France, and the other is the nab-paclitaxel/gemcitabine regimen, which was FDA approved in 2013. In the United States, for frontline therapy, these are the regimens currently used.

There are differences between these regimens. FOLFIRINOX is generally reserved for younger patients; it has more toxicity, and patients need to be carefully monitored for toxicities. Nab-paclitaxel/gemcitabine is applicable to a broader group of patients. Approximately 20% of patients in frontline still get single-agent gemcitabine. These are typically older patients with an ECOG performance status of 2.

Looking at the landscape of resectable disease, there have been a lot of advancements, and there has been a change in how we stage patients. MRI scans are increasingly being used but the gold standard is still CT scan with contrast or the commonly used pancreatic CT protocol. That is essential when staging patients with operable pancreatic cancer.

The major change in the last couple of years is the increasing use of preoperative chemotherapy and radiation therapy in borderline pancreatic cancer. Borderline pancreatic cancer is where there is involvement of arteries or veins, patients don’t do as well after surgery, and they tend to have microscopic positive margins and a higher rate of recurrence.

Pilot studies suggest that, by giving chemotherapy with or without radiation therapy, you can improve the outcome and have a higher chance of a negative margin surgery. In practice at most academic centers, patients who have what we call borderline resectable disease or high CA 19-9 will typically undergo chemotherapy. Some centers will use radiation therapy or stereotactic body radiation therapy and then go into surgery. We have seen randomized studies starting; those will be important to see if the strategy is going to be helpful.

There certainly has been a lot of activity with clinical trials and new agents for pancreatic cancer. One of the strategies that is being explored is the tumor microenvironment and how we can use agents that deplete stroma, or increase immune cells into the stroma, so that immunotherapy may be active.

What is it about pancreatic cancer that there is this difficulty with response to treatment?

You mentioned immunotherapy has not shown any benefit. What regimens are being explored?

As of now, immuno-oncology has really not worked in pancreatic cancer. However, we are hopeful that newer combination immunotherapy agents will start making an impact in pancreatic cancer. Pancreatic cancer is very resistant to systemic chemotherapy. We only have a handful of drugs that have some activity, and the response rates are usually in the 20% to 30% range. One reason is, perhaps, that there is no pattern in mutations that we see from patient to patient. Also, unlike other tumors, pancreatic cancers are centered by a very dense stroma. This can prevent chemotherapy drugs and immune cells from entering tumor cells, and that has been a barrier for effective agents. Those studies are just starting. In preclinical studies, we are using one of the checkpoint inhibitors with IDO inhibitors and others; they have shown very promising results but they are still in the laboratory and in mice. Those studies are now starting in patients and that’s very encouraging.

Where is the field at currently regarding biomarker development?

What are the well-known risk factors of pancreatic cancer?

What do you hope that community oncologists will take away from your presentation?

Chimeric antigen receptor T cells look promising. There is very, very early data and there have been some side effects in early studies, but it looks encouraging. There is a lot of research in biomarker development. The one that is the most advanced in clinical trials is hyaluronan and a drug called PEGPH20; they have been shown in preclinical studies to deplete the stroma in pancreatic cells. This is for patients whose tumors have high-hyaluronan content, so that’s the first biomarker study in the phase III setting. There is really no typical risk factor. The most common risk factor is cigarette smoking; 30% of patients have a history of cigarette use. Other risk factors are not clear. It seems that those who develop diabetes, are middle-aged, and then experience weight loss—that may be an indicator of pancreatic cancer. Increasingly, we are recognizing that there is a genetic component to pancreatic cancer. It is still small—in the 5% range—but it’s very important if somebody has a family history of pancreatic cancer that we evaluate for BRCA and PALB2 genes. The important thing is that, still, surgery is only the curative modality for pancreatic cancer—so you need to get a patient with operable disease to a good surgeon. There needs to be more awareness of pancreatic cancer and possible treatments. When you look at the SEER data, there are still a large number of patients who don’t get chemotherapy or are not referred for clinical trials. All of these advances come from clinical trials so, whenever possible, patients should be referred for a suitable clinical trial.