Expert Highlights Ongoing Research and Challenges in Pancreatic Cancer

Ramesh K. Ramanathan, MD

Beyond agents such as gemcitabine, nab-paclitaxel (Abraxane), and FOLFIRINOX available in the pancreatic cancer paradigm, Ramesh K. Ramanathan, MD, explained that there are a number of other strategies under investigation.

One agent being explored is pegylated hyaluronidase (PEGPH20), which has also received much attention. A pilot study with PEGPH20 plus gemcitabine/nab-paclitaxel (Abraxane) showed potential for patients with high levels of hyaluronan (HA) and is now in a phase III study (NCT02715804).

Moreover, the stemness inhibitor napabucasin (BBI-608) is also in a phase III trial in combination with gemcitabine and nab-paclitaxel (NCT02993731).

“There’s been a lot of attention on the pancreatic stroma,” said Ramanathan. “Everyone has been investigating agents that affect the stroma in combination with an increased delivery of chemotherapeutic agents.”

OncLive: What are the treatment choices and optimal sequencing in advanced pancreatic cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Ramanathan, professor of medicine at Mayo Clinic, discussed sequencing strategies and emerging therapeutic targets in pancreatic cancer.Ramanathan: For pancreatic cancer, we have 2 regimens for first-line therapy: gemcitabine/ nab-paclitaxel and FOLFIRINOX. I spoke about the relative merits and side effect profiles of both of these agents and how, in practice, you could pick the most appropriate agent for the individual.

There are sequencing strategies. Generally, patients will be on 1 regimen for 4 to 6 months or, as a result of adverse events (AEs), you may have to switch to a second regimen. We also have a new drug for second-line therapy—MM-398 (irinotecan liposome injection; Onivyde)—in combination with 5-fluorouracil (5-FU). It is typically used after gemcitabine and nab-paclitaxel or single-agent gemcitabine.

There are a number of new agents in clinical trials. Increasingly, we are doing molecular profiling for patients with pancreatic cancer. It’s important to know whether their tumors are microsatellite instability—high (MSI-H), even though that’s about 1% of all pancreatic cancers. Pembrolizumab (Keytruda) is an approved checkpoint inhibitor for those patients.

What would you consider to be the role of chemotherapy in this field?

Have there been any surgical advances worth mentioning?

How do you determine the optimal sequence of treatment for an individual patient?

There’s a lot of interest in identifying patients with BRCA mutations—typically BRCA2, which represents approximately 5% to 7% of patients. These patients typically respond better to platinum agents like gemcitabine and cisplatin—even FOLFIRINOX. They tend to respond better and perhaps may have a better survival. PARP inhibitors may be useful for this group of patients in a clinical trial.Unlike other diseases, chemotherapy is still the standard of care for all stages of pancreatic cancer, and increasingly so for patients with localized pancreatic cancer. These are patients who have localized or borderline resectable pancreatic cancer. The patients can undergo surgery, but we’re concerned about the margin. Therefore, chemotherapy has been moved into that category, as well. We’re certainly behind in using targeted agents for pancreatic cancer; that still has not been shown to be effective.There have certainly been advances. Surgery for pancreatic cancer is much safer these days; mortality rates are less than 1%. Laparoscopic procedures have been increasingly used, especially for cancers in the tail of the pancreas and sometimes the head of the pancreas in which a Whipple procedure is used. Surgeons are now using laparoscopic or robotic procedures. Robotic is still in very few centers, but it’s increasing across the country.Typically, when I see a younger patient with good performance status, I tend to use FOLFIRINOX. For a majority of patients, [I give] gemcitabine and nab-paclitaxel. A clinical trial is the standard of care in our center and in most centers.

What are some emerging therapeutic targets?

Most of the clinical trials we have are with gemcitabine/ nab-paclitaxel and [a novel drug]. If I don’t have a clinical trial [to put them on], I would say 25% [of patients] will get FOLFIRINOX and the others will get gemcitabine/ nab-paclitaxel. Single-agent use of gemcitabine is not very common in our practice. It’s reserved for the elderly and patients with a performance status of 2.One agent that I’ve been involved with is PEGPH20, which has been in clinical trials in combination with FOLFIRINOX. Surprisingly, that had negative results. PEGPH20 with gemcitabine/nab-paclitaxel has shown promising efficacy for patients with a biomarker of high levels of hyaluronan. That has led to a phase III study with a biomarker component.

What is an area of research you would like to see addressed?

Is there anything else that you would like to emphasize?

There are a number of other drugs that target the stroma including napabucasin, which is also [being explored] in a very large randomized phase III study with gemcitabine and nab-paclitaxel.The biggest area is immuno-oncology; these drugs have not really worked in pancreatic cancer. Vaccines have not worked. There are new strategies combining oncolytic viruses—vaccines with immunotherapy agents that look very exciting.Surgery is still the only curative modality we have. Patients who have resectable pancreatic cancer should be referred to a high-volume institution with a multidisciplinary team because we find that the outcomes are better and patients do better there.

It is very important to put patients with metastatic disease on clinical trials. It’s not always easy, and if you don’t have a suitable clinical trial, patients have to travel. However, [patients should travel] as far as possible to be on a clinical trial.