Emerging Developments in NETs, Liver Cancer

Scott Paulson, MD

Rapid advancements in understanding the biology of neuroendocrine tumors (NETs) has made this a thrilling time to be an oncologist in this field, according to Scott Paulson, MD.

“It has really been a pretty exciting field the past couple of years,” said Paulson. “[There has been] a lot of energy and excitement about how things are changing.”

At the 2017 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Paulson, medical director for the Neuroendocrine Research and Treatment Center at Baylor Charles A. Sammons Cancer Center, gave lectures on the NETs landscape as well as emerging treatments for patients with hepatocellular carcinoma (HCC).

OncLive: Can you provide an overview of your presentation on NETs?

In an interview during the meeting, Paulson highlighted developments with NETs and liver cancer that community oncologists should keep in mind moving forward.Paulson: There have been quite a few drug approvals coming through and a lot of positive trials. It’s starting to change the landscape about how we think about this as, classically, a very surgical, interventional radiology (IR)-based disease.

What are the most exciting regimens that we have seen approval of recently. Are there others in the pipeline that have practice-changing potential?

There’s an increasing number of drugs that are coming into it, as well. The other thing, too, that I didn’t even go into in that talk is that medical oncology, surgical techniques, and IR-directed techniques are getting a lot better.The improved understanding of somatostatin analogs is very helpful. This includes where to use them, how to use them, and how best to pick out patients who need to start therapy. A challenging aspect of this disease is that if patients have a NET…perhaps they have a [malignant] cancer, [or] maybe it’s…benign and you say, "Oh, even though it’s a cancer, we're not going to do anything about it. We're just going to watch you for a while." That can be very deeply unsettling for a patient. Trying to be able to pick the people who need aggressive therapy upfront versus those who can sit back and be followed very closely is what has changed some of the landscape.

We are getting some of that information out of those trials that have been done with drugs that we've been using for a while. That’s an exciting thing when you take the clinical data. The other exciting data have been from Gallium-68 DOTATATE imaging, which has changed how we work these patients up. It has changed management decisions. I have certainly seen it directly change in the clinic; a number of times it has changed what we would have done with somebody. It’s changed how we look at their disease as more or less aggressive, and very much changed the way we would sequence therapy—so that has been exceptionally exciting.

What are some current unmet needs in this space?

The final and most exciting piece in all of this is the advent of peptide receptor radionuclide therapy (PRRT), which is going to change how we treat these patients. We don't know where that's going to fit into this grand sequence of how we treat them, but it certainly changed the outlook on people who have nonsurgical, very advanced disease. It has offered quite a bit of hope. The early data are extremely appealing. There are a lot of historical data to support its use. It’s going to be interesting to see how it fits when it comes into the clinic, which we expected to do once the FDA has looked at it and moved forward with it.One of the things I didn't talk about at all is symptom control. This happens when about 20% of these patients who have tumors that make a lot of hormone—because these are funky tumors, they make a lot of chemicals—can have a very high symptom burden. These patients, if they're not really aggressively treated, can have a pretty poor quality of life.

We've seen quite a few new therapies work their way in that have started to help. Telotristat ethyl (Xermelo) was approved because it helps reduce the burden of serotonin production for patients with carcinoid syndrome. Patients who have refractory carcinoid syndrome have a lot of diarrhea and flushing. If you can get those symptoms under control, you can really change somebody's day today.

What ongoing trials do you find to be exciting?

We couple that with the ability to shrink tumors, with things like PRRT and better surgical and liver-directed techniques, you can take a patient who is feeling pretty sick or has a carcinoid tumor or NET that dominates their entire life, and render them to a point where it’s not at the constant forefront of their mind. As we see more and more options to help with that, symptom control is one of the more unmet needs. We need more [focus there], but it’s been encouraging to see it be able to change people’s lives. The question of immunotherapy is going to be interesting. There are quite a few immunotherapy studies that are looking at NETs. They have enrolled very quickly. We expect more to be done in this field; whether or not you can generate an immune response to neuroendocrine cancer cells is going to be interesting. That, I would argue, is one of the hotter topics that’s out there.

You gave another lecture on liver cancer. What is important to highlight here?

The other types of therapies that are going to be moving forward will continue to target the somatostatin receptors, much like somatostatin analogs and PRRT that have been used before, but targeted more aggressively and specifically, and be able to offer sequential lines of therapy. Targeted therapies, such as everolimus (Afinitor) or cabozantinib (Cabometyx), are certainly not done. They continue to show activity. One of the big questions that’s out there is, “Is cabozantinib going to meet its endpoint and offer an additional line of therapy for these patients?” We don’t know yet. That trial is currently ongoing.What has been challenging for medical oncologists is that we haven’t really had drugs. Sorafenib (Nexavar) made an explosion onto the scene, and it did so because it was the first drug to show a significant benefit in these patients. It continues to demonstrate that benefit in a number of subsequent studies, so we are seeing it happen again and again. We need more than that for medical oncologists to get engaged with the field.

What about lenvatinib (Lenvima)? Where are we with that agent in liver cancer?

With the approval of regorafenib (Stivarga) in the second-line setting and the expedited approval of immunotherapy with nivolumab (Opdivo), we are starting to see other types of drugs work their way in so that medical oncologists have options for patients with advanced HCC.Lenvatinib was in an interesting study. The issue of looking at lenvatinib with sorafenib is that those were compared to head to head. While there was a little bit of a trend of improvement in response rates with lenvatinib, the toxicity was noticeably higher. I wonder where that’s going to sit in the landscape. It offers an additional therapeutic option for patients with HCC. In people who a have a lot of familiarity with the drug, you may see it used in the frontline setting or other settings if it comes into the United States. However, people are a little bit more familiar with sorafenib.

What do you do for patients who relapse on regorafenib or sorafenib?

I can’t say that the data shape and move the standard of frontline therapy, so I don’t know how much it is going to be used. There may be patients where you look at that response rate and say, “If we try to push a little bit more shrinkage, maybe this is a compelling option,” but you have to do so carefully. The lack of familiarity with it versus sorafenib, which has been around longer, will be interesting to see whether is uptake of it in the community. It certainly did demonstrate at least some degree of noninferiority in the frontline study.With most of those patients, we try to get them on clinical trials. You’re going to see that activity in immunotherapy be used to try to leverage an additional number of trials, including checkpoint inhibitors [and in combination] moving into the frontline and second-line settings, as well as additional immune-activating agents being sequentially added into the secondary lines. The immunotherapy signal is compelling.

It’s compelling not just because nearly every disease is showing at least about a 20% response rate with checkpoint inhibitors in some degree—which isn’t massive. It’s compelling in HCC because not much has traditionally shrunk these tumors and [also] been tolerable. While chemotherapy has had activity, it’s tended to hurt the liver as much as it helped and it has not translated to people living longer.

What else about this talk do you think is important to mention?

I would also argue that it is not just the refractory patients. We are trying get [patients] on active agents in combination for frontline studies, as well. To finally see some smoke around the fires that are there in some active drugs, we're trying to get people into more active areas of research—earlier rather than later. We talked about biliary cancers, [which are] traditionally underserved and ignored. The BILCAP data, which demonstrated a positive adjuvant study for biliary cancers with the addition of capecitabine versus observation, was important. While the results weren’t overwhelming, these studies have been done a number of times and had not shown dramatic or positive results with gemcitabine plus oxaliplatin.

We are also seeing those biliary cancers being broken up into baskets, at least in the refractory setting beyond gemcitabine and cisplatin. We are starting to see FGFR-targeted agents and IDH inhibitors show activity. This is a disease that, molecularly, if there is enough tissue that we can look at, there are some options that are active for those patients. I would very much encourage clinical trial participation, because the second- and third-line settings do not perform well for those patients. We do not have a lot of data to support active regimens there.