Immunotherapy, Emerging Agents Offer Hope in GI Cancers

Johanna C. Bendell, MD

Much ground is being covered in the space of gastrointestinal (GI) cancer treatment, with a focus on how more subsets of patients can benefit from immunotherapy agents alone or in combination and have improved, long-term outcomes.

“In terms of the evolution of the field of GI oncology, we are seeing small starts—small hope coming through across multiple tumor types,” said Johanna Bendell, MD, director of GI Oncology Research at Sarah Cannon Research Institute. “I don’t think we have hit the big one yet, but we are on the cusp of seeing some real improvements in how patients are doing, particularly with immunotherapy combinations and modifying immunotherapies, so it works for more patients with GI cancers.”

PD-1 inhibitors in combination with CTLA-4 inhibitors is one example of a research method being studied in these malignancies, while more novel approaches include the incorporation of stemness inhibitors, like napabucasin (BBI-608) to target cancer stem cells, Bendell adds.

In an interview during the 2017 OncLive^® State of the Science Summit on GI Cancers, which Bendell chaired, she provided further insight on the emerging treatment landscape in GI malignancies, with a special focus on cancers of the liver, GI tract, and pancreas.

OncLive: What are the latest developments in the liver cancer?

Bendell: We have known that drugs that block the angiogenesis pathway for liver cancers, such as sorafenib (Nexavar), do work for patients with liver cancer. But now, we’ve seen data that show that another VEGF inhibitor, regorafenib (Stivarga), works for these patients, as well.

What is even more exciting is that we’re seeing data that immunotherapies are very promising agents for the treatment of patients liver cancer.

Can you elaborate on the significance of the immunotherapy data?

In liver cancer, they have looked at checkpoint inhibitors like anti­—PD-1/PD-L1 agents alone and in combination with CTLA-4 inhibitors. Different drug companies have looked at their different agents and they’re all currently in clinical trials, but are looking very promising. They are also looking particularly promising is patients with hepatitis, particularly hepatitis C.

Regorafenib currently has a priority review designation with the FDA for liver cancer. What did we see in the pivotal study that could lead to its approval?

We saw recent data at the 2017 GI Cancers Symposium from the RESORCE study, which took patients with liver cancer who progressed on sorafenib and randomized them to regorafenib or placebo. What we saw was an improvement in both progression-free survival (PFS) and overall survival (OS) using regorafenib versus placebo.

What major questions remain with regorafenib?

The biggest thing with regorafenib is how to dose it safely and how to limit the toxicities that we see. Right now, the starting dose is 160 mg per day. If you are going to start that high, you definitely need to educate patients about the toxicities, and have them call in if they start to have any of them so you can hold the drug quickly before it becomes too bad.

Some practitioners, though, are starting at lower doses—120 mg or even 80 mg. Currently in the colon cancer field, researchers are beginning a trial that will compare starting at the higher dose versus lower dose of regorafenib to see if it’s just as effective to start at a lower dose rather than the higher.

You also spoke on gastric cancer at tonight’s meeting. What is new in this area?

It is such an amazing time in the development of drugs for patients with gastric cancer. We’ve seen that immunotherapies—checkpoint inhibitors alone and even in combination—help patients with gastric cancer.

We saw our first randomized phase III study’s data at the 2017 GI Cancers Symposium, which looked at patients with gastric cancer that was refractory to at least 1 line of therapy. These patients were treated with the PD-1 inhibitor nivolumab (Opdivo) versus best supportive care. We did see an improvement in OS in these patients, finally giving us phase III evidence that immunotherapy is active for patients with gastric cancer.

What role could immunotherapy have in gastric cancer treatment?

We see that immunotherapy is very active in patients with gastric cancer; about 20% to 30% of them have a chance of responding to immunotherapy. Now, we also have to think about what’s going to happen to the other 70% to 80% of patients who don’t respond.

One way people are looking at it is combining immunotherapy—like PD-1/PD-L1 inhibitors with CTLA-4—as well as newer immunotherapy targets that are in development.

Also, we already know that antiangiogenic agents work for patients with gastric cancer, noting the approval of ramucirumab (Cyramza). We have also seen randomized phase II data that suggest that regorafenib may also be a potential option for these patients with gastric cancer, as well.

The other big question is, how about the combination of antiangiogenic agents and checkpoint inhibitors? We’ve seen some preliminary data of pembrolizumab (Keytruda) plus ramucirumab, and we are not quite sure how much it might benefit patients yet. It was very early data but, certainly, looking at those combinations as options for these patients is very exciting.

What are your thoughts on stemness inhibitors?

One new class of drugs that people are very interested in are the stemness inhibitors. We know that, in general, chemotherapy will kill off the weaker cancer cells in a tumor. However, the stem cells are sort of the “king and the queen on the chess board” and are very chemotherapy-resistant, and are left to repopulate the cancer after chemotherapy. Targeting these stem cells is particularly interesting.

We have seen different stem cell inhibitors; one of them is called BBI-608, which is a STAT3 inhibitor. We have looked at it in combination with multiple chemotherapies across different tumor types, and we’ve certainly seen a lot of promising preliminary results that are being taken into larger trials right now.

What does the safety profile look like of these types of agents?

So far, the primary toxicity we have seen with these cell-cycle inhibitors—particularly the STAT3 inhibitor—is diarrhea. However, this can be controlled by drug holds, dose reductions, and antidiarrheal medications.

Does the STAT3 signaling pathway seem to be a promising target?

It’s too early to say about that.

Finally, you lectured on the state of the science surrounding pancreatic cancer. What is new?

We have made a lot of progress in the last couple of years, in terms of the treatments of patients with advanced pancreatic cancer. We have regimens like gemcitabine/nab-paclitaxel (Abraxane) as well as FOLFIRINOX, which improves survival overall, but we certainly have a long way to go.

There are a number of agents currently in study, including agents like PEGPH20, which is trying to break down the stroma around the tumor. We know that, in pancreatic cancers in particular, there is a lot scar tissue, which makes it hard for chemotherapy drugs to get to the tumor. Ways to break down that scar tissue and potentially deliver the chemotherapy better is a very interesting way to look at treating patients with pancreatic cancer.

Certainly, we’re seeing trials with PEGPH20; we’ve seen data in the randomized phase II HALO-202 study with people who have high levels of hyaluronan in their tumors—it’s about 50% of patients with pancreatic cancer. When they’re treated with PEGPH20 in combination with chemotherapy compared with chemotherapy alone, we saw some preliminary results that suggest an improvement in PFS; that’s now in a randomized phase III study.

Another thing that people are trying to do is look at immunotherapy options for pancreatic cancer. Common checkpoint inhibitors pretty much don’t work across the board for pancreatic cancer in general. However, there are new agents in development including interleukin-10 (IL-10) agonists that activate T cells, as well as others. We have a lot of things going on right now in terms of research for pancreatic cancer.

What are some other exciting ongoing trials in pancreatic cancer?

Another trial that is particularly interesting for patients with pancreatic cancer is using the stem cell inhibitor in combination with chemotherapy. There is a randomized phase III study in the works that is looking at gemcitabine/nab-paclitaxel with or without the stem cell inhibitor. We saw very interesting data in the phase I study, showing a lot of responses for patients with pancreatic cancer. Hopefully, that might translate to some benefits we can see in a phase III study.

You were the chair of this State of the Science Summit. Why is it important for community physicians to attend?

It is so important to stay educated now in oncology. I don’t know how people do it who see all different types of tumors, because there is so much development going on and so many new FDA approvals. We just had another approval for patients with breast cancer. How can you keep track of it all? The educational events are great ways to do it, where you can actually be with folks who are treating those types of tumors specifically, and you really get a chance to hear the latest and greatest from them.