Expert Highlights Potential of Immunotherapy in Gastric Cancer

Zev Wainberg, MD

A number of clinical trials have been examining the potential of immunotherapy agents in the field of gastric cancer, though several questions remain regarding what role this type of therapy could actually have.

The phase II FAST trial, for example, examined the monoclonal antibody IMAB362 in gastric cancer. The agent improved median progression-free survival (PFS) by 3.1 months and median overall survival (OS) by 4.8 months in combination with a 3-drug chemotherapy regimen. This treatment was compared with chemotherapy alone in results of the FAST trial, where it was shown that the former's benefit was more pronounced among patients with high expression levels of CLDN18.2.

Secondly, the JAVELIN trial is currently investigating avelumab in patients across multiple solid tumor types who progressed on more than 2 lines of prior therapy, or had received 1 line of chemotherapy without progression. Data show that, of the 75 patients with gastric cancer/gastroesophageal junction who were treated with avelumab, responses were observed in 7 patients. PD-L1 expression was evaluable in 55 patients, including in 3 patients with a response. Median PFS in patients who had received 2 or more prior lines of therapy was 36 weeks (95% CI, 6.0-36.0) for PD-L1—positive patients and 11.6 weeks for PD-L1−negative patients. Among patients who had received 1 prior line of chemotherapy, the median PFS was 17.6 weeks for PD-L1–positive patients and 11.6 weeks for PD-L1–negative patients.

OncLive: Can you discuss the clinical trial you're involved in with pembrolizumab?

In an interview with OncLive, Zev Wainberg, MD, an assistant professor of Medicine at UCLA and co-director of the UCLA Gastrointestinal Oncology Program, discusses a plethora of immunotherapy agents, such as pembrolizumab (Keytruda), durvalumab, avelumab, and apatinib, for the treatment of patients with gastric cancer, as well as a number of ongoing clinical trials in this space.Wainberg: That has been studied in several different settings, including the third-line setting, for which preliminary evidence of activity has already been presented in small patient numbers at previous meetings. That data has been reported now a few times, with response rates and some of the activities of this agent in a group of patients who have not historically responded very well. These are the third-line typical patients, or advanced patients with metastatic gastric cancer.

The bigger study that's being done is to confirm those results in a very large number of patients with that profile. Additionally, there are randomized trials going on with that agent in both the first-line setting—so newly diagnosed patients with metastatic gastric cancer, either by itself or in combination with chemotherapy—and in second-line metastatic gastric cancer, randomized, and with chemotherapy as the control arm.

Thus far, does it seem like a promising agent in this space?

Has PD-1 positivity been investigated in this space?

What about PD-L1 agents? Do you see potential for that class of drugs?

We have, to my knowledge, at least 3 very large studies looking at pembrolizumab in gastric cancer. These are 3 very large, international trials with about 100 patients each trials.I think the hints of activity in these small groups suggest that it is promising, or this group of therapies is promising. It remains to be seen who these patients are; certainly not a large number of them, but rather the minority of them, do respond. There is this group of patients that respond, and these things really need to be reproduced in a much larger set of data to be confident that it's real.That's one of the factors, and PD-L1—positive staining is one of the criteria for at least 2 of the trials that I mentioned. It hasn't been worked out to the extent that it has in lung cancer, and we don't even know, to be fair, what percentage of patients are PD-L1–positive in gastric cancer. It is one of the criteria that are used, and on some level, there does seem to be this suggestion that if one doesn’t have staining of the antigen, the likelihood of the response is very low.On some level, there have already been reported results from the JAVELIN trial with avelumab, and there have been reported results of durvalumab with gastric cancers. We're seeing a little more than anecdotal responses in this group of patients that have 10% or 20% responses. I don't think it's going to be pembrolizumab that's going to produce the responses here. I think if it's a true phenomenon in gastric cancer, and we've already seen it with nivolumab as well, then it won't be these one or two drugs. It's going to be across the board.

The question is if the study designs will be adequate to answer the questions they're asking. Different companies use different strategies, so for example, with pembrolizmuab, their strategy is PD-L1 positive, randomized to chemotherapy, or randomized with chemotherapy, whereas some of the other trials are using nuances of that strategy with either combinations with CTLA-4 inhibitors.

Will these treatments will be useful in combination?

What other agents are you excited about?

With avelumab, they're doing an interesting strategy called a switch-maintenance strategy, to see if the drug has an effect in gastric cancer, maybe as a maintenance drug.In gastric cancer, we know it's not going to be like it is in melanoma, and probably not like lung cancer either. It's going to be a small group, and the big focus is going to be on what the group is. Whether that's PD-L1 positive, there are subtypes of gastric cancer that might be more responsive to immunotherapy drugs like Epstein-Barr Virus (EBV). For example, there's a subgroup of patients with gastric cancer that are part of the EBV group. There's a subgroup of them that are microsatellite unstable (MSI), which is the area in colon cancer where immunotherapy really works. We really need to tease out whether these patients with gastric cancer are among those 2 groups.There was a very promising drug presentation at ASCO from Germany from a small company called Ganymed with a trial called the FAST trial. The target is something called a Cloudin antigen, and that looked really promising in the phase II study results. So they've already, I think, launched a phase III trial in that setting. That looks really promising based on the results.

What is the reasoning behind looking at that particular drug?

One drug I'm involved with that we're running a phase III trial in gastric cancer for is sponsored by Gilead Pharmaceuticals, and the drug is MMP9, which is an antibody against that target. That one is already launched, we just launched a phase III trial, and we're combining that drug with chemotherapy versus chemotherapy as the control arm.MMP9 has a lot of roles to play in the tumor stromal interaction, as well as an antigen in improving, and decreasing on some level, the immune response. The monoclonal antibody has been shown in phase I studies and in other phase II studies to have promising activity, better than one would expect with the control, affecting the tumor stromal environment in a favorable way. There is promise, and there aren't that many of these out there, and that's what makes it a unique and interesting target.

The trial itself combines the antibody with standard chemotherapy because the hypothesis is that this drug will not work as a standalone agent, but when combined with chemo, it will allow, on some level, chemotherapy penetration to be greater into the tumor cells. It will deplete the tumor stromal factors that will allow chemotherapy to be at a higher concentration in the tumor cell.

What point are you at in that trial?

There's been some data with apatinib, another VEGF inhibitor. Do you have any thoughts on it?

That's one of the big hypotheses behind how this drug classes. This isn't even really a class of drugs; it's just one drug to my knowledge, which makes it a bit of a higher-risk endeavor in some respects, but in many ways, it'll be very interesting.We launched phase III. We did phase I and phase I expansion, and they showed promising results, so the decision was made to essentially go to a phase III.On the surface, and if you look at the manuscripts, it looks like an active VEGF agent that has activity in gastric cancer. That's what they're reporting, and that's what seems to be the case in the presentations and applications. I think, in terms of the agent being potentially controversial, if the trials have exclusively been done in China, the question is, should the data be replicated before proceeding? I think we do that with every drug, and to get the FDA approval, those require some degree of certainty among other centers and across international studies.

What would you say are the biggest challenges in gastric cancer that you would like to see tackled?

It seems like an active VEGF inhibitor in that respect. One could imagine that it might work.Immunotherapy has taken a lot of effort and a lot of interest, and I think one of the challenges is going to be in knowing which patients should be getting these drugs. There's been such competition in that field that the rush to get these trials done has made it more challenging to develop them in a clever way. We want to learn from the other malignancies that have had these drugs, and this is not going to be like melanoma or lung cancer. This is most likely going to be a small group that benefits—smaller than the other groups that have FDA indications for PD-1 inhibitors.

Is that going to take more molecular classification?

So who are these patients? It’s important to really be thorough about things. That's going to be the key, and I hope we can do that.The patients are there, and the patients have been enrolled in a lot of these studies, but this has to be similar to what we’ve seen in colon cancer, where it was very clear that it didn't work in all colon cancers, but it worked in MSI colon cancer. So we stopped testing it in all colon cancers, and I think that's the wise thing to do. We would like to see gastric cancer use some of that to see if we can refine the patients, and maybe it's not MSI or EBV. We've got some classification schemes that might be really critical to interrogate thoroughly as to who the patients are that benefited.