Novel Targeted Approaches in Gastroesophageal Cancer
Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Peter C. Enzinger, MD, Dana-Farber Cancer Institute; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Kohei Shitara, MD, National Cancer Center Hospital East; Eric Van Cutsem, MD, PhD, University of Leuven
Johanna C. Bendell, MD: We have a number of targeted therapies that are coming, that people are looking at. Yelena, tell us a little about this MMP-9 antibody.
Yelena Y. Janjigian, MD: MMP-9 is being explored as a target in first-line setting; again the idea is if there is no pathognomonic driver and the majority of the patients are HER2-negative, how do we target the stroma, the microenvironment, and potentiate the effects and permeation of chemotherapy and effect of that? It’s an interesting study. There are a lot of data to support it preclinically, and we will just have to see if the idea sticks.
Johanna C. Bendell, MD: Yes, if the studies accrued, we shall wait and see. And then Kohei, we have the anti-claudin. What in the world is that?
Kohei Shitara, MD: This is a very important and interesting target, claudin 18.2 antibody is a major structural component in cell junctions. It was always expressed in normal tissue cancers but more highly expressed in gastric cancer. Fifty percent of patients showed a positive staining and there was a high percent of patients who showed a very strong staining of claudin 18.2. This claudin 18.2 monoclonal antibody, claudiximab, showed efficacy as monotherapy in human trials conducted in January, with an approximate 10% response rate as a targeted agent. Then a phase II trial was conducted to compare to the standard chemotherapy with or without this claudiximab. It showed a remarkable survival benefit. The hazard ratio is 0.6, a highly desirable endpoint to express in gastric cancer. This is a very good survival advantage. So, a phase III trial is ongoing, which has FOLFOX as a control arm.
Johanna C. Bendell, MD: Very good, very good. This importance of doing some next-generation sequencing to identify specific patient populations, potentially rare patient populations with the FGFR inhibitors for patients with gastric cancer that we’re seeing now. Eric, are you looking for these patients?
Eric Van Cutsem, MD, PhD: Indeed, we are looking with NGS, as you said, to different subgroups of patients. We know that FGFR alterations occur in a small number of gastric cancer patients and the number is around 10%, I would say. We have seen some disappointments with some FGFR inhibitors in the past. There’s a new generation of FGFR inhibitors now under investigation. It’s not yet clear what’s going to be the fate. We hope that for these subgroups, this subsegment of patients that the newer generation of drugs, that they will lead to some benefit that would maybe challenge us on what is the optimal selection. Should we look at amplification, alteration, whatever? So that’s not yet clear to my knowledge. But there are some challenges after some disappointments in gastric cancer, and some hopes for new drugs. We hope that this will be among the drugs that will lead to some success in this situation.
Johanna C. Bendell, MD: Yes, and then immunotherapy. Now we’re looking at all different ways to augment immunotherapy. We do better by using ways to get the tumor to augment its own immune response, but now we’re all learning how to have to inject tumors in our clinics; or our gastroenterologists or interventional radiologists are learning this. Yelena, tell us a little bit about these oncolytic viruses.
Yelena Y. Janjigian, MD: Well, the wave of the future is to go beyond combination of anti-PD-1 and anti-CTLA-4; what are the other novel ways to make the immune system see the tumor. There’s a lot of interest to look at use of oncolytic viruses. It’s not prime time at all. It’s not even in phase II yet, and then tumor vaccines. There are several companies looking at personalizing tumor vaccines. Probably as monotherapy it’s not going to be effective, but in combination with anti–PD-1 therapy, this is where the field is going. Other immunotherapy tactics are very interesting but may be quite toxic; and you can ask about CAR T-cell therapy. It’s very difficult to direct a T cell against solid tumor because a lot of these antigens are in normal organs as well. But I think the vaccines and the oncolytic viruses will be the next positive hit in the future.
Kohei Shitara, MD: We are currently doing the phase I trial of oncolytic viral therapy for gastric and esophageal cancer in combination with a PD-1 therapy. This is a novel concept, so the study is ongoing.
Johanna C. Bendell, MD: Very exciting, super exciting.
Peter C. Enzinger, MD: The problem with all these is that they’re extremely expensive and really can only be given at centers that have significant expertise. So, even though they may be effective, I wonder how disseminated these will be. I think the problem is that the expense and the difficulty in giving these treatments will probably limit them, and ultimately will be surpassed by probably things that can come out of the box. So, even though I agree with you that it probably will work in a select group of patients, it’s probably going to be difficult to give this to the whole population.
Johanna C. Bendell, MD: Yes, it’s interesting. Even just to go off topic a little bit, when you look at CAR T for the approval, we have to learn how to be able to do this well, and I think there’s going to be a learning curve with that, too.