The Hunt for Predictive Biomarkers

Transcript:Mark A. Socinski, MD: Inhibition of angiogenesis doesn’t last forever, right? What do we know about mechanisms of resistance to antiangiogenic drugs?

Manish A. Shah, MD: Part of that might be related to the lack of biomarkers for what types of patients, what types of tumors may be sensitive to antiangiogenic therapy. In gastric cancer, the AVAGAST study was a large 700-patient study and 90% of patients did provide tissue samples. And, we were able to look at two candidate biomarkers. One was OSMA-VEGFA (Ohio State Medical Association-vascular endothelial growth factor A), which is the ligand for bevacizumab, and then the other was neuropilin-1 expression on the tumor cells, which is a co-receptor for VEGFR-1 and VEGFR-2. These are both sort of candidate biomarkers for the efficacy of bevacizumab. So, a postulate might be that other mechanisms of angiogenesis might play a role for when patients fail bevacizumab therapy. I think that for ramucirumab—from the REGARD and RAINBOW studies—the biomarker analysis is just now being completed, and they haven't identified a biomarker that actually demonstrates sensitivity at a much less identifying mechanism of resistance.

Yelena Y. Janjigian, MD: But, interestingly, building on the VEGFA point, there’s data to suggest that in patients outside of other treatments—if you just look at the blood samples of patients in the west versus east—the western patients tend to have higher level of VEGFA and, actually, a stage for stage. Again, the patients with higher VEGFA tend to do worse, perhaps validating the observation that VEGF inhibition is more important in the west.

Mark A. Socinski, MD: So, Roy, in lung cancer, the biomarker has been elusive to date.

Roy S. Herbst, MD, PhD: Right. It’s hard because, as I said earlier, you’re not looking only on the tumor. You’re looking at the endothelial cells, and biopsies are hard enough to come by—a little bit better now in this era of molecular targeted therapy. But, really, it’s been very hard to identify what is the right marker, how you measure VEGF. With the antibodies, you always had the concern of, are we truly blocking all the VEGF? It’s more of a trap because you have the VEGF ligand interacting with the receptors. So, do we know we’re even using the right dose, that we’re getting it into the tissues, that we’re having an effect? I think in all the time I’ve used the drug, bevacizumab—and I did the first early phase I study with a group at MD Anderson—I’ve seen maybe one patient have a frank response as a single agent. So, really how it’s working, it’s sort of working as an enhancer with chemotherapy. It’s really hard, and I think what we’ve seen now as we’ve talked that it works in some areas really well, and in some areas it works okay, and in some it doesn’t work. When you see something like that, it tells you that it’s a population that’s benefitting, but we just can’t pick it out. But I think that, now, there will be some new life. These agents will be important to test with the immunotherapy platforms, which are moving into the frontline and second-line. And also let’s not forget that there are other mechanisms. Isn’t there a drug, Johanna that you’re studying now that actually targets an old TNP-470 analog?

Johanna Bendell, MD: Yes, the fumagillin analogues, and certainly there are multiple different ways we’re going after the angiogenesis pathway, aside from just attacking VEGF. So, a lot to come, and targeting the TI-2 receptor; all different types of ways to get a better lock on the angiogenesis pathway.

Roy S. Herbst, MD, PhD: I know of this drug but we’re not studying it. I think it’s definitely important that there are now other ways of more directly targeting angiogenesis. Looking at microenvironment is going to be critical. So, when we talk about microenvironment, these are agents that target the microenvironment.

Yelena Y. Janjigian, MD: And, if I may add to this point, I think the challenge with the VEGF biomarker is that it’s probably not a simple tissue biomarker. You can’t just re-biopsy and find VEGFR, HER2, or T790M. I think it’s a more dynamic biomarker. It’s in the bloodstream, and as our technology evolves, every year there’s a new circulating DNA testing or liquid biopsy test. So, as our technology evolves, we will be able to find it but it’s likely more of a dynamic biomarker.

Mark A. Socinski, MD: Obviously, the mechanism of action—at least of the antibodies—is mostly ligand-directed. Obviously, the receptor binding is to prevent ligand receptor interaction. How much do we know over the lifecycle of the tumor, issues about the ligands? There are a number of different proangiogenic ligands.

Roy S. Herbst, MD, PhD: Of course. Like in any biologic system, you block VEGF, you’re going to increase BFGF (basic fibroblast growth factor). We’ve not been that successful at blocking that, at least in the lung cancer studies that we’ve looked at. So, that’s the thing, you have to look at the whole milieu and really think about blocking multiple pathways. But, it’s progress, and it’s good that these drugs are available. I’m actually impressed with how they seem to work much better in the GI tumors than in lung. But, in lung, we have it for certain patients, which is great.

Transcript Edited for Clarity