Video
ASCO GI 2023: SPOTLIGHT Study
The SPOTLIGHT study results presented at the 2023 ASCO GI Cancers Symposium are explored by Dr Marshall.
John L. Marshall, MD: Zolbetuximab is a drug that you probably don’t know the name of, but you’re going to soon. Though you may have heard of claudin 18.2. Now, that’s been in the literature for a while, this is a junction protein that can be seen in GI [gastrointestinal] cancers. By that, we mean that it’s hidden from the immune system because it’s folded in, and the immune system can’t really see it. But when there’s cancer, this junction protein becomes exposed, if you’re with me. That’s what makes it specific. If you think about targeted monoclonal antibodies, the trick is not making the monoclonal antibody, that’s easy. The trick is finding the thing to aim it at because if you aim it at something normal, that monoclonal antibody will attack normal, right? Why do we need HER2 overexpression for patients? Because HER2 overexpression is on the cancer, not on the normal cells. So claudin 18.2 is something that’s expressed more highly on GI cancers. And in this case, the study was done in GE [gastroespophageal] junction cancers. I say it’s been around a while because this target has been known for a while, and some studies have been done previously that came out positive, but not strongly enough.
This study was done in adenocarcinoma gastric and GE junction [cancers], metastatic, FOLFOX [folinic acid, fluorouracil, oxaliplatin] standard of care, plus or minus this monoclonal antibody, zolbetuximab, that binds to this. The way this drug works is it sort of brings in an immune response. We think that’s how it works. [This was a] big study, 500 or 600 patients, 1:1 randomization; response rates, survival, and safety were all in play on this.The reason you’ve picked it and the reason we’re excited about it is, it’s a positive study. Only about 30% to 35% of patients with this tumor have overexpression of this claudin 18.2 marker. Very quickly, molecular profiling panels are being upgraded and updated to include this marker, so they’ll report it for us. It’s an immunohistochemistry [IHC] test, so it can be done locally. You need to know that you can do this locally.
The study was positive, as I said, both on progression-free survival and overall survival, but interestingly, not on response rate. That’s sort of funky. It kind of suggests, how does this drug work? Maybe it is some sort of immune system or something that’s affecting the tail of the curve more than it is the impact of the chemotherapy itself. We are anticipating, unless there are some issues discovered with the study, FDA approval for this and incorporation into the algorithm of treatment for patients with gastroesophageal junction and gastric adenocarcinomas.
This is IHC, not next-generation sequencing [NGS]. Right now, for this patient population, you need immunohistochemistry tests, and all can be done locally. You need MSI [microsatellite instability] by IHC, and you need PD-L1 by IHC. You need HER2, also by IHC. And you need claudin-18.2. So this is an easy assay to run, it can be run locally, and can have a quick several-day turnaround time from your local pathology laboratory. That doesn’t mean we don’t want to also do NGS on these patients to find other markers, but the key initial lines of therapy we want to go for, this was one of those markers that will be part of that. Where this gets to be interesting is what if you have more than one of these? What if your PD-L1 is high, and your claudin 18.2 is positive? Would you pick this agent, the zolbetuximab, or would you pick some IO [immunotherapy]? What if HER2 and this is positive? So you’re going to have some interesting juxtaposition of maybe more than 1 option for these. Of course, with this positive study, lots of work is going into combinations, adding IO to this combination, for example, being one of them. This will be a standard of care as a single agent, is my prediction, for a window of time. But over the next year or two, I’m hoping that we’ll see that combinations are not only safe but effective in further pushing the bar for the 30% or so who have a claudin 18.2 positivity.
Transcript edtied for clarity.
