Gastric Cancer Treatment: T-DXd

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Transcript:

Benjamin P. Levy, MD: Ben, I’ll turn it over to you, T-DXd [trastuzumab deruxtecan,] and gastric cancer and gastroesophageal junction cancers. [Do] you want to walk us through that data, what you’re seeing, and then Michal [F. Segal, RN]can come in also and talk about the experience at Memorial [Sloan Kettering Cancer Center in New York, New York]?

Benjamin L. Musher, MD: First of all, as everyone probably knows, you’re talking about overexpression, 20% to 30%, depending on what study you look at and depending on the location of the tumor. Since I treat 2 very different populations, we have a primarily Hispanic population or a county hospital that has poorly differentiated Signet ring cancers. Almost none of those cancers overexpress HER2. On the other side of the spectrum, you have these gastroesophageal well to moderately differentiated, maybe as high as 30% overexpression again, overexpression 3+ or 2+ FISH [fluorescence in situ hybridization] positive. And that’s where the approvals are at this point as far as how we treat these patients. The recommendation still is to give trastuzumab with chemotherapy first line and then give [them] a second-line therapy, which tends to be ramucirumab-paclitaxel, and then third, a taxane-based therapy. The third line is when these antibody-drug conjugates [ADCs] have their approval, the time being, it’s only T-DXd; the other agents have not either shown benefit yet from negative studies or some data are developing.

A similar article was published in the New England Journal of Medicine a few years ago, in June of 2020. This was a randomized phase 2 study, 2 to 1 again, 2 lines of therapy having gotten trastuzumab, HER2 as we defined it before, overexpression. And 2 to 1, either the ADC or physician’s choice of third-line chemotherapy, probably irinotecan if they got taxane before or taxane if they’d gotten a irinotecan before, and the data were pretty clear. The response rate was much higher with the ADC, 51% vs 14% with the disease control of 85%, and for third-line gastric cancer, these are pretty shocking results. This is not colon or breast or one of these cancers we can treat for many years.

Now, if you responded, the median duration of response was about 11 months. So if you responded, you responded for quite a while. Maybe not a year and a half you might have with breast cancer, but that 11 months is pretty darn good. We don’t even get that with first-line therapy in gastric cancer typically. In a 12-month overall survival, 50% vs 30% PFS [progression-free survival] at 12 months, 30% vs 0%. So you will have about one-third of patients who still have really well-controlled disease after a whole year on this regimen. Toxicities are pretty much the same, as we’ve seen in other cancers, but you have to remember the dose is higher with gastric cancer. Do you guys use a higher dose for lung cancer?

Benjamin P. Levy, MD: We’re at 5.4 [mg/kg] now.

Benjamin L. Musher, MD: Oh, you guys went down? The dose for gastric cancer is 6.4 mg/kg. But, you know, again, the toxicity, and the main one we are scared about, is that is the ILD [interstitial lung disease], which is about 10% or so, and the other stuff too; nausea has actually just been upgraded to a highly emetogenic regimen a few months ago. So we do tend to hit them hard with the neurokinin and 5-HT and steroid combination, even using olanzapine if they’ve got issues. So we do tend to really attack the nausea and try to prevent the nausea as hard as we can. But I’ll tell you, we’ve seen some pretty remarkable responses. For me, the biggest question is whether we should be using it second line.

Benjamin P. Levy, MD: Right? That’s really my question.

Benjamin L. Musher, MD: …Yeah. I mean, at a certain point we’re speaking unethical. Seriously, trying to follow guidelines and do these kinds of things is sort of like the checkpoint inhibitor in earlier-stage disease for rectal or gastric or whatever. I mean, at a certain point we’ve got to wait around for these randomized data to come out when we all know what the data are going to show. So I’m not going to lie to you and tell you that I only use this third line because I don’t only use it third. I think the main issue is getting approval for it from insurance companies.

Benjamin P. Levy, MD: Yeah. Kevin, did you have your hand up?

Kevin Kalinsky, MD, MS. I did. I mean, we face this in breast [cancer] also for HER2-positive disease, but really for triple-negative breast cancer, where we have patients who rapidly progress on their operable therapy, and if we want to give T-DXd, patients would have to have received prior chemotherapy. And sometimes, insurance companies will still cover it, but not always. So it does feel like, do I really need to go through just the exercise of giving patients that, when we’ve already seen that it’s really chemorefractory? It really is not fair for patients.

Benjamin L. Musher, MD: Not knowing you might miss the opportunity to use it if they get really sick and die or so sick that their performance status changes or they have just given up or whatever it is. So, it’s a dilemma, but those are really the data in gastric [cancer] that’ are out. Other drugs are being looked at right now and there have been some failures, unfortunately, along the way, with futuximab and trastuzumab in the first line and apatinib have not proven to be effective in gastric cancer. This is what we’re dealing with. I actually don’t even know the data on HER2-low gastric cancer. Maybe, Michal knows that, but I do not.

Benjamin P. Levy, MD: [Dr Musher], obviously, I’m learning this on the fly here about the data in gastric and breast [cancers]. But I mean, it’s a pretty remarkable third line, it’s hard for me to believe; if this were my family I wouldn’t want that second line and not want to wait for the third. We know there’s a drop-off of every single line a patient goes through.

Transcript is AI-generated and edited for clarity and readability.