Johanna C. Bendell, MD: Let’s come out of the surgical area, and let’s move into the metastatic area. Peter, NCCN Guidelines—you keep telling us they’re getting more clear.

Peter C. Enzinger, MD: Yes.

Johanna C. Bendell, MD: It seems like there are a lot of different potential options for frontline therapy. What does NCCN tell us? Then, outside of NCCN, what do you like as your first-line option?

Peter C. Enzinger, MD: I think you bring an important point. The NCCN guidelines have been criticized, not just in this disease but in other diseases, of being an inclusive guideline where multiple regimens are included and don’t give guidance as to which is the best regimen. In fact, one of my colleagues at Dana Farber recently presented the largest database of regimens given in the United States. You can see that basically, people are all over the place with different regimens, and it’s based on small single-institution phase II studies that might have been done in that area.

Ultimately, what we’ve been trying to do in the NCCN Guidelines is to give more guidance. When you poll the NCCN members, really everybody uses the FOLFOX regimen. FOLFOX is really the de facto standard of care in the United States. My colleague’s data show that with every 5-year period, FOLFOX has increased by another 10%. Although it’s not given now by the majority of oncologists, it’s 40%, up from 2010. It’s probably now in the majority, particularly now that the guidelines have changed.

We’ve kept cisplatin 5-FU. The reason is that it still is, unfortunately, the regular standard in the United States, as well as in East Asia and Europe—the only one that we seemed to be agree upon. There’s good—well, not necessarily good, but there’s level I evidence—for cisplatin and 5-FU. None of us would ever be seen printing with cisplatin and 5-FU. Only when we’re required to in these global registration trials do we put our patients on cisplatin and 5-FU.

The guidelines really have 2 recommendations. First of all, we recommend doublets because we feel that in a palliative setting, the addition of a third agent really leads to significant increased toxicity without a survival benefit. There are clearly subgroups of patients who would benefit from more aggressive therapy, particularly in the neoadjuvant setting; that’s why FLOT is important to know about for patients who are very symptomatic who need to have a response; but generally speaking, a doublet—5-FU, leucovorin, oxaliplatin—should do it for most patients.

The guidelines do still include some of the lesser regimens, but really…one of the important ones to know about is FOLFIRI. Some people can’t tolerate platinum-based therapy, so—irinotecan. The Europeans, the French, did a very nice study comparing an ECF (epirubicin, cisplatin, capecitabine) variant with FOLFIRI. The primary endpoint was time to progression. FOLFIRI was superior to the ECF variant. The other parameters—overall survival, progression-free survival—were all the same between the 2 arms.

Johanna C. Bendell, MD: Peter, just a quick side note. You were the author of one of the main studies that kicked off epirubicin.

Peter C. Enzinger, MD: Yes.

Johanna C. Bendell, MD: So, are you not an epirubicin fan?

Peter C. Enzinger, MD: The short answer is no, but I think that the problem with epirubicin is really that it became so ingrained with the MAGIC study and the REAL-2 study that many people used it. After all, it’s in the New England Journal of Medicine, so that must be the standard of care. I think that we’ve come to understand that epirubicin probably adds very little to the treatment, and it does have significant toxicity, so we avoid this as much as we can.

There are some interesting fourth- and fifth-line regimens that incorporate this class of agent. When I run out of standard treatments, and the patient is not a candidate for a clinical trial, I sometimes back up and use those, but that’s really the only scenario.

Yelena Y. Janjigian, MD: If they’re not a candidate for a clinical trial, I don’t know if they’re going to be a candidate for epirubicin.

Peter C. Enzinger, MD: No, it’s like zonal doxorubicin—it’s a little bit better.

Yelena Y. Janjigian, MD: Now, Eric, is it that different from what you guys recommend?

Eric Van Cutsem, MD, PhD: No, it’s quite similar to epirubicin; the regimens came, of course, from Europe. That’s mainly done in the UK, Scandinavia, and the Netherlands, but now in the last 2 years, that has lost popularity, and I would even be a bit stronger than Peter in saying that there is no evidence of any activity at all for epirubicin; there’s evidence for toxicity. Nobody has ever shown that there’s evidence of this triplet with epirubicin, so the standard in first line is indeed FOLFOX in the HER2-negative patients, in HER2-positive patients.

Then cisplatin is officially on the label with trastuzumab in some countries. That’s an indication where you have to use cisplatin because of the label. In some countries, that can be replaced by FOLFOX plus trastuzumab in this situation; that’s the standard. My guess is that there are 10% to 15% of patients in first line across Europe that get a triplet. They’re not the original ECF regimen because with those or docetaxel, cisplatin, 5-FU, as we described, that was too toxic. Physicians give a modified regimen, and there are different variations with 5-FU, oxaliplatin, and docetaxel; 50 mg every 2 weeks instead of 75 mg every 2 weeks.

This is done sometimes in younger patients with a high cure burden that you really want to hit, but that’s just a small number of patients. Also in my practice, I give to most of the patients today FOLFOX as a first-line regimen, with or without trastuzumab, depending on the 2 stages.

Johanna C. Bendell, MD: I think very important to remind the audience, although I know they’re older data, is that, again, breast cancer and gastric cancer are not the same. We saw those results from JACOB.

Eric Van Cutsem, MD, PhD: Yes, that’s right. Trastuzumab has shown activity in gastric cancer in the HER2-positive patients. Pertuzumab plus trastuzumab led to a small benefit, but this was not significant. The trial was negative of chemotherapy doublet plus trastuzumab, plus or minus pertuzumab. Then also, the second-line trial in gastric cancer, to positive gastric cancer with PD-L1 first in the taxane, was also negative. For different reasons—because of the differences in the role of HER2 in gastric versus breast cancer—unfortunately, the combination with pertuzumab and trastuzumab failed. Also, PD-L1 was not positive.

On top of that, we have also in second line, and later lines, progression continuation with trastuzumab, as is being done in breast cancer. Also, here we see a difference. Until recently, we didn’t have any data. Now, recently, we have this presentation over a study that shows no benefit of the trastuzumab plus progression continuation—a Japanese study. Trastuzumab is there in first-line HER2-positive patients, not in second line.

Another important and interesting aspect, to come back on the HER2, is that we see, for instance, patients with a GE junction cure; they’re around 30% HER2 positive with a more distal gastric cancer; the rate is lower. Patients with a single-cell cure, there the chance of having positive tumor is very, very low, just a few percent, so there are some interesting differences in this situation.

Johanna C. Bendell, MD: Right, very interesting. Now, Kohei, in Japan—I’m jealous because you have more things to play with. In Japan, are there differences then in the treatment regimens you use?

Kohei Shitara, MD: Yes. Actually, we revised the Japanese treatment guidelines early this year in the treatment regimen we classified as the most recommended regimen for fit patients; and secondly, the ultimate recommended regimen based on condition.

We can also use FOLFOX because we have a long history of colorectal cancer treatment. If a patient had a dysplasia or so forth, FOLFOX is a very good treatment. But otherwise, S-1 is the most commonly used regimen, because our phase III study showed a very clear outcome with AS1 therapy; hazard ratio and overall survival is 0.96. We prefer to use CAPEOX. This is also common in colorectal and is more common in gastric cancer.

In second line, maybe we can discuss weekly paclitaxel. This is the most recommended treatment, and nivolumab and irinotecan is also recommended in third line.

Transcript Edited for Clarity