Advanced Gastric or Gastro-Esophageal Cancers - Episode 5

Treatment in HER2-Positive Disease and Dosing Preferences

Transcript:Johanna C. Bendell, MD: You mentioned sort of shifting things later down the line. I’ve seen some people take the approach, and I’ve seen questions being asked: Do you just give the frontline metastatic regimen for 6 months and stop? Or do you keep treating through with your entire first-line regimen? Or do you do it like colon cancer and make a maintenance regimen?

Manish A. Shah, MD: Right. When we developed the modified DCF [docetaxel, cisplatin, fluorouracil] regimen, that was our strategy— to do about 6 months of treatment with the triplet and then a maintenance 5-FU [5-fluorouracil]. That strategy actually worked out quite well. I think a lot of people have adopted that strategy, at least in the United States. I think in the United Kingdom they do stop at 6 months and then observe patients. For me, in my practice, I prefer an approach in which we pull back the cytotoxic drugs and create a maintenance 5-FU [5-fluorouracil] schedule. That works out very well. And actually, in first line, we should talk about patients who are HER2-positive. They get trastuzumab. And so FOLFOX [folinic acid, fluorouracil, oxaliplatin]—trastuzumab or cisplatin–5-FU [5-fluorouracil] and trastuzumab would be very appropriate. The reason why I mentioned that is because in the maintenance setting you pull back the platinum and you can do Xeloda and trastuzumab or sometimes even trastuzumab alone. The high HER2 expressers can do very well for quite a long time with that regimen.

Johanna C. Bendell, MD: I’m going to ask you another question that comes up a lot. With the different regimens, q3 [every 3] weeks versus q2 [every 2] weeks, we have the trastuzumab loading dose. How do you dose your patients q3 [every 3] weeks versus a q2 [an every-2]-week regimen?

Manish A. Shah, MD: That’s a great question. When the ToGA study was first presented, there was some suggestion that we were underdosing patients, because about a third of patients, on their PK [pharmacokinetic] analysis, had lower levels of trastuzumab than a breast cancer patient. That led to a phase III study testing a higher dosage of trastuzumab versus the standard dosage. Just to remind everyone, the standard dosage in a 3-week schedule is an 8 mg/kg load, followed by 6 mg/kg every 3 weeks. We tested a higher dosage and found no difference. We think that for that 3-week schedule, that’s the correct schedule. For an every-2-week schedule, what I do is a 6 mg/kg load and a 4 mg/kg every-2-week schedule, which is very similar to what we do in breast cancer.

Johanna C. Bendell, MD: Very good. David, how do you approach these patients?

David H. Ilson, MD, PhD: I just want to make a comment regarding the FLOT [fluorouracil, leucovorin, oxaliplatin, docetaxel] regimen. We should obviously discuss that this is now the standard neoadjuvant regimen based on a head-to-head comparison with ECF [epirubicin, cisplatin, fluorouracil], in which FLOT [fluorouracil, leucovorin, oxaliplatin, docetaxel] was superior for neoadjuvant chemotherapy, probably improving surgical outcomes, with an increased resection rate, better down staging. But clearly, it is the new standard for neoadjuvant treatment. For metastatic disease, triplet regimens are less used. I think the Japanese study showing that there was no survival benefit in a 700-patient trial adding a taxane to up-front chemotherapy versus doublet therapy clearly indicates that the vast majority of patients are not going to benefit from triplet therapy.

And even in 1 randomized trial from Germany, in patients over age 65, which looked at FLOT [fluorouracil, leucovorin, oxaliplatin, docetaxel], which is FOLFOX [folinic acid, fluorouracil, oxaliplatin] plus docetaxel versus 5-FU [5- fluorouracil]—oxaliplatin alone, did not show a survival benefit in older patients. So doublet therapy is really the preferred way to go. For toxicity, and now with the use of taxanes more in second-line treatment, we don’t want to necessarily enhance the toxicity of up-front treatment and potentially use up a viable second-line option. And quality of life is important. The triplet regimens are very difficult to tolerate. We really reserve use of those regimens for young patients without comorbidities who are very symptomatic with a high disease burden, in which we need that little bit of extra response up front. But now the NCCN [National Comprehensive Cancer Network] Guidelines really endorse doublet therapy for most patients.

In terms of key molecular testing, I think next-generation sequencing is important, but the 3 key molecular tests are HER2, MSI [microsatellite instability] testing—we’ll talk about checkpoint inhibitors, which are very active in MSI-high tumors—and PD-L1 [programmed death-ligand 1] testing, for which we now, at least in the United States, have an approved indication for checkpoint inhibitors in PD-L1—positive patients.

Johanna C. Bendell, MD: There are a lot of data out there. Why isn’t gastric cancer like breast cancer with HER2-positive disease? What’s going on with all these trials? Why can’t I use T-DM1 [ado-trastuzumab emtansine] for my patients with HER2-positive disease? Manish, tell us a little bit about what’s going on here.

Manish A. Shah, MD: Sure. That’s a great question, and I get these questions as well. It was revolutionary, really, about 6 years ago, with the ToGA study results. We realized that trastuzumab was a viable option for patients with gastric cancer in the first-line setting. And actually, for the first time, we were seeing patients typically with survivals of more than a year. All previous studies were less than that. So that was really quite practice changing. Since that time, several studies have examined continuation of Herceptin, or HER2-targeted therapies, and lapatinib, and Perjeta, and T-DM1 [ado-trastuzumab emtansine].

Unfortunately, unlike in breast cancer, all those studies were negative. Perjeta plus Herceptin with chemotherapy was not better than Herceptin plus chemotherapy. T-DM1 [ado-trastuzumab emtansine] was not better than chemotherapy in the second-line setting. And lapatinib in both the first- and second-line settings was not better than Herceptin. In each of these settings, it suggests that breast cancer and gastric cancer are, in fact, different. I guess it shouldn’t be a surprise, because we really know that even the definition of HER2-positivity, at least by IHC [immunohistochemistry], is also different in terms of how many cells you need, what’s the membranous staining, and things like that. The main explanation is that there’s disease heterogeneity. The HER2 signaling is not so prevalent in gastric cancer. We can lose HER2-positivity with first-line therapy. For all these reasons, we really do not continue targeting HER2 therapy in the second-line setting because we don’t have the data that support it.

Transcript Edited for Clarity