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Key trials in upper GI cancer from ESMO 2017

Interview with Axel Grothey

‘Filmed by PracticeUpdate with permission for inclusion on Advances in Gastrointestinal Cancer. More information and additional ESMO coverage can be found at

Interview transcript

Dr. Caudle: Welcome to PracticeUpdate. I’m your host, Dr. Jennifer Caudle, and joining me, today, is Dr. Axel Grothey. Dr. Grothey, welcome to the program.

Dr. Grothey: Thanks for having me.

Dr. Caudle: Well, we’re excited that you’re joining us today, so let’s go ahead and begin. The results of the MAGIC trial, that’s where I wanted to, first, start talking about. The results, of this trial, have made ECF, really, the standard in resectable esophageal gastric cancer, for the last 10 years. Tell us your thoughts on the FLOT4 trial and really are these results practice changing.

Dr. Grothey: So, it’s very good to dive into that right away. So ECF is a combination of epirubicin, cisplatin, and fluorouracil, which is, kind of, a triplet where we don’t know whether all three components work equally, though. The anthracycline component, epirubicin, has been questioned whether it really contributes anything to the efficacy in gastric, gastroesophageal cancer. So, to backtrack, a little bit, the MAGIC trial really established the standard of care as perioperative chemotherapy, with this triplet, ECF, around surgery for adenocarcinoma of the gastroesophageal junction gastric cancer. We saw a survivor benefit, which was quite impressive and really established perioperative treatment of standard of care, at least in Europe and most other western countries. The United States had some time to catch up, but you know, even in the United States, we use ECF perioperatively or EOX, in its variation of standard of care.

Now, FLOT is a new regimen comprised of leucovorin, 5-FU, oxaliplatin, and paclitaxel or docetaxel, so that’s FLOT. Now taxanes, like docetaxel have established efficacy in the management of gastroesophageal cancers, so this triplet could have been superior to the ECF, epirubicin-based triplet, and in the perioperative setting, this is exactly what the FLOT4 trial showed. It compared the old standard of care, epirubicin, to a different triplet with docetaxel, a clearly an efficacious agent, and it showed, in a perioperative setting, that the survival benefit, progression free, disease free, survival benefit and overall survival benefit, so it had established a new standard of care. It was a little bit more toxic, in terms of side effects, but this was clearly outweighed by the potential for better overall survival in patients.

You know, at Mayo Clinic, we adopted it as a standard of care. It’s a little bit of an unusual regimen because its weekly 5-FU over 24 hours, not every other week, over 46 hours, like in the FOLFOX regimens that we’ve been used to, but the data, this is the new standard of care. Interestingly, same as in the MAGIC trial, the benefit was really with the preoperative treatment because not every patient, actually, received postoperative treatment, so the neoadjuvant aspect, of this treatment, is very important. We see this happening in other cancers, like lung cancer, breast cancer, now gastric cancer, rectal cancer, that we really put more emphasis on the neoadjuvant component, even in the cancer like pancreas cancer, we start treatment, upfront, with chemotherapy, nowadays, then lead patients to surgery, and then we see survival benefit.

Dr. Caudle: Right. Right. It’s very interesting. Interesting, also, you know, as you said, the results really are practice changing. It’s, essentially, a new standard of care, so that’s very helpful.

Dr. Grothey: It is.

Dr. Caudle: So, let’s move on to the Jacob trial. Results, of the Jacob trial, failed to show statistical significance with addition of pertuzumab to trastuzumab with chemotherapy, so why do you think the benefit of HER2 blockade was not seen in gastroesophageal cancer, like we see in breast cancer? 

Dr. Grothey: So, in breast cancer, and gastric cancer, we both target HER2. We have positive data for trastuzumab, you know, in first line treatment, but it’s a very different biology. HER2, in breast cancer, is associated with poor prognosis. It’s a driver of malignancies, so when you target this protein, with trastuzumab, or trastuzumab, pertuzumab, you not only target tumor cells, you take away bad biology. You counteract bad biology. In gastric cancer, HER2 overexpression is not associated with poor prognosis. Actually, it’s kind of awash, you know, there’s even some data showing that HER2 overexpressing, gastroesophageal cancer had better prognosis of chemotherapy, so you’re not targeting bad biology. I think it’s enough to target it with trastuzumab, and the addition of pertuzumab is not as important as in breast cancer.

We also have negative data for T-DM1, which is an approved agent in breast cancer, in second line therapy, so second line T-DM1 in a prior trial, again, in gastroesophageal cancer, did not show survivor benefit compared to chemotherapy alone, so different biology, different tumor type. I’m happy that we have one targeted agent against HER2, trastuzumab, which works, seeing clear survivor benefit, and we, a lot of times, actually move trastuzumab from first line into second line therapy, beyond progression, like in breast cancer, but clearly, I think it’s the different biology that makes it not as attractive as important target for intervention.

Dr. Caudle: Right, which is, I mean, from a biological standpoint, it’s fascinating, right, how the role of HER2 is different in different organs and different cancers, so it definitely plays a role. So, moving on, tell me about your thoughts on the results of the ATTRACTION-2, and the KEYNOTE-059 trials, and can you speak, a little bit, also, about the combination, excuse me, can you speak a little bit about the role of immunotherapy in upper GI cancers?

Dr. Grothey: So, KEYNOTE-059, and the ATTRACTION-2 a trial tested PD1 antibodies, one pembrolizumab, the other one Nivolumab, in gastroesophageal cancers, adenocarcinomas, and they have very consistent results, so KEYNOTE-059 is actually a complicated study because it had three different cohorts, a heavily pretreated cohort, monotherapy pembrolizumab, a first line cohort, monotherapy pembrolizumab, and a combination chemotherapy, a combination with chemotherapy and pembrolizumab. You know, none of these arms were randomized. KEYNOTE-059 did not have randomization, so the purest data we have were really, kind of, the later line, salvage treatment, with pembrolizumab, where we saw about 30 percent disease control rate, 20 percent response rate, and some of the responses are long lasting. The same is true in first line, pembrolizumab single agent, first line, you see a subgroup of patients, about 20 percent respond, some of the responses are long lasting. Then you combine it with chemotherapy, it’s not quite sure what really works, you know, and it’s a smaller study, 25 patients, 30 patients, and it’s intriguing to see that some patients, again, have long term benefit.

Now the ATTRACTION -2 study was a randomized comparison. It compared Nivolumab in a later line setting plus second and third line setting with placebo, and the investigator showed a survivor benefit. Based on this data, the drugs, Nivolumab, is already proved, in Japan, where the incidents of gastric cancers are higher, and they’re looking for the salvage treatment option, so these two trials do show that there’s a subgroup of patients with GE junction adenocarcinoma, or gastric adenocarcinoma, that benefit from checkpoint inhibitors immunotherapy.

There’s, at least, some discussion that higher PD-L1 expression levels might predict a better response. Having said that, there are patients with negative PD-L1 expression, or tumors with negative PD-L1 that also respond, probably not as frequent, in terms of response, but they do respond. So, question, we don’t have a great biomarker to positively or negatively select the patients, so in the end, I can see if we see more data with survival benefit there are first line trial, single agent, combination, randomized trials ongoing. We will probably use these checkpoint inhibitors in all patients, in the absence of a biomarkers, and we, then, observe these long-term responders. These tumors that are immunogenic and really can provide a long-term survival. It’s exciting times. I’m very happy to see a new treatment option, in these patients, because gastric cancer, a very bad disease, high lethality, and high incidents, actually, worldwide, 1.1 million cases, so it’s something we really have an unmet need, and anything that can help us, here, is good.

Dr. Caudle: Exactly. It’s what we want. Absolutely.

Dr. Grothey: Exactly. Dr. Axel Grothey, thank you, so much, for joining us today.

Dr. Caudle: Thank you, very much, for having me.

Dr. Grothey: Thank you, for tuning into PracticeUpdate.

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