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The IDEA trial: Perspectives and practice implications

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 www.practiceupdate.com

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.

Dr. Caudle: Well, we’re excited that you’re here. I first wanted to talk a little bit about the BEACON trial. Can you tell us about the trial and talk about the results and what your thoughts are about it?

Dr. Grothey: Yeah. So, BEACON is a trial that targets patients with metastatic colorectal cancer patients with a BRAFV600E mutation. Why is that important? BRAFV600E mutations have a very poor prognosis in metastatic colorectal cancer.

Actually, recently published data on the BRAF mutant versus BRAF wild-type patients treated MD Anderson and at Mayo Clinic, BRAFV600 mutant tumors have a median survival of less than 12 months, whereas a patient with BRAF wild-type tumor is about 40 months, so it’s a big difference, and you consider BRAF mutations, BRAFV600E mutation, as driver mutation that can really initiate a bad biology.

In melanoma, for instance, we know that we can inhibit BRAF mutation, a BRAF mutation melanoma of 50 percent, in colon cancer it’s about 12%, but the same mutation, when we inhibit BRAF with a single agent melanoma, like dabrafenib, vemurafenib, or encorafenib, we see about 80% responses. When we use the same drugs in colon cancer, in the same mutated patient population, five percent responses, and not durable responses, so it’s not just the presence of this biomarker, but the histologic context and the presence of other factors.

What’s different between melanoma and colorectal cancer is the presence of EGF receptor because what happens, when you inhibit BRAF in colon cancer, it inhibits the pathway, the MAP kinase pathway, leads to downregulation of ERK, phospho-ERK, and that sends a feedback loop upwards and activates EGF receptor again, and then the pathway is reactivated, and EGF is, sometimes, absent in melanoma cells. It just doesn’t happen, so you don’t have this feedback.

So, we found out that we probably have better efficacy if we combine a BRAF inhibitor with an EGF receptor inhibitor, like cetuximab or panitumumab, and then if you want to do a little bit more, you block MEK-2, which is one step down of BRAF, so the idea of the BEACON study is to investigate a triple combination of a BRAF inhibitor, encorafenib, a MEK inhibitor, binimetinib, and a EGF receptor inhibitor, cetuximab and compare this to the standard of care, of cetuximab or irinotecan.

So, that is the framework. So here, at ESMO, we’re presenting, in a poster, the safety lead-in phase because when we initiated the trial, we didn’t have any safety data of this triplet combination, so we have 30 patients with BRAFV600E-mutant cancers, and interestingly none of these patients have progressive disease, with a triplet.

They all had, except for one patient, they all had some form of tumor shrinkage, and most patients, at the time of the interim analysis are still on treatment, so it’s a long lasting, durable effect, which is quite interesting because we’re looking at a second and third line patient population. Overall, 41% of responses really confirm responses, so this is, actually, pretty exciting, unprecedented, you know.

Dr. Caudle: I’m excited. Yeah. It’s very exciting.

Dr. Grothey: So, now we’re moving this forward into phase 3 setting, where we know the median survival of standard treatment is about six months, and if the data, of this lead-in phase, only halfway hold up, I’m sure that this will be a positive study, and then, and this is no chemotherapy, this is just biologically targeting the biologically aggressive feature of metastatic colorectal cancer, BRAFV600E mutations, so it sets an interesting precedent of translating preclinical studies into exactly clinical practice that will hopefully lead to the approval of this combination therapy, non-chemotherapy containing combination.

Dr. Caudle: That’s very exciting.

Dr. Grothey: It’s really exciting. Yeah.

Dr. Caudle: Yeah. Yeah, and you know, very hopeful. You know, very hopeful for further results. Absolutely.

Dr. Grothey: These patients have an unmet need, you know. I always like to see if we can target patients with unmet need, you know, the gain we can make is so much more precious and so much more important.

Dr. Caudle: Absolutely. Yeah. Very exciting. So, let’s move forward, a little bit, and talk about another trial, the TRICOLORE trial, and I want you to just, sort of, discuss that, if you can just discuss the results, of the trial, but my specific question, in addition to that, is, you know, why is S-1 not used in the United States? So, if you can, kind of, talk about a little bit of that for us.

Dr. Grothey: So, the TRICOLORE trial was a trial conducted in the Asian environment, in Japan, actually, comparing standard oxaliplatin-based first line treatment, FOLFOX, CAPOX, plus bevacizumab, to a combination of irinotecan, S-1, and bevacizumab, the IRIS combination, which I think is nice. S-1 is an oral fluoropyrimidine, and it is not available in the United States for various reasons, which I’ll go into in a second because it’s quite interesting what happened.

Dr. Caudle: Sure.                                                                                                    

Dr. Grothey: Now, IRIS compared to the CAPOX, FOLFOX combination was non-inferior, it actually trended a little bit better, even, in patients with metastatic colorectal cancer, in this Asian environment, and in Japan, actually, is one of the standards of care.

So, IRIS, a combination of irinotecan and the oral agent, S-1, is one of the standards of care elsewhere in the world. Now S-1 is not available here. Why is that? So S-1, it ties into some interesting phenomenon that oral fluoropyrimidines, like capecitabine, like UFT, like S-1 are better tolerated in the Asian patients based on pharmacogenomic differences compared to western patients. In particular, in the United States we see an interesting poor tolerability of capecitabine likely because we enrich all of our food with folate, which is a unique American phenomenon, which contributes to the toxicity, potentially, activation of these fluoropyrimidines. And so, the tolerability, they actually have different dosages, you know, from S-1, in the western patient population, the Asian patient population, and there’s some concern about the toxicity of S-1 in the US population.

So, there was a pivotal study in gastric cancer, the so called the FLAGS study, several years ago, which was meant to bring S-1 to the US market. That was the main trail that could have shown that S-1 could have been here, the trial was negative. It didn’t show improvement in survival compared to the standardly available fluoropyrimidines, so the FDA rejected S-1, and no one has, since then, picked it up again and brought it back to the American market, went through the process of FDA registration studies, etcetera, which is quite cumbersome. We have other oral fluoropyrimidines like capecitabine, for instance, like TAS-102, so we have other alternatives available, so it’s not this unmet need that you need to have these drugs, so for now it’s going to be, still, let’s say, an Asian focused phenomenon, but it’s interesting to see, too, here, at ESMO, we have a global environment, cancer is a global phenomenon, we need to know about S-1. S-1 is standard of care in Japan.

Dr. Caudle: Yeah. That’s very interesting. Very, very interesting. Yeah. Well, Dr. Axel Grothey, thank you, so much, for sharing your insights and joining us today.

Dr. Grothey: It’s great to be here.

Dr. Caudle: And thank you for tuning in to PracticeUpdate.


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