Ushering in the Era of Precision Medicine

Treatment for patients with gastrointestinal (GI) cancer, specifically colorectal cancer (CRC), has undergone a major paradigm shift. Improvements in the understanding of cancer biology and the implementation of precision therapy have allowed oncologists to begin to deliver the proper treatment to the proper target, improving outcomes.

ONCOLOGY® recently sat down with Tanios S. Bekaii-Saab, MD, of the Mayo Clinic in Phoenix, Arizona, to discuss the rapidly evolving treatment landscape of GI cancers, the most recent practice-changing studies, and the need to make genomic sequencing the standard of care for all patients with GI cancer.

Q: Can you discuss the importance of next-generation sequencing in GI cancers?

Bekaii-Saab: I don’t think anymore that genomic sequencing, next-generation sequencing (NGS), is a privilege; it should be a right. I think every single patient with a GI malignancy—specifically colon cancer, but [actually] all GI malignancies—has the right [to be sequenced], and we have to find every way possible to get them sequenced.

I need to understand what the rare mutational status of each patient is. What does BRAF look like? Do we have a BRAF mutation? I want to know about HER2 amplification. I want to know about tumor mutational burden (TMB), [since] now we have an approval with high TMB for pembrolizumab (Keytruda). The cutoff point may be a little controversial; the 10 is not as meaningful but many of these patients with TMB of 15 and 20 are actually [having] great responses and responding really well to immune therapies. And in pancreas cancer, for example, I want to understand if there is a BRCA mutation that may essentially be driving the cancer.

So, you can see the story forming here. But going back to colon cancer, I have at least 4 or 5 things I need to know from the get-go before I even start treating the patient. One could argue that, hey, let’s get microsatellite instability–high (MSI-H) and RAS and BRAF and HER2 separately. But it turns out that if you get them separately, it’s much more expensive than getting NGS. And with NGS, you actually get more than just the 3 or 4 things; you can get other things like NTRK fusions.

Now we know that NTRK fusions, which are incredibly rare, can be found. So, we’re looking at needles in a haystack. The less you test, the less likely it is that you are going to find rare targets. So, we’re not only looking for the common targets, but for the rare ones as well. And so, 1 snapshot with NGS should give you all the tools you need—or most of the tools, I should say, because there are still a lot of unknowns. But it should give you most of the tools you need to essentially plan ahead of time for that patient. What biologic am I going to start with? Is that a hopeful immunotherapy in this patient? Is chemotherapy the best choice, or is pembrolizumab the better choice? Should we enroll this patient on the BRAF V600E–mutated study, the follow-up to BEACON CRC (NCT02928224)?

Let me tell you why [identifying] HER2 amplification is important. HER2 amplification not only puts the patient on path for HER2-targeted strategies, which are being studied in multiple trials with multiple agents being developed, but it turns out that HER2 amplification tells us quite a bit about resistance to EGFR inhibitors. So, let’s say you have a left-sided tumor—naturally, you would think this patient should do great on an EGFR inhibitor. But it turns out that if the patient has a HER2 amplification, which occurs in about 4% of the patients, that patient will not respond to an EGFR inhibitor. And in fact, they progress very rapidly. So, all of these things—MSI-H, TMB, RAS, BRAF, HER2, plus a slew of others—can be a part of this NGS, this genomic profiling of the tumor. So, [again,] I think at this point in time, NGS should become a right and not a privilege, and all patients should have access to it. And the sooner the better, because it sets us on a much better track in terms of identifying the best options for patients with GI cancers.

Q: What is driving the current progress in the field? Is it the increased testing?

Bekaii-Saab: The answer is not just testing alone; testing was so random in the past that you couldn’t make sense out of it. We also didn’t have any agents or studies being looked at in the different spaces. Rather, I think what’s energizing the field is the fact that while testing is being done, we’re understanding more, and with more clarity, about what these different targets mean, what these different expressions mean, and how we can go after them. Six or 7 years ago it started with MSI-H cancer; we started seeing those results [from immune-based therapy] percolating in the later line[s of therapy] and moved [those therapies] to the first line, which just transformed the way we treat this disease. The biology that we’re learning about starts in the later stage, then moves to the first line, and also ultimately moves to the adjuvant setting. So, we’re starting to transform this cancer earlier and earlier. I think in 3 to 5 years, survival, for many patients, is going to be the equivalent of a cure, when we do things earlier on and the right way. A lot of work is still ahead of us, though, with tons of information [to work through]. This is where meetings like ISGIO [International Society of Gastrointestinal Oncology] [are so important, to] keep you up to date with where the science is, what’s changing practice today, what is likely to change practice tomorrow, and what we should be looking at after tomorrow.

Q: Can you tell me a little more about the ISGIO conference? What will we see at this year’s meeting? This is your first year as the program director.

Bekaii-Saab: The meeting this year is certainly revamped. We’re going to be changing a few things and keeping some things that worked in the past, especially the focus on fellow education and fellows’ involvement. We’re also diversifying the chairs of the different sessions quite a bit, ensuring [more] diversity, including representation from multiple institutions. We’ll also introduce some debate-style crossfire and other elements that will keep it quite interactive. But we also want to preserve the spirit of ISGIO. That will essentially ensure that it’s a meeting where not just fellows, but young faculty, early in their career, will not only be able to be involved but [will] be quite educated [from the discussions of the meeting], in terms of how they practice and in terms of understanding the evolving landscape of research and standard-of-care therapies in various GI malignancies.

Q: What are some of the key studies that have come out in the past year or two that have been practice-changing within the field?

Bekaii-Saab: I think that [the results] of KEYNOTE-177 (NCT02563002) are among the biggest stories over the last few years—at least in colon cancer. We’ve known for a while that in this subgroup of patients with MSI-H metastatic CRC, we have up to 30% to 40% of patients who have a response to pembrolizumab in the refractory setting. For most of these patients, the response is quite meaningful. What I mean by that is it’s not just the level of response—which in many patients is actually a complete response—but the durability of the response as. About 20% to 30% of patients continue to respond, even after you stop the treatment at 2 years, and then continue to be in remission. So, the natural question leading to KEYNOTE-177 was, ‘We see these incredible responses in the later lines—can we bring this up to the first line?’ And I’ll be frank with you, in my practice, I actually changed—even before [the results of] KEYNOTE-177 [were published]—to using pembrolizumab in the first line for patients with MSI-H tumors. And my thought was originally that, you know, some of these patients, 20% to 30% of them, will never need chemotherapy in their lifetime. They respond so well to these agents; I don’t want to wait too long before [using it].

And so, I was very pleased with the results of the study, which essentially showed that indeed, in about one-third of the patients at least, if not more, pembrolizumab induces a significant response. [The results] essentially transform this disease from one where we have to try chemotherapy first and fail before we go to immunotherapy, to patients now getting immunotherapy first. And then, as I said, for 30% to 40% of those patients—and I don’t like to use the word “cure” loosely in stage IV disease—this is the equivalent of a cure. Those patients end up in remissions that are durable, and they may never ever see chemotherapy in their lifetimes. So that’s great.

Now survival—we’re still waiting on that. There are 2 possible scenarios. The first scenario is what a lot of people are predicting: Survival won’t be much different between pembrolizumab given first versus chemotherapy being given first. The reason, [according to] a lot of folks, is, well, when you give chemotherapy first when patients progress, they will all have access to pembrolizumab and therefore most of them will be crossed over to immunotherapy. So, the thought is that, whether you get it first or later, it won’t change the overall survival much. On the other hand, a small group of folks thinks that actually, we’re probably going to see a survival benefit. It may not be as big as the PFS, but it will be there and it will be meaningful. Their reasoning is, since this is appears to be a game-changer, the sooner you change, or the sooner you attack the biology of the cancer, the better you will do on the long run and, therefore you will affect overall survival positively. I’m kind of closer to this camp, but I’ll tell you that either way, I frankly don’t care what the survival results are going to be. We know that they’re not going to be detrimental and when I have about one-third to 40% of my patients go on pembrolizumab for a couple of years, and they’ll be in durable complete remission and may never see chemotherapy in their lifetime, I think that’s an achievement.

So, if the survival is positive, that’s great. If the survival is borderline better, with pembrolizumab versus some sort of chemotherapy, when you look at the big story, prolonging their likelihood of not progressing, with a quality of life that’s much better, I think it’s a no-brainer. This has changed the landscape of how we treat MSI-H metastatic CRC. But let me even go further: I would say this has transformed the way we treat MSI-H tumors, period, beyond just metastatic CRC. [In other words], if I have a gastric cancer or a pancreas cancer or a cholangiocarcinoma patient who has MSI-H, I will treat them with pembrolizumab first, before even trying to treat them with chemotherapy. I do believe that the results, as we’ve seen in the later lines, are consistent regardless of anatomic site. It doesn’t matter where the cancer starts; it’s the MSI-H phenotype that’s essentially determining the level of response. So that’s [practice-changing]. I think that is an incredible study that just changed the way we think about those patients—4% of all our patients with colon cancer. That’s a lot of patients in a very common disease. It gives us a lot of hope that we’re curing patients in stage IV disease with this modality.

The other trial that comes to mind is BEACON CRC (NCT02928224), a phase 3, randomized trial with encorafenib plus cetuximab plus or minus binimetinib versus irinotecan and cetuximab in patients with refractory BRAF V600E–mutated [tumors]. What we’ve seen in this study is that the biologic combo, [versus chemotherapy plus cetuximab], is improving survival and overall survival. Up to 25% of patients will have a meaningful response, and patients’ quality of life is significantly better, with less toxicity. So that now is a standard for our patients with CRC and BRAF V600E mutations. We talked about this with KEYNOTE-177 and now with BEACON CRC; it is essentially leading the way to move these combination of agents into the first line and into the adjuvant setting, ultimately.

Another study that I think changed or transformed the way we treat patients, with caveats, is POLO (NCT02184195), which looked at patients with pancreatic cancer with germline BRCA1/2 mutations. The results showed that if you treat patients with a platinum-based therapy and then, after at least 16 cycles of exposure [if they’re stable and have had a response, they take] olaparib [Lynparza], which is a PARP inhibitor, their progression-free survival is significantly improved. That study was transformative, in a sense; it doesn’t necessarily change practice for most patients, but for the first time, in pancreatic cancer, we have a biologic option that was shown to essentially prolong progression-free survival and [patients had] a response to it. We never had that in pancreas cancer: to have a target and an agent that goes after the target. So that is transformative. That tells us that biology drives cancer, and when you identify the driver, you can actually flip a switch or offload the switch in a way to essentially establish some form of remission and for some, it’s a durable remission.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.