Marshall Recaps Milestones in CRC Paradigm

John L. Marshall, MD

Advancements in next-generation sequencing have opened the door for therapeutic options for patients with gastrointestinal (GI) cancers. Specifically, microsatellite instability (MSI) and PD-L1 testing has allowed for patients with GI cancers to benefit from immunotherapies previously thought to have little effect in these types of tumors.

Currently, the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) are FDA approved for patients with MSI-high (MSI-H) or mismatch repair deficient colorectal cancer (CRC) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan regimen. Moreover, while these single-agent therapies only spur responses in a small percentage of patients with CRC, the importance of testing for MSI-H and PD-L1 in these tumors remains high. It is also essential to test for BRAF and RAS mutation status, as well as determining tumor sidedness, experts say.

“The call to arms here is that all oncologists managing patients with metastatic disease should know [if their patient is] MSI or not and PD-L1 or not,” said John L. Marshall, MD.

OncLive: Can you discuss the recent progress made in GI cancers, specifically in CRC?

In an interview with OncLive, Marshall, chief, Division of Hematology/Oncology, MedStar Georgetown University Hospital, professor of medicine and oncology, Lombardi Comprehensive Cancer Center, Georgetown University Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, recapped some of the biggest CRC advancements of 2017, and explained what those successes mean for the treatment paradigm moving forward.Marshall: Starting at the top and working down, the new standard of care in gastroesophageal junction cancers, and in gastric cancers with the FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel] regimen. There have been new approvals with immunotherapy in the space of gastric cancer, upper GI cancers in general, liver cancer, and CRC.

Once we had all of that new stuff out there, we stepped back and said, "How are we going to use all of this and how are we going to deal with first-line, second-line, and beyond?" Now, we have some really “funny” rules—with right-sided and left-sided colon cancers, and we have MSI, RAS-, and BRAF-mutant tumors. Therefore, to make that good frontline decision, you need to know a lot more than you did before, because not only does it matter what drugs that you use, it’s sort of a strategy question as well.

With these different drivers now being identified in CRC, when do you recommend getting next-generation sequencing?

Additionally, the multidisciplinary nature of colon cancer is a team sport, I like to say. You need outstanding surgery and radiation, imaging, pathology, and molecular profiling to deliver the best outcomes for our patients.When you are making a decision for patients with metastatic CRC, depending on the location of the tumor, you may have to know the molecular testing results. Now, I would argue that you want to know that right from the beginning—really, in everybody—because you want to know whether they are microsatellite stable or MSI-high. Now, the minority are going to be MSI-high, but you want to know because it could change your thinking about everything.

If it is right-sided colon cancer, it appears, based on all of the evidence that we have, that EGFR therapies won’t work very well, at least in the frontline space. Therefore, you could argue that if you already knew the MSI results with a right-sided colon cancer, you don't really need to know RAS and BRAF just yet, but you are going to want to know. I would argue that the sooner that you can get that information, the better.

Do you wait on a treatment? The only thing I would wait on would be giving EGFR-targeted therapy to a right-sided tumor or a left-sided tumor when you don't know the RAS and BRAF status because we know that those drugs don't work well on those mutations. On the flip side, in patients with left-sided CRC where there is significant metastatic disease and you want to use an EGFR-targeted therapy, knowing the molecular testing results is key. If it is all wild-type, then the drugs work very well and maybe better than bevacizumab (Avastin), for example.

What therapies are in the pipeline for patients with RAS- or BRAF-mutant tumors?

It really depends on location, your overall goals, and the regimen you are trying to pick for your first-line treatment. As we have pulled out more and more of our molecular testing, BRAF has emerged as a negative prognostic marker. We have BRAF inhibitors but, unfortunately, the BRAF inhibitors, at least by themselves, have no activity in BRAF-mutated CRC.

What has it been like seeing an immunotherapy breakthrough in the MSI-high population?

Dr Scott Kopetz and others did studies looking at combining BRAF inhibitors with EGFR inhibitors, and it demonstrated some significant positive clinical outcomes. There are definitive clinical trials being done right now, but my prediction would be that not long from now, if you have BRAF-mutated metastatic CRC, you are going to be using BRAF inhibitors combined with EGFR therapy. We have to be really careful about what we mean by "immune therapy.” The breakthrough has been this thing called checkpoint inhibition and, in that situation, the immune system is all ready, charged, and ready to go, but the tumor is preventing it from being attacked. All these drugs do is take that force field out so that the immune system can go in and do its thing.

Therefore, if that immune system is not out there, if the tumor hasn't “pissed off” the immune system enough, then those drugs will not work. Recent observations have been that if you give it to the wrong patient, then [in some cases] the tumor grows fast. But we have other markers, such as MSI and PD-L1, where there is a lot tumor mutational load. I will challenge that most oncologists, including me, don't really understand all the molecular testing that is going on to pick which one needs the treatment and which one doesn't. I would argue that for all our patients with metastatic disease, we need to know the MSI status. For some of our patients, such as those with gastric cancer, we need to know PD-L1, as well. And, you need to be doing these tests in almost everyone.

With these new agents being studied, what is the role of chemotherapy?

If your patient is positive for any of these things, immune therapies have profound positive effects and we are all chasing this. We are going to try them in almost all our patients. I am surprised at the number of patients that I see in second opinion to this day where this hasn't been done.We are not done with chemotherapy. Chemotherapy is very important, as it is a fundamental part of the treatment of GI cancers across the board. There are few cancers where biologics or targeted therapies will have a role, maybe even by themselves, but that is the minority. The majority of patients are going to be using chemotherapy. Let’s face it, even a lot of the trials using immunotherapy are combining this with chemotherapy and showing some interesting and positive results.

We are going to be using chemotherapy. Which chemotherapy and how to use it will depend a lot on what is in front of you. Where is the tumor? What is the molecular profile? What are my choices? If I really need a response, we have FOLFOX, FOLFIRI, and bevacizumab [Avastin] as one of the best response rates. Or, if I have a left-sided BRAF wild-type or RAS wild-type tumor, then I use EGFR therapy. Those are the 2 best response rates, but they are "spicy" in some patients. Therefore, do I need that right now, or can stable disease be just fine?

Decision-making needs to be individualized; there is no single guideline or pathway. It’s like playing chess: you play it differently based on your opponent. It’s not checkers where you can make the same move every time. I really encourage doctors to know the basics of this and play the smartest “chess game” they can play.