Expert Discusses Future of Treatment in CRC

John L. Marshall, MD

With three FDA-approved VEGF inhibitors—bevacizumab, aflibercept, and regorafenib—a 2015 approval of TAS-102, and the emergence of PD-1 inhibitors, plenty of therapy options exist for patients with colorectal cancer (CRC), but how to best use them remains a challenge, explains John L. Marshall, MD.

Another exciting CRC development, according to Marshall, are results of a phase II study presented at the 2015 ASCO Annual Meeting, which showed that individuals with CRC who have high levels of deficiency in DNA mismatch repair (MMR) have a higher production of neo-antigens and are potential candidates for immunotherapy.1 In the study, patients with MMR deficiencies who received pembrolizumab (Keytruda) had an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors.

OncLive: Can you give a general overview of some of the key ongoing issues in the field?

In an interview with OncLive, Marshall, chief, Division Of Hematology/Oncology, Medstar Georgetown University Hospital, Georgetown University Hospital Associate Director, Clinical Research, Lombardi Comprehensive Cancer Center, discusses these treatment advancements and other ongoing developments in CRC.Marshall: Collectively, we have moved the bar. There has been success, we have improved outcomes, and we have new good medicines. Also, we are learning a lot on how to better use them, when to use them, and, more importantly, when not to use them. With that, we have improved survival and outcomes.

Cost effectiveness is something that has been brought up with these advancements. We know that what we are doing is expensive, and one of the new themes in oncology is, how do we innovate? How do we move the bar forward and yet still not break the bank? How do we justify what we are doing? On top of that, how do we expand access to cancer therapy and cancer care, to people who currently don’t have it because of money?

Can you reflect on some of these exciting advancements?

We are using colon cancer, and the success we have had in colon cancer, as a model for how to move forward.The number one thing that every doctor on the planet who takes care of CRC should know is the mismatch repair story. Dr. Dung Le from Johns Hopkins School of Medicine and a group around the country did a clinical trial of a PD-L1 inhibitor in mismatch repair tumors, and it showed a dramatic positive effect. Those agents are going to be approved, which means you’re going to need to know if that biomarker exists in all of your patients. For the metastatic patients, it’s only 5% of the total, but you still need to know it. The genetic testing needs to be done for those patients.

What have we learned in sequencing all of these various therapies?

Also, we are seeing more evidence around HER2, BRAF, and stem cell targeting. We are seeing new vulnerabilities, if you will, in CRC. For me, that translates into the increasing need to do broad molecular profiling. The more we know, even about rare mutations, the better we will do. Do you do “a la carte ordering”—this test, that test, that test? Or, do you just send for one test? Perhaps, in genetic testing, we are moving toward that way. Again, colon cancer is teaching us that we need to know a lot of different genes, not just the ones that are under a light post.We now have first, second, and third lines of therapy, and those lines are really different for every patient. It’s a different chess game for every patient. We know that maintaining VEGF inhibition through lines of therapy does convey a survival advantage, so keeping a little something going in every line is a good idea. There is not a big difference between oxaliplatin and irinotecan in the frontline setting, and there’s not a big difference between EGFR and VEGF in frontline, so you sort of decide when you want to treat, with what treatment.

Regarding treatment beyond disease progression, what should oncologists be made aware of?

I think one of the most important lessons that we have is that we don’t want to be too heavy-handed. We want to use the medicines we need, and then back down. Stop completely with some therapies and do a maintenance approach with others. Doctors who have to know about every cancer tend to be less comfortable backing down. One of the messages is, don’t be so heavy-handed.Based on findings from a previous study, the main message is that there was not a difference in patients, even in the RAS wild-type population, between EGFR and VEGF agents in terms of overall survival. However, this remains controversial because a European study suggests anti-EGFR agents might have an advantage, even in RAS.

Secondly, we must understand extended RAS testing. A lot of people are testing for KRAS, but not extended RAS testing. It is so important, and we are not measuring it a lot of times, and we have to.

What progress has been made with antiangiogenesis agents?

In the metastasectomy patients, we have created this new subgroup that’s now stage IV and has no evidence of disease. More importantly, we really don’t know what to do with those patients. My advice to oncologists out there is, either treat them as adjuvant or treat them as metastatic—not both. I don’t know which option is right, but don’t do both.We have three VEGF inhibitors. They all basically do the same thing, and they all have a slightly different side effect profile. However, they don’t cost the same. Newer drugs have been priced higher than the older drugs. I would never say that bevacizumab is a bargain, but it relatively is now. Not because its price has dropped, but others’ have gone higher.

What potential do you see for immunotherapy in CRC?

Therefore, this discussion has gone around: is there one better than another? Really, the answer is no. You don’t necessarily mix and match them. It’s not really clear that one after the other is better. A lot of that is happening out there because patients want new treatments, doctors have them to offer, and they’re hoping that they’re a better mousetrap. However, the data show that there is not really a difference; they’re the same.Clearly you need to understand microsatellite instability and the single-agent activity in these patients. The other piece of it is, how do we use our new knowledge of immunotherapy in other patients—the ones that are not immediately responsive? There is a great deal of work going on in this area where we are combining with vaccines and other strategies.

What are some of the remaining large questions in CRC?

I think it is a “stay tuned” perspective, but that is still an area of clinical research. There is progress being made, but not the dramatic kind of progress we have seen with the single agent in the right patient.A theme of everything I try to do is: how are we going to cure this disease? That is what our patients think we are doing. They don’t think we are just trying to extend survival—they think we’re trying to cure it. So, maybe we should try.

This is complicated. A lot of smart people don’t think we’ll be able to do that because it changes, and it is highly variable. What we are seeing now is recognition of the variability, and an increasing ability to capture and measure the complexity. The next step will really be how to understand how CRC is a bunch of different diseases. When we start to do that, we hope that it will fall into categories, and it won’t just be chaos. It is possible that it will be chaos. However, if it’s not, and it really does fall into 5 subgroups as the current thinking, then we will start to really make the inroads to get to the core vulnerabilities to cure the disease.

1. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;(suppl; abstr LBA100).