John L. Marshall, MD, Discusses the Growing Treatment Paradigm in CRC

Growing Treatment Paradigm in CRC

John L. Marshall, MD

With an expanding treatment paradigm for patients with colorectal cancer (CRC) at their fingertips, oncologists are working out the best methods of use for their new armamentarium, says John L. Marshall, MD.

"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," said Marshall, chief, Division Of Hematology/Oncology, MedStar Georgetown University Hospital, associate director, Clinical Research, Lombardi Comprehensive Cancer Center, in an interview withTargeted Oncology.

"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?"

Marshall says with three FDA-approved VEGF inhibitors, those being bevacizumab, aflibercept, and regorafenib, as well as an 2015 approval of TAS-102, and the emergence of PD-1 inhibitors, treatment options for CRC abounds.

Another development adding to the accumluation of treatments 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.

"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," sais Marshall.

"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."

Marshall adds that along with news studies in CRC comes a revealing of the cancer type's vulerabilities. He says the more oncologists know about mutations, even rare mutations, the more genetic testing can be utilized.

On the topic of new antiangiogenesis agents, Marshall says he believes that most treatments are created equally.

"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," he said.

"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."

Looking toward the future of treatment for CRC< Marshall remains hopeful.

"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&rsquo;t think we are just trying to extend survival—they think we&rsquo;re trying to cure it. So, maybe we should try," he said.

"This is complicated. A lot of smart people don&rsquo;t think we&rsquo;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&rsquo;t just be chaos. It is possible that it will be chaos. However, if it&rsquo;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."