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Expert Discusses Future of Treatment in CRC

Gina Columbus @ginacolumbusonc
Published: Wednesday, Dec 30, 2015

John L. Marshall, MD

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.

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.

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

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?

We are using colon cancer, and the success we have had in colon cancer, as a model for how to move forward.

Can you reflect on some of these exciting advancements?

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.

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.

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

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.

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.

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

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.

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