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Marshall Recaps Milestones in CRC Paradigm

Angelica Welch
Published: Wednesday, Jan 10, 2018

John L. Marshall, MD
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.

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.

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

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.

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.

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

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. 

It really depends on location, your overall goals, and the regimen you are trying to pick for your first-line treatment. 

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

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.

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