Marshall Reflects on Major Advances in mCRC

John L. Marshall, MD

The treatment of patients with metastatic colorectal cancer (mCRC) should be approached with more fluidity than rigidity, said John L. Marshall, MD, who added that the use of upfront and potentially repeat molecular testing can help optimize such an approach.

“The treatment of colon cancer is sort of billed as lines of therapy, and I don't like that because it implies that once you've done one thing you move on to something else. [The treatment of patients with CRC] is more like a chess game. You've been given a bunch of pieces on the board, and most of the time you get to move your chest pieces more than once. I think that's especially true in CRC,” said Marshall.

In an interview with OncLive during the 5th Annual School of Gastrointestinal Oncology™, Marshall, chief, Division of Hematology/Oncology, Medstar Georgetown University Hospital, professor of medicine and oncology, and director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, Georgetown-Lombardi Comprehensive Cancer Center, reflected on recent advances in the field of mCRC and discussed ongoing research efforts in the space.

OncLive: Could you discuss the shift toward precision medicine in colorectal cancer?

Marshall: Colon cancer [is the most common gastrointestinal (GI) cancer], and has led the way in terms of precision medicine. We have to know microsatellite instability (MSI). I think everyone understands that. We have to know HER2. I think HER2 is the peripheral radar a little bit. We have to know NTRK for all metastatic cancers. In addition, we have to know BRAF. That’s not just a bad prognostic marker; it’s a therapeutic marker. [We’re looking for] RAS, BRAF, HER2, MSI, NTRK with broad testing because we’re finding brackets in colon cancer. We’re finding other targets that we weren't expecting. I would encourage all patients with colon cancer to get broad testing.

Is there an optimal time to perform molecular testing? Is there any value to repeat testing?

We need to know the molecular characteristics of a patient’s GI cancer right from the beginning. We now know that cancer is not clonal. We know it's polyclonal, so I would repeat testing, if I have the opportunity to. If there's a good reason to go in and get more tissue, I would. Liquid biopsy has not really become entrenched [in GI cancers] like it has in lung cancer in terms of looking for resistance. I think the more we incorporate that [into practice], the more we will start to see changes over time in resistance patterns. I think [repeat testing] may affect our therapeutics, both closing some doors and opening some others. However, our culture is not quite at the point where we can say repeat testing is mandatory in a guideline.

You’ve done a lot of research in later-line settings of CRC. What have you found through that research?

In the frontline setting, we're evolving toward an aggressive initial therapy of FOLFIRINOX and bevacizumab (Avastin) for almost all patients followed by maintenance therapy. Then, we back off and let go of some of the chess pieces so that we can use them again later. We reset things, and we radiate things. We do all sorts of little moves along the way.

One of the biggest problems in cancer medicine today is this concept that certain medicines are meant for refractory patients and certain medicines are meant for frontline treatment. Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) are both valuable drugs that don't cause responses but give patients sometimes as much as 6 to 9 months of stable disease, and that's valuable. If you wait too long, you'll lose that opportunity, so it's a chess piece that can't really be your last move on the board. You need to move them earlier. I keep telling people not to save drugs that have a survival advantage to a time when they won't have that survival advantage. We should be using these drugs in earlier maintenance windows and the like. The evolution of both of those medicines in the second- and later-line settings is to move them earlier when stable disease matters.

Are there any studies in CRC or gastric cancer that you are particularly excited about?

The combination of TAS-102 with bevacizumab led to some very exciting data [in the phase I/II C-TASK FORCE trial] in the refractory setting. The combination showed benefit versus TAS-102 alone. I think we’re going to see more with TAS-102 in gastric cancer. We’re going to see combinations moving earlier. Instead of 5-fluorouracil (5-FU) beyond progression, you might switch out 5-FU with TAS-102. There are a bunch of new therapies targeting HER2 and EGFR that are further improving those outcomes. The most impactful study that read out recently is the [BEACON CRC] trial which investigated targeted therapy for patients with BRAF V600E-mutant mCRC and showed really positive results. It wasn’t a home run, but certainly these data will make a difference for patients.

Could you elaborate on the results of the BEACON CRC trial?

[The development of] BRAF therapy in colon cancer had some bumps early on and then moved like lightning. We credit a few people for that, Scott Kopetz, MD, PhD, FACP, being 1 of them. At first, we thought BRAF was just a bad prognostic marker. We had tried single-agent BRAF inhibitors that work in melanoma, but they didn't really work in colon cancer. Then, [several investigators] suggested that we combine drugs along that same pathway. We know how resistance [manifests] along that pathway, so let's come at the same pathway more than once and see what happens. Some of the initial studies combined EGFR and BRAF inhibitors with irinotecan. These were and positive, small randomized phase II studies but positive that shifted the bar immediately.

The BEACON study, the most dynamic of those studies, evaluated the addition of a MEK inhibitor to BRAF and EGFR inhibitors. The MEK inhibitor did appear to increase the response rate and to some degree, the progression-free survival. Interestingly, the addition of the MEK inhibitor did not improve the overall survival (OS) compared with the EGFR and BRAF inhibitors without irinotecan. [If the combination is approved, it’ll be the first nonchemotherapy-containing regimen] we have for BRAF V600E-mutant patients with mCRC. Moving forward, what about the other BRAF mutations, and can other combinations help to further improve outcomes for our patients?

Do you anticipate triplets taking on a greater role in CRC?

No. We’ve tried triplets, and so far, they haven’t really worked. Perhaps different triplets may work. It's biology, not just three's a charm. Does the drug hit a pathway that mediates resistance? If it does, then it will add OS benefit. This is going to take a little bit more refining. In the last couple of years, we’ve been able to identify roughly BRAF V600E as a valid target, changing the standard of care and bringing what we expect will be a new FDA approval.

What can we look forward in the CRC space?

I closed the 2020 SOGO Annual meeting by discussing where the field is headed. We talked about everything from telemedicine to precision medicine and how to apply that in a valuable way. How are we going to apply financial metrics to what we're doing moving forward from innovative clinical trial designs to working together? This is all about collaboration. How can we, in our separate worlds, work together to drive cures on a faster basis?

Looking ahead, we have to remember that our job is hard. [Medical oncologists], particularly those [in the community setting] have to keep up with so much. We have to stay up to date as best we can. We have to deliver compassionate care as best we can, and we have to do so without going crazy. There's a lot of burnout in oncology today, and we have to be mindful of that. However, our job is getting cooler. We’re becoming more successful at what we do. Therapies are improving. Our diagnostics are improving. The tools and the therapies we have been transformative. Some of the younger doctors have no idea what it used to be like.

Could you discuss the importance of holding meetings like SOGO?

It has been an honor to be part of SOGO from the beginning. Now in our fifth year, we've [moved to a virtual platform because of the novel coronavirus]. Getting together and sharing the latest data, stopping for just a minute to take a breath, and making sure you're up to speed with what you know [is important], so that [you can apply the information to your practice] on Monday morning. GI cancers are by far the most common and most fatal cancers. Research is happening in all of the major GI cancers from CRC to gastric to pancreas to bile duct tumors, hepatocellular carcinoma, and neuroendocrine cancers. You need to be up to speed, and we hope that [this meeting] provides that for you.

We also know that GI cancer is multidisciplinary perhaps unlike some other cancers. Without our surgeons, our intervention radiologists, our radiation oncologists, and supportive care specialists, we couldn't [care for patients properly]. We have to work in a team, and the SOGO meeting has always worked to be multidisciplinary. My co-chair Michael Choti, MD, MBA, FACS is a world-class surgeon, and [we] have always tried to shape [the program] so that there's something for every member of the multidisciplinary team.