Progression on Metastatic Colorectal Cancer Treatment

EP: 1.Getting to Know Colorectal Cancer

EP: 2.Frontline Treatment and Maintenance for Metastatic Colorectal Cancer

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EP: 3.Progression on Metastatic Colorectal Cancer Treatment

EP: 4.Regorafenib as a Metastatic Colorectal Cancer Therapy Option

EP: 5.Regorafenib Sequencing and the Future of Metastatic Colorectal Cancer Management

John Marshall, MD: Colon cancer can be tricky to interpret how a patient is doing on their treatment. If all you do is take the report that comes back from radiology and say, “Ah, they say they progressed,” and you don’t look at the scans or the fine print, you’re going to make some mistakes. We teach our fellows and remind ourselves every day to look at the scan and the fine print of the report, because if somebody had a 7-mm lung nodule that is now 9 mm—that is not progression, in my opinion, but the report will say “progression of disease.” If somebody has a bunch of new lesions that are growing significantly, that’s someone for whom you need to change therapy. Pseudoprogression is not something we see that often in metastatic colon cancer, but minor progression or smoldering progression is something we see a lot. Maybe it comes down to just tweaking your maintenance therapy a little or allowing some minor progression to occur. Just stay with what you’re doing if the patient is tolerating it well, and only change therapy if you think that you’re clinically losing ground. This is a good way I like to think about it.

Now of course patients are watching their scans as well and are nervous about any progression, so they’re eager to change to something that won’t allow any progression. In large part, what you change to depends on where you are in all of this. If you started with the 4-drug recipe—FOLFIRINOX [leucovorin, fluorouracil, irinotecan, oxaliplatin], or [bevacizumab], or something like that—and let’s say you have a RAS mutation, you are down to regorafenib [Stivarga], Lonsurf [trifluridine/tipiracil], or recycling 1 of the chemotherapy regimens you have. In second-line therapy, you very quickly could be using something like regorafenib or Lonsurf, and that is a good idea, particularly if the cancer is slow growing, or where stable disease is a perfectly appropriate thing to get. That is a perfect window to use that regimen and save any of your recycling of chemotherapy for later.

On the other hand, if the patient is RAS wild-type left-sided and you have not yet used your EGFR therapy—well, in this case, this is a patient where EGFR therapy is likely to generate a response. Remember they should also be HER2-negative and BRAF wild-type. All wild-type HER2-negative left-sides—that’s only about 20% of all the patients—are going to get a good response to that. The question is, when do you play that? If somebody has a couple of 3-cm nodules somewhere, you could justify giving that intensive therapy to shrink those.

On the other hand, you could also try a maintenance drug like, say, Stivarga or Lonsurf, and hold it and save your response for a later time. Remember this is not checkers, where one must be done right after the other. This is more like chess, you can replay some of the pieces. Deciding in second line, and certainly in third line, you cannot just say, “What would you do?” because it all matters as to how the game has gone so far. How much toxicity is there? How much tumor burden? What are the molecular characteristics? What chess pieces do I still have on the board? Then you make your best play for the patient at that time.

I will continue to say that it’s important for our patients to get exposed to all the effective agents that are out there. There have been clear publications that, when we do that, we improve survival. If you hold some of your drugs too long, you will lose that window, and you won’t offer that benefit to those patients. We need to get a little out of our first, second, and third line and take it more like chess. What is the right treatment from the menuat that momentfor that patient? Nonchemotherapy recipes are certainly appropriate early on in these patients.

There is a new pathway that you could envision where patients, by the third line, still have not seen chemotherapy, and this is your MSI [microsatellite instability]-high patient who also has a BRAFV600E mutation. They often run together. Here, you could see a frontline IO [immuno-oncology] therapy, such as pembrolizumab, a second-line BRAF-targeted combination—again, no chemotherapy involved in that—and a third line still not having to give chemotherapy. We’re slowly getting to that place in metastatic colorectal cancer where our targets are strong enough to get away from chemotherapy, but that is for a fairly rare subset. That decision—regarding when progression happens and what to switch to—it’s important to take a pause; don’t just go by the cookie-cutter next guideline step, think about what the best thing is for your patient.

This transcript has been edited for clarity.