Case 4: Standard of Care and Second-Line Therapy for mCRC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDShubham Pant, MD:Richard, this patient comes in. You tested upfront and they do have microsatellite instability [MSI]. Will you give them immunotherapy upfront? If so, which one?

Richard Kim, MD:So as of…

Shubham Pant, MD:I gave you the tough question, I’m sorry.

Richard Kim, MD:Yes. For patients who are MSI-high, I still think that the standard is to give chemotherapy upfront. Chemotherapy works quicker. Immunotherapy, on average, takes 2 to 3 months to respond. So therefore, unless there’s a trial that shows that immunotherapy is better or is equal to chemotherapy, because of tolerability I will still go with chemotherapy upfront. Once they fail first-line therapy, that’s when I would consider using immunotherapy as a second-line therapy. But I think to this day, I need to see additional data to use immunotherapy upfront.

Also, one must be aware that it’s not indicated either. So an insurance company is not going to pay for a checkpoint inhibitor in the first-line setting. I guess you could make the case that older patients, such as an 80-year-old with an ECOG [Eastern Cooperative Oncology Group] performance status of 1 to 2, may not even be able to tolerate capecitabine with Avastin [bevacizumab]. Maybe those patients would benefit from a checkpoint inhibitor as a single agent? That’s unclear. But to this date, it’s not reimbursable. At least in the first-line setting, I will still use chemotherapy first.

Shubham Pant, MD:I have a tough question for you. Now this patient has progressed on the frontline chemotherapy that Richard has given. When they come to you after they have been treated with frontline chemotherapy, would you use a single checkpoint inhibitor? Would you use a CTLA-4 [cytotoxic T-lymphocyte—associated protein 4] combination? When do you decide that? Would you use single-agent nivolumab or pembrolizumab, or would you use a combination of ipilimumab or nivolumab?

Michael Morse, MD:This is in the process of being evaluated right now. The CheckMate-142 trial was not specifically a randomized study. When you compare the nivolumab results with nivolumab plus ipilimumab results, they are put on the same graph. People should understand that even though the results looked superior with the combination, we still haven’t fully worked out who those people are that truly get more benefit.

The other important thing is this regimen uses the nivolumab 3 mg/kg and ipilimumab 1 mg/kg, which is a very tolerable combination. More people are probably acquainted with the nivolumab 1 mg/kg and ipilimumab 3 mg/kg regimens, which are sometimes given for other malignancies. And so, again, until that’s completely worked out, I think single-agent therapy is probably the preferred way to go for most people.

Shubham Pant, MD:Richard, what is your preferred option?

Richard Kim, MD:I agree. Once again, there are no head-to-head studies so you cannot say that the doublet is better than a single-agent checkpoint inhibitor. The response rate seems to be a bit higher—50%. But that’s in cost of adverse events. Grade 3/4 adverse events seem to be a bit higher for the doublet as well. So for the bulk of patients, I would use single-agent checkpoint inhibitors. If the patient progresses to second-line therapy and they’re symptomatic from the disease and you want to induce response, maybe doing the doublet is reasonable. They’re both approved at this moment, so you have a choice. Because the single-agent checkpoint inhibitor is very well tolerated without many grade 3/4 adverse events, that was my first choice. However, in certain patients, if they have tumor burden—in a downstage case or if they are symptomatic from the rectal tumor—that’s when I would possibly use a doublet regimen.

Shubham Pant, MD:I’m going to throw a curveball. Mike, if the patient is microsatellite unstable and you test them and they’ve got aBRAFmutation, how would you sequence your therapies? What would you do in the second-line setting?

Michael Morse, MD:The highest response rates that we’re seeing are in the MSI-high patients who get the checkpoint blockade. So I think that clearly would be the preferred regimen.

Shubham Pant, MD:Richard?

Richard Kim, MD:I agree. I think MSI takes precedence over theBRAFmutation.

Michael Morse, MD:In CheckMate-142,BRAFmutational burden did not dictate whether people did or didn’t respond to the checkpoint blockade. So it’s an issue to consider for later, perhaps, if the person progresses.

Shubham Pant, MD:I think these are really good points. The take-home points from our discussion are: in the frontline setting, we should be checking this in all patients. We should at least be doing an IHC [immunohistochemistry] to look for microsatellite instability. We should be thinking about their family history all the time. We should take a detailed family history to see if the patient needs to be referred to a genetic counselor. A patient may have a different mutation from one normally found in colorectal cancer. It’s also very important to recognize that these checkpoint inhibitors are truly transformational for the small percentage. About 5% of patients in the metastatic setting are MSI-high; versus earlier stages where it’s higher. In the metastatic setting, about 4% to 5% of these patients have MSI-high disease. In the second-line setting, they are eligible for a checkpoint inhibitor. If they’re MSI-high, we should check for aBRAFmutation because that could be a sporadic case and not a germline case of MSI-high disease.

Also, look at the toxicities of the immunotherapies. They’re different from what we are used to. Look for pneumonitis, colitis, hepatitis, and all of these toxicities that may occur with these immunotherapies. We should all be well-versed on these toxicities.

This has been a great discussion. Thank you so much. I want to thank Dr. Morse, Dr. Kim, and Dr. Riedlinger for your insight and a really good discussion. To our viewing audience, thank you for joining us for thisTargeted Oncology Expert Perspective Virtual Tumor Board^®presentation. We hope that you found this discussion to be informative and that you have acquired some practical knowledge to share with your patients in your clinic.

Transcript edited for clarity.