Evolving Strategies for Advanced Colon and Rectal Cancer - Episode 14

Immunotherapy Combinations in MSI and MSS mCRC


John L. Marshall, MD: Wells, is there anything new out there? Any drugs coming down the pike?

Wells A. Messersmith, MD, FACP: There are. Most of them, I must say, the immunotherapies or a fever continues to be very compelling to both patients and physicians, and there really are hardly any consults I do nowadays where that doesn’t come up. Colorectal cancer, for whatever reason, has been resistant to immunotherapy.

John L. Marshall, MD: Non-MSI, MSS, though.

Wells A. Messersmith, MD, FACP: MSS, correct—the most common subtype. And so, I’m seeing a lot of combination studies coming; I’m seeing a lot of novel agents by specific antibodies, antibody-drug conjugates, etc. However, at least at ASCO 2018, we’re not seeing anything presented that’s sort of groundbreaking quite yet, but we’ll see what happens.

The trial looking at the STAT3 inhibitor ended up being a negative trial. There’s this question of phospho STAT3 maybe picking out a subtype of patients who benefit. But it’s always hard to know how to move that type of thing forward. And if you think about it, when has a phospho antibody really been a predictive marker that’s reliable?

John L. Marshall, MD: Bert, cobimetinib and atezolizumab got everybody excited with a few responses in a phase II study and a large phase III international trial that was done. A press release reported that it was negative but full data to come. This is obviously disappointing. Should we keep pursuing these kinds of combination immunotherapy approaches?

Bert H. O’Neil, MD: I think we have to. You know this has been such a game changer in other types of cancer, and then I think we’ll eventually figure it out.

John L. Marshall, MD: So, you think we’ll convert these cold tumors to somehow hot if we just figure out the right way to do it.

Bert H. O’Neil, MD: Well, you know, these things are hard to predict. Right now, we didn’t predict the PD-1 antibodies until just a few years ago. So, I certainly think we should continue to study that; we shouldn’t give up on that.

John L. Marshall, MD: How about the nivolumab/ipilimumab data with MSI-high colorectal cancer, which showed a nice response rate? Does this mean we should go there when we find one of those patients with metastatic IMiDs-high colon cancer?

Gabriela Chiorean, MD: I currently use pembrolizumab for the MSI-high patients, or nivolumab. I haven’t really gone to the nivolumab/ipilimumab to CTLA4 inhibitor. I still feel that the differences are small. Again, some may argue that maybe the durability of responses is better with CTLA4 inhibition, but I also feel that the toxicities are significantly higher, too. So, I’m not, again, sold on…the nivolumab/ipilimumab in MSI-high colorectal cancer.

John L. Marshall, MD: Wells is going to put a dollar sign in front if you.

Wells A. Messersmith, MD, FACP: Well, no. I think of it a little bit like FOLFIRINOX or FOLFOXIRI—do you need a response, and how quickly do you need a response? So, from my standpoint, given the extra 15% to 20% points of response that you get when you add the CTLA4, if a patient’s symptomatic or having other issues, then I might add it on, knowing I’m probably going to get more adverse effects. And then, if not, I think I can get away with the single agent. I think one of the interesting things about these studies in MSI high is that the response rates and the benefit have slowly dropped with each meeting. You know, when it first was reported, this was a total miracle drug. And I must say, I’ve seen responses in the clinic I’ve never seen before, and I don’t know when to stop. To me, that’s going to be one of the interesting questions: When can we stop these therapies? But I would say overall, in the past year, the efficacy has been tempered a little bit from what we initially saw with single-agent PD-1 or PD-L1.

Transcript Edited for Clarity.