Emerging Immunotherapy Combinations in MSS CRC

Video

Transcript:

John L. Marshall, MD: Every one of us is guilty of what I am about to say. We have taken some sort of immunotherapy and, based on something that we found on Google, we have combined it with something else and threw it at patients. Combination immunotherapy is all the rage, and all of us have a portfolio of those trials that are open right now. Sorry? You were going to come right at me?

Cathy Eng, MD, FACP: Well, no. The data demonstrate that there are no responses, in certain situations, for single agents. So, that’s why we’re doing combinations.

John L. Marshall, MD: Fair enough. I totally get it. I get the excitement. The question is, has all of the low-lying fruit been plucked? Or, is there going to be some magic combination of therapy? You’re the furthest along because you’ve got a randomized study. Maybe you can give us an update on what we’re going to hear at this meeting? What is your gut feeling about these microsatellite-stable patients in colorectal cancer?

Johanna C. Bendell, MD: The issue is that microsatellite-high tumors have lymphocytes in them. So, when you look in the microscope, there they are. All you have to do is turn them on. For patients with microsatellite-stable disease, we have what we call the “immune desert” or “immunologically cold tumors,” where there’s not really any lymphocytes in there. Or, they’re surrounding the periphery of the tumor. But there’s nothing to turn on. The data that you’re referring to are the combination data of cobimetinib, which is a MEK inhibitor, plus atezolizumab, a PD-L1 inhibitor. Preclinically, when you give a MEK inhibitor, it increases intratumoral CD8-positive T cells and the expression of class 1 MHC (major histocompatibility complex), which means that the tumors are showing more of their antigens for the T cells to react to. You throw a little gasoline, in the form of atezolizumab, on the fire. Then, you can create immune response.

In data that were shown earlier, we saw about a 17%, 20% response rate in a small group of KRAS- mutated patients with colon cancer who were treated. The data that we’re going to be showing tomorrow are of a much larger set. There were 84 patients, and this includes patients who were KRAS wild-type as well as KRAS mutated. The response rate is now sitting at about 8%. But, interestingly enough, it doesn’t matter if you’re wild-type or mutant. We still see the same potential benefit.

John L. Marshall, MD: All of these were confirmed MSS, right?

Johanna C. Bendell, MD: Of the 7 patients who had PRs, 5 of them were confirmed MSS or MS-low, which is thought to behave like MSS. In 2 of them, we did not have the status for microsatellite. When we pull out the group of patients who were MSS and confirmed MSS, the response rate still sits at around 8%. But the median overall survival is about 13 months. So, a small population of patients are potentially helped by this. This showed us that it is potentially possible to convert a cold tumor into a hot tumor. Now, we have to build on that.

John L. Marshall, MD: We don’t absolutely know that those few patients wouldn’t have responded. Or, maybe we say that because we’ve tried it in other MSSs, we didn’t find them before?

Johanna C. Bendell, MD: Exactly.

John L. Marshall, MD: So, your argument is that the combination may have made these few patients respond?

Johanna C. Bendell, MD: Exactly.

Cathy Eng, MD, FACP: And, these were heavily pretreated patients.

Johanna C. Bendell, MD: Right. Most of the patients had at least 5 or more prior therapies.

John L. Marshall, MD: Yes. Mike, you’ve spent your career trying to make tumors hot, now that we’re thinking about it with immune-stimulation. Checkpoints are brake cutters. This is to turn it on. Do you see a window here—where checkpoints will make the therapies that you’ve been working on for the last 20 years more effective?

Michael A. Morse, MD: I sure hope so. I think you’re talking about the concept of either cancer vaccines or other immune-stimulatory approaches. There are other approaches for getting the T cells to the tumors. These are bispecific T-cell engagers. The point is, it’s very clear that if you don’t have T cells in the tumor, there is nothing for the checkpoint to work on. In our preclinical work, which we’ve published on, vaccines can increase the T-cell infiltrate and the T-cell type. It’s not just about getting any old T cell into the tumor. You pointed out that the CD8-positive T cells are the ones. There are other T cells that you don’t want—like regulatory T cells in the tumor. There are studies that are trying to inflame the tumors in that manner.

John L. Marshall, MD: We know about CAR T cells, bispecific monoclonal antibodies, and the growing of TILs and force-feeding them cancer. Does anybody have a recommendation for an investment to our listeners? What’s going to work here?

Cathy Eng, MD, FACP: I think there are a lot of new, interesting drugs. We really just need to keep a look out for them. As long as the patient feels well and the labs are good, we should continue to put them on clinical trials and continue to try to encourage pharmaceutical companies to open more trials in the United States. We see a lot of great trials that are largely being done overseas. Yet, we have so many patients here in the United States who also need assistance.

John L. Marshall, MD: Yes. We love these kinds of trials because we’re hopeful and positive. But, I’d still have to say that my basic comment is that it feels like we’re just throwing everything at the wall and seeing what sticks.

Dale R. Shepard, MD, PhD, FACP: I think that’s true. The data you describe are really encouraging. If we can continue to do these things, to sort of make the current checkpoint inhibitors better, that is great. But I think it’s going to take another big break and another big way to modulate the immune system to really make an impact.

Transcript Edited for Clarity

Related Videos
A panel of 4 experts on colorectal cancer
A panel of 4 experts on colorectal cancer
A panel of 6 experts on colorectal cancer
A panel of 6 experts on colorectal cancer
Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center
A panel of 4 experts on colorectal cancer
A panel of 4 experts on colorectal cancer
A panel of 6 experts on colorectal cancer
A panel of 6 experts on colorectal cancer
Riccardo Lencioni, MD, FSIR, EBIR