The Biology of Extending Survival in Advanced CRC - Episode 15

CRC: Emerging Immunotherapy Strategies in MSS Tumors


John L. Marshall, MD: Let’s shift gears one last time and talk about the emerging data that are coming out. While we’re talking about immunotherapy, Tony, give us a little bit of a high-level overview of how we treat microsatellite stable patients with immunotherapy? What is some of the science going on in that direction?

Tanios Bekaii-Saab, MD: Those are the 95-percenters—essentially, everybody else—who, unfortunately for those patients, single-agent PD-1 inhibitors or PD-L1 inhibitors do not have much activity. I can’t say it’s 0%, but it’s close to 0%. These are less-hypermutated patients. They’re actually hypomutated, for the most part, so there is less mutational burden. They don’t have these infiltrating lymphocytes around the tumors, which are important for these PD-1 inhibitors to do the job. So, we’re finding strategies to introduce agents like the MEK inhibitors. Most strategies include beta-catenin inhibitors, and, actually, agents like regorafenib, for example, which hits multiple targets and seems to enrich the tumor with these TILs. So, a lot of these strategies are being looked at, in clinic, in combining a PD-1 inhibitor or PD-L1 inhibitor with one of those agents. The one that’s farthest out is, essentially, the study with atezolizumab and cobimetinib, which showed promising data in the phase Ib trial and then moved to a phase III trial.

John L. Marshall, MD: I just want to point this out: in terms of a changing landscape, that study showed what, 4.5 responses?

Tanios Bekaii-Saab, MD: Yes. It was 21% if you count the 1 patient that essentially didn’t have the MSI status.

John L. Marshall, MD: Right, so we don’t know about that 1. That’s why the half number is there.

Tanios Bekaii-Saab, MD: We don’t know that, so, really, 3 responders ends up being about 17%.

John L. Marshall, MD: And, then, they launched this huge study to look at this.

Tanios Bekaii-Saab, MD: The PFS is not impressive. The PFS was what you would expect from regorafenib or from TAS-102. But, what was interesting was—and this is where I think it will be interesting to see the results of the phase III trial—whether or not those few patients who seem to benefit tremendously will be able to pull that curve and pull that median in a positive direction, at least in the survival curve. I don’t know about for the PFS curve—if it’s going to look any different—but we’ll see.

John L. Marshall, MD: Other comments? We’ve got radiation being given to try and induce more neoantigens or to expose. Chemotherapy combinations are being done around other biologics and targeted agents. So, it’s easy for a patient to find a trial with 1 of these drugs if they’re a candidate, right?

Fortunato Ciardiello, MD, PhD: Yes.

John L. Marshall, MD: Does anybody know the answer yet? It’s exciting. It’s very easy to enroll into these trials. Patients want them, but the reality out there is we aren’t moving the bar that quickly, right? Is that fair?

Tanios Bekaii-Saab, MD: That’s a fair assessment, yes.

Transcript Edited for Clarity