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Other I-O Approaches to Metastatic Colorectal Cancer

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Johanna C. Bendell, MD, Sarah Cannon Research Institute
Published: Thursday, Oct 11, 2018



Transcript:

Johanna C. Bendell, MD: For patients with microsatellite stable colorectal cancer, we have not really been able to see any benefit from using immunotherapies. They’re what we think of as immunologically cold tumors. A lot of research has been focused on, can we convert cold tumors into immunotherapy-responsive tumors? One study that looked at trying to do this was a study that looked at the combination of atezolizumab plus cobimetinib, which is a MEK inhibitor. We saw cobimetinib preclinically increase the intratumoral CD8-positive T cells and increase expression of class I MHC [major histocompatibility complex], suggesting a more immune responsive environment of the tumor. Giving atezolizumab, the PD-L1 inhibitor, on top of it made a lot of sense to try to then drive the immune response.

There was a phase Ib study that looked at patients with refractory colorectal cancer, and we saw some responses in patients with microsatellite-stable disease to atezolizumab plus cobimetinib, and this led into a randomized phase III study that compared atezolizumab plus cobimetinib versus atezolizumab versus regorafenib.

We were all very excited for this study. It’s the first immunotherapy that might work for patients with microsatellite-stable disease. The study enrolled very quickly and revealed its results back in June of 2018. Unfortunately, what we saw in the study was that there was no difference between giving regorafenib alone or cobimetinib and atezolizumab. We think that cobimetinib and atezolizumab had some activity; it was just no better than regorafenib. Unfortunately, we didn’t see any benefit with this particular combination. But there are a lot more immunotherapy combinations that are being looked at right now for these patients. When we looked at the safety and efficacy of the combination of cobimetinib and atezolizumab, we really didn’t see anything different than the individual safety profiles. They were just combined on top of each other. We did see diarrhea from the cobimetinib, as well as rash and some fatigue.

Some people were particularly interested in the combination of atezolizumab plus cobimetinib for patients with RAS-mutated disease. We know that the MEK inhibitors hit downstream on RAS mutation, so there was some thought that patients with RAS-mutated disease may do better with the combination of atezolizumab and cobimetinib. Unfortunately, we didn’t see anything significant to point necessarily that way. We’re still doing a lot of biomarker analysis of the patients on this trial to see if there may be any signatures or if there might be anything that would point out to a particular subset of patients responding better. But with the trial being so negative, we hold that in reserve for now.

Tanios Bekaii-Saab, MD: The subgroup of patients with MSI [microsatellite instability]–high metastatic colorectal cancer, which amounts about 4% of patients with metastatic colorectal cancer, tends to have a high mutational burden. This is what we call tumor mutational burden–high. Now, not all tumor mutational burden–high patients are MSI-high, but there’s a nice overlap between the two, a quite significant overlap, and that’s important to know.

Patients with MSI-high disease across the board, not just for colorectal cancer, seem to respond exquisitely to these PD-1 inhibitors, specifically pembrolizumab, which has been looked at in colorectal and noncolorectal cancer, as well as non-GI [gastrointestinal] malignancies. Overall, the response rate was about 40% or greater, with a number of patients having complete responses. These responses tend to be curable. In fact, for many patients, there are years and years of response and stability. A lot of these responses eventually translate into complete responses, and some of the stable disease over time translates into PR [partial response]. It’s an ongoing response.

In our clinic, everyone with an adenocarcinoma gets checked for an MSI-high status. We also have the tumor mutational burden available as part of the genomic testing of the tumor. We have these elements, and then we must decide who is the patient who should receive pembrolizumab. In colon cancer, of course, that’s about 4% of patients.

In my clinic, I actually tend to bring those PD-1 inhibitors earlier in the line of therapy rather than wait for later lines of therapy. The responses and durability of responses that we see with these PD-1 inhibitors are unmatched by any chemotherapy-particular regimens I’ve used in these patients; therefore, I hate to waste the opportunity of exposing these patients in the first line, if possible. The indication is for the third line, and most folks do use it in the second- or third-line setting because that’s how it’s dictated by insurance. But the reality is that in studies ongoing now looking at first-line pembrolizumab versus chemotherapy, the reality is it’s very likely the PFS [progression-free survival] will be much more meaningful with pembrolizumab, at least historically. That’s how I see it when you compare the 2 versus chemotherapy.

Transcript Edited for Clarity.
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Transcript:

Johanna C. Bendell, MD: For patients with microsatellite stable colorectal cancer, we have not really been able to see any benefit from using immunotherapies. They’re what we think of as immunologically cold tumors. A lot of research has been focused on, can we convert cold tumors into immunotherapy-responsive tumors? One study that looked at trying to do this was a study that looked at the combination of atezolizumab plus cobimetinib, which is a MEK inhibitor. We saw cobimetinib preclinically increase the intratumoral CD8-positive T cells and increase expression of class I MHC [major histocompatibility complex], suggesting a more immune responsive environment of the tumor. Giving atezolizumab, the PD-L1 inhibitor, on top of it made a lot of sense to try to then drive the immune response.

There was a phase Ib study that looked at patients with refractory colorectal cancer, and we saw some responses in patients with microsatellite-stable disease to atezolizumab plus cobimetinib, and this led into a randomized phase III study that compared atezolizumab plus cobimetinib versus atezolizumab versus regorafenib.

We were all very excited for this study. It’s the first immunotherapy that might work for patients with microsatellite-stable disease. The study enrolled very quickly and revealed its results back in June of 2018. Unfortunately, what we saw in the study was that there was no difference between giving regorafenib alone or cobimetinib and atezolizumab. We think that cobimetinib and atezolizumab had some activity; it was just no better than regorafenib. Unfortunately, we didn’t see any benefit with this particular combination. But there are a lot more immunotherapy combinations that are being looked at right now for these patients. When we looked at the safety and efficacy of the combination of cobimetinib and atezolizumab, we really didn’t see anything different than the individual safety profiles. They were just combined on top of each other. We did see diarrhea from the cobimetinib, as well as rash and some fatigue.

Some people were particularly interested in the combination of atezolizumab plus cobimetinib for patients with RAS-mutated disease. We know that the MEK inhibitors hit downstream on RAS mutation, so there was some thought that patients with RAS-mutated disease may do better with the combination of atezolizumab and cobimetinib. Unfortunately, we didn’t see anything significant to point necessarily that way. We’re still doing a lot of biomarker analysis of the patients on this trial to see if there may be any signatures or if there might be anything that would point out to a particular subset of patients responding better. But with the trial being so negative, we hold that in reserve for now.

Tanios Bekaii-Saab, MD: The subgroup of patients with MSI [microsatellite instability]–high metastatic colorectal cancer, which amounts about 4% of patients with metastatic colorectal cancer, tends to have a high mutational burden. This is what we call tumor mutational burden–high. Now, not all tumor mutational burden–high patients are MSI-high, but there’s a nice overlap between the two, a quite significant overlap, and that’s important to know.

Patients with MSI-high disease across the board, not just for colorectal cancer, seem to respond exquisitely to these PD-1 inhibitors, specifically pembrolizumab, which has been looked at in colorectal and noncolorectal cancer, as well as non-GI [gastrointestinal] malignancies. Overall, the response rate was about 40% or greater, with a number of patients having complete responses. These responses tend to be curable. In fact, for many patients, there are years and years of response and stability. A lot of these responses eventually translate into complete responses, and some of the stable disease over time translates into PR [partial response]. It’s an ongoing response.

In our clinic, everyone with an adenocarcinoma gets checked for an MSI-high status. We also have the tumor mutational burden available as part of the genomic testing of the tumor. We have these elements, and then we must decide who is the patient who should receive pembrolizumab. In colon cancer, of course, that’s about 4% of patients.

In my clinic, I actually tend to bring those PD-1 inhibitors earlier in the line of therapy rather than wait for later lines of therapy. The responses and durability of responses that we see with these PD-1 inhibitors are unmatched by any chemotherapy-particular regimens I’ve used in these patients; therefore, I hate to waste the opportunity of exposing these patients in the first line, if possible. The indication is for the third line, and most folks do use it in the second- or third-line setting because that’s how it’s dictated by insurance. But the reality is that in studies ongoing now looking at first-line pembrolizumab versus chemotherapy, the reality is it’s very likely the PFS [progression-free survival] will be much more meaningful with pembrolizumab, at least historically. That’s how I see it when you compare the 2 versus chemotherapy.

Transcript Edited for Clarity.
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