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I-O Therapy in mCRC: Ipilimumab + Nivolumab

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 instable [MSI] colorectal cancer, we have seen benefits of immunotherapy. We do have multiple FDA approvals for these patients of agents, including pembrolizumab, nivolumab, and now nivolumab plus ipilimumab. We see single-agent response rates in the range of 30% to 50% for patients with PD-1 inhibitors, and we also know that patients who respond to these PD-1 inhibitors tend to have very prolonged responses.

The CheckMate-142 study looked both at single-agent nivolumab and nivolumab plus ipilimumab. The 2 arms weren’t meant to be compared to each other, they just enrolled side-by-side. Very interestingly, the nivolumab-plus-ipilimumab data showed a response rate of about 55% and showed a 1-year overall survival of over 85%, which is very significant for patients with advanced colorectal cancer and probably the basis of nivolumab/ipilimumab being approved for this subset of patients.

We do see toxicities with immunotherapies. The combination of nivolumab plus ipilimumab for patients with colorectal cancer is a dosing of nivolumab 3, ipilimumab 1. You only receive ipilimumab for a certain prescribed period of time. We do see some increased toxicities with the combination as compared to the single agent, mostly noted in terms of colitis. We are educating our patients and educating other physicians about potential toxicities from immunotherapy, which can include thyroiditis that then leads into a hypothyroidism. We have diarrhea and colitis. We have pneumonitis, hepatitis, and all different kinds of autoimmune-type effects.

We definitely have to monitor patients. We monitor their thyroid carefully. We look for rashes. We tell people to let us know if they have any more shortness of breath or if they’re having diarrhea. We’ve monitored their liver function tests and their other less common ‘itises,’ autoimmune effects that we see, like myocarditis and hypophysitis. We always have to keep those in mind if our patients on immune therapy are having any type of toxicity. Typically, these are treated with stopping the immunotherapy; starting steroids, usually 1 mg/kg of prednisone or 2 mg/kg of prednisone with slow tapers; and then monitoring these patients very carefully for resolution.

Tanios Bekaii-Saab, MD: Recently, the FDA has approved nivolumab plus ipilimumab for patients with MSI [microsatellite instability]–high colorectal cancer. My big problem with this study is that it really hasn’t randomized patients with nivolumab plus ipilimumab versus nivolumab. When I look at this study, I really can’t tell which patients need the 2 drugs versus the 1 drug. Now, this is why it’s important. When you have the 2-drug combination, you end up adding significant toxicities and significant cost. But I’m not sure that you’re adding superior efficacy, because they’ve never been compared. It makes it very difficult to really understand how to position this dual-inhibitor regimen of dual-checkpoint blockade.

The same applies when if you want to compare it historically to pembrolizumab. Now, that’s only applicable to colorectal cancer. MSI-high tumors are a type of colorectal cancer that only had 1 indication, pembrolizumab. For colorectal cancer now, we have nivolumab, pembrolizumab, and ipilimumab plus nivolumab. From my standpoint, for any patient with an MSI-high tumor, I would treat them with nivolumab or pembrolizumab. I would not go for the dual inhibitor.

The dual inhibitor will only come to play for those patients who may have a response initially and then escape that response. I may then try the doublet, the dual inhibitor, in those patients. I don’t feel compelled right now to use the 2 drugs instead of the 1 drug, primarily because cost, toxicity, and a lack of comparative efficacy or superior efficacy. We don’t know that. To expose my patients to the effects of the 2 drugs, I have to have a study that tells me it’s better than 1 drug. Historically, it seems maybe a little bit better, but it’s impossible to say without comparing the 2 regimens.

The standard in clinic is PD-1 inhibition, so nivolumab or pembrolizumab. And for those patients who fail after an initial response—we’ll talk about the nonresponders—those patients would become eligible for the 2-drug regimen. Those who fail immediately are unlikely to respond to immunotherapy, dual or not. Those patients would probably go a different path. It could be another immune therapy, studies that we have on hand, or back to chemotherapy.

Transcript Edited for Clarity.
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Transcript:

Johanna C. Bendell, MD: For patients with microsatellite instable [MSI] colorectal cancer, we have seen benefits of immunotherapy. We do have multiple FDA approvals for these patients of agents, including pembrolizumab, nivolumab, and now nivolumab plus ipilimumab. We see single-agent response rates in the range of 30% to 50% for patients with PD-1 inhibitors, and we also know that patients who respond to these PD-1 inhibitors tend to have very prolonged responses.

The CheckMate-142 study looked both at single-agent nivolumab and nivolumab plus ipilimumab. The 2 arms weren’t meant to be compared to each other, they just enrolled side-by-side. Very interestingly, the nivolumab-plus-ipilimumab data showed a response rate of about 55% and showed a 1-year overall survival of over 85%, which is very significant for patients with advanced colorectal cancer and probably the basis of nivolumab/ipilimumab being approved for this subset of patients.

We do see toxicities with immunotherapies. The combination of nivolumab plus ipilimumab for patients with colorectal cancer is a dosing of nivolumab 3, ipilimumab 1. You only receive ipilimumab for a certain prescribed period of time. We do see some increased toxicities with the combination as compared to the single agent, mostly noted in terms of colitis. We are educating our patients and educating other physicians about potential toxicities from immunotherapy, which can include thyroiditis that then leads into a hypothyroidism. We have diarrhea and colitis. We have pneumonitis, hepatitis, and all different kinds of autoimmune-type effects.

We definitely have to monitor patients. We monitor their thyroid carefully. We look for rashes. We tell people to let us know if they have any more shortness of breath or if they’re having diarrhea. We’ve monitored their liver function tests and their other less common ‘itises,’ autoimmune effects that we see, like myocarditis and hypophysitis. We always have to keep those in mind if our patients on immune therapy are having any type of toxicity. Typically, these are treated with stopping the immunotherapy; starting steroids, usually 1 mg/kg of prednisone or 2 mg/kg of prednisone with slow tapers; and then monitoring these patients very carefully for resolution.

Tanios Bekaii-Saab, MD: Recently, the FDA has approved nivolumab plus ipilimumab for patients with MSI [microsatellite instability]–high colorectal cancer. My big problem with this study is that it really hasn’t randomized patients with nivolumab plus ipilimumab versus nivolumab. When I look at this study, I really can’t tell which patients need the 2 drugs versus the 1 drug. Now, this is why it’s important. When you have the 2-drug combination, you end up adding significant toxicities and significant cost. But I’m not sure that you’re adding superior efficacy, because they’ve never been compared. It makes it very difficult to really understand how to position this dual-inhibitor regimen of dual-checkpoint blockade.

The same applies when if you want to compare it historically to pembrolizumab. Now, that’s only applicable to colorectal cancer. MSI-high tumors are a type of colorectal cancer that only had 1 indication, pembrolizumab. For colorectal cancer now, we have nivolumab, pembrolizumab, and ipilimumab plus nivolumab. From my standpoint, for any patient with an MSI-high tumor, I would treat them with nivolumab or pembrolizumab. I would not go for the dual inhibitor.

The dual inhibitor will only come to play for those patients who may have a response initially and then escape that response. I may then try the doublet, the dual inhibitor, in those patients. I don’t feel compelled right now to use the 2 drugs instead of the 1 drug, primarily because cost, toxicity, and a lack of comparative efficacy or superior efficacy. We don’t know that. To expose my patients to the effects of the 2 drugs, I have to have a study that tells me it’s better than 1 drug. Historically, it seems maybe a little bit better, but it’s impossible to say without comparing the 2 regimens.

The standard in clinic is PD-1 inhibition, so nivolumab or pembrolizumab. And for those patients who fail after an initial response—we’ll talk about the nonresponders—those patients would become eligible for the 2-drug regimen. Those who fail immediately are unlikely to respond to immunotherapy, dual or not. Those patients would probably go a different path. It could be another immune therapy, studies that we have on hand, or back to chemotherapy.

Transcript Edited for Clarity.
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