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Role of Immunotherapy in Microsatellite-Stable R/R mCRC

Insights From: Marwan Fakih, MD, City of Hope Comprehensive Cancer Center; Axel Grothey, MD, West Cancer Center; Scott Kopetz, MD, PhD, The University of Texas MD Anderson Cancer Center
Published: Wednesday, Mar 25, 2020



Transcript: 

Marwan Fakih, MD: Is there a role for immunotherapy in patients with metastatic colorectal cancer who have microsatellite stability [MSS]? We know that patients with microsatellite instability derive an excellent benefit, protracted progression-free survival, and major improvements in overall survival when we use immunotherapy in those patients. However, microsatellite-stable colon cancer, which constitutes about 95% of our patients with metastatic disease, has been a very tough patient population to help with immunotherapy. They do not respond well to immunotherapy. There have been many studies that have evaluated PD-1 [programmed cell death protein 1] targeting alone, such as nivolumab or atezolizumab, with PD-L1 [programmed death-ligand 1] targeting and have failed to show benefit in that population.

Recently, the Canadian Cancer Trials Group CO26 trial has evaluated a different approach in combining both a PD-L1 inhibitor, durvalumab, with a CTLA4 inhibitor, tremelimumab, in hopes of having a combination immunotherapy approach as an effective approach in targeting patients with microsatellite stability. This is an important study because it’s a relatively large study. It’s 180 patients, but you have to note that this was actually a randomized phase II trial. It was a 2:1 randomized study where two-thirds of the patients would receive combination immunotherapy and one-third best supportive care. The study was designed with a 10% possible error.

The study showed an improvement in overall survival of 2½ months in favor of immunotherapy, saying that the P value there was .07, which is less than the 10% error with the P value set at .1. Therefore, technically it’s a positive study. But it’s a positive phase II trial where there were practically no responses, and there was no improvement in progression-free survival. What’s somewhat surprising is that we’ve seen patients without an improvement in progression-free survival, yet they derived a benefit in overall survival of 2½ months. Still, these patients didn’t fare extremely well, and the median overall survival was still in the range of 6 months with the combination immunotherapy.

Is this enough evidence to use combination immunotherapy in microsatellite stability? No. Does this provide me hope that there are potential ways of accentuating further the benefits of checkpoint inhibitors in the future by looking at different combinations? Yes. I think the Canadian trial is a landmark trial, as far as giving us hope that immunotherapy should still have potentially a role in microsatellite stability but certainly not enough to implement it in standard practice at this time.

Scott Kopetz, MD: One of the combinations of interest is the regorafenib and nivolumab study. This was based on a study that came out of Japan looking at a series of patients with colorectal cancer treated with this combination. These patients were refractory, almost all MSS: microsatellite-stable patients. When the combination was given, a response rate of 30% or slightly more was seen in colorectal cancer and in gastric cancer as well. This is a striking finding. Many of these appeared to be durable responders, and there’s been interest in trying to replicate that moving forward in future studies. We’ll need to see those results before we’re ready to act on those, but there are a number of phase II studies with this concept that are ongoing, and a randomized phase III that may be launching soon as well.

Axel Grothey, MD: The question of what does the addition of PD-1, PD-L1 antibody to chemotherapy, and potentially with the EGF receptor antibody contribute in patients with MSS colorectal cancer is of course of interest. We have very limited data suggesting that MSS colorectal cancer can be immunogenic at all. All attempts so far have actually failed to show that MSS colorectal cancer would respond to immunotherapy alone. There are data from the MODUL study, which looked at a combination of bevacizumab, 5-FU [5-fluorouracil], and atezolizumab in a maintenance therapy setting. No signal at all.

Now, using a combination of avelumab, cetuximab, and FOLFOX [folinic acid, 5-fluorouracil, oxaliplatin] up front was interrogated in a German study of about 40 patients. They showed response rates that are on the high end of what we normally see—about 75% to 80%. But the question is, what is really contributing to the response rate here? What’s the active component of the treatment when you have a doublet chemotherapy and cetuximab in a RAS-selected patient population? I’m not quite sure what we really understand of whether the addition of avelumab to the other agents actually made a difference in this study.

Transcript Edited for Clarity
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Transcript: 

Marwan Fakih, MD: Is there a role for immunotherapy in patients with metastatic colorectal cancer who have microsatellite stability [MSS]? We know that patients with microsatellite instability derive an excellent benefit, protracted progression-free survival, and major improvements in overall survival when we use immunotherapy in those patients. However, microsatellite-stable colon cancer, which constitutes about 95% of our patients with metastatic disease, has been a very tough patient population to help with immunotherapy. They do not respond well to immunotherapy. There have been many studies that have evaluated PD-1 [programmed cell death protein 1] targeting alone, such as nivolumab or atezolizumab, with PD-L1 [programmed death-ligand 1] targeting and have failed to show benefit in that population.

Recently, the Canadian Cancer Trials Group CO26 trial has evaluated a different approach in combining both a PD-L1 inhibitor, durvalumab, with a CTLA4 inhibitor, tremelimumab, in hopes of having a combination immunotherapy approach as an effective approach in targeting patients with microsatellite stability. This is an important study because it’s a relatively large study. It’s 180 patients, but you have to note that this was actually a randomized phase II trial. It was a 2:1 randomized study where two-thirds of the patients would receive combination immunotherapy and one-third best supportive care. The study was designed with a 10% possible error.

The study showed an improvement in overall survival of 2½ months in favor of immunotherapy, saying that the P value there was .07, which is less than the 10% error with the P value set at .1. Therefore, technically it’s a positive study. But it’s a positive phase II trial where there were practically no responses, and there was no improvement in progression-free survival. What’s somewhat surprising is that we’ve seen patients without an improvement in progression-free survival, yet they derived a benefit in overall survival of 2½ months. Still, these patients didn’t fare extremely well, and the median overall survival was still in the range of 6 months with the combination immunotherapy.

Is this enough evidence to use combination immunotherapy in microsatellite stability? No. Does this provide me hope that there are potential ways of accentuating further the benefits of checkpoint inhibitors in the future by looking at different combinations? Yes. I think the Canadian trial is a landmark trial, as far as giving us hope that immunotherapy should still have potentially a role in microsatellite stability but certainly not enough to implement it in standard practice at this time.

Scott Kopetz, MD: One of the combinations of interest is the regorafenib and nivolumab study. This was based on a study that came out of Japan looking at a series of patients with colorectal cancer treated with this combination. These patients were refractory, almost all MSS: microsatellite-stable patients. When the combination was given, a response rate of 30% or slightly more was seen in colorectal cancer and in gastric cancer as well. This is a striking finding. Many of these appeared to be durable responders, and there’s been interest in trying to replicate that moving forward in future studies. We’ll need to see those results before we’re ready to act on those, but there are a number of phase II studies with this concept that are ongoing, and a randomized phase III that may be launching soon as well.

Axel Grothey, MD: The question of what does the addition of PD-1, PD-L1 antibody to chemotherapy, and potentially with the EGF receptor antibody contribute in patients with MSS colorectal cancer is of course of interest. We have very limited data suggesting that MSS colorectal cancer can be immunogenic at all. All attempts so far have actually failed to show that MSS colorectal cancer would respond to immunotherapy alone. There are data from the MODUL study, which looked at a combination of bevacizumab, 5-FU [5-fluorouracil], and atezolizumab in a maintenance therapy setting. No signal at all.

Now, using a combination of avelumab, cetuximab, and FOLFOX [folinic acid, 5-fluorouracil, oxaliplatin] up front was interrogated in a German study of about 40 patients. They showed response rates that are on the high end of what we normally see—about 75% to 80%. But the question is, what is really contributing to the response rate here? What’s the active component of the treatment when you have a doublet chemotherapy and cetuximab in a RAS-selected patient population? I’m not quite sure what we really understand of whether the addition of avelumab to the other agents actually made a difference in this study.

Transcript Edited for Clarity
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