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Treatment Options in Refractory mCRC

CRC Insights (ASCO GI 2018) 0 2/16/18 Insights From:Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center; Zev A. Wainberg, MD, David Geffen School of Medicine at UCLA
Published: Tuesday, Feb 20, 2018



Transcript: 

Andrea Cercek, MD: Options for patients in the third-line setting depend a bit on their molecular genomics. In patients who are MSI-high, we have approved therapies— Keytruda (pembrolizumab) and nivolumab. Often, if they have progressed after first-line and second-line therapy and have not been exposed to immunotherapy, that’s what we would consider. In our patients who are all–RAS wild-type, we think about anti-EGFR therapy cetuximab or panitumumab with or without irinotecan.  

In patients who are RAS-mutated, which is roughly 50% of our patients, the options include a clinical trial with either targeted agents or immunotherapy combinations. The large majority of our patients are MSS (microsatellite stable), and do not benefit from single-agent immunotherapy. In this case, we look for clinical trials. There are several ongoing trials that are looking at combinations—immunotherapy plus targeted agents, plus a type of stimulus that might stimulate the immune response. Or, of course, we have our standard approved therapies for refractory disease—Stivarga (regorafenib) and Lonsurf (trifluridine/tipiracil).
For many patients, it’s really about maintaining quality of life. A lot of our decisions include deciding what will give the best quality of life. Of course, we also consider duration to be incredibly important. But, it really is important that patients suffer as few side effects as possible, and are able to live a good quality of life for whatever the duration might be, at that point.

Tanios Bekaii-Saab, MD, FACP: We have 2 options for our patients with refractory metastatic colorectal cancer, assuming that we don’t have a clinical trial available that’s specific for colon cancer. Oftentimes, you think about clinical trials as phase I, nonspecific. I think all of these trials have their roles. But, both TAS-102 and regorafenib are part of our standard. Both would be considered as standard of care treatment options. The question is, how do you choose one versus the other?

There is no data that compares one versus the other. We do not have randomized trials that inform and teach us about which one to start with. We have some data here and there, and some more emerging data from ASCO’s 2018 Gastrointestinal Cancers Symposium, that gives us a hint about some kind of sequencing.

The RECOURSE trial looked at TAS-102 versus best supportive care. A little less than 20% of patients received regorafenib before they received TAS-102, and the benefit of TAS-102 was not compromised by prior exposure to regorafenib. We know that it’s a subset analysis, so it’s taken with a grain of salt.

We also know of a study with regorafenib from Asia that had patients with less pre-exposure to EGFR and VEGF inhibitors. That study showed that regorafenib may actually have a larger level of efficacy in patients who are less preexposed.

There’s also a study from ASCO’s 2018 Gastrointestinal Cancers Symposium that looked at treating patients with regorafenib in earlier lines of therapy. It was a phase II study, but the results looked somewhat better than those demonstrated in the historical CORRECT trial. So, all of these are hints.

Then, we have the REVERCE trial, also presented at ASCO’s 2018 Gastrointestinal Cancers Symposium, that suggested that the sequence of regorafenib before cetuximab, rather than the other way around—starting with cetuximab, and waiting on cetuximab to fail before going to regorafenib— produced a close to 6-month survival benefit. This was highly, statistically significant.

So, when we take all of this data and put it together, it becomes clear that it’s important to expose patients to as many lines of therapy as possible, as indicated, first. It’s also very important to consider regorafenib as an option for patients at the time for which it’s indicated, but not wait too long or far too long in the therapy, when you’re likely to lose benefit. That’s what we saw in the REVERCE trial. It was very interesting. The loss of benefit was clearer as you got into lower lines of therapies.

Zev A. Wainberg, MD: When patients are found to be MSI-high in colon cancer, we have 2 options that are approved for patients in the refractory setting—nivolumab and pembrolizumab. Both are FDA approved, and both have been studied extensively. At this year’s meeting, we saw some data with nivolumab. It showed long-term survival numbers, which are quite impressive. With pembrolizumab, we’ve seen that data before. It’s already published in several journals.

So, fundamentally, you have 2 options. From my perspective, it’s hard to distinguish between the two. They both have fairly equivalent response rates and fairly equivalent toxicity profiles. We find it reassuring, as oncologists, when 2 drugs really have very similar clinical activity. The decision between nivolumab and pembrolizumab, in this setting, in my opinion, is fairly arbitrary. It’s based on features that are outside of the data, perhaps. It is based more on individual practitioner preference and experience with those agents. So, it’s good to have 2 options. We happen to have 2 FDA-approved drugs for that indication. Both nivolumab and pembrolizumab are active and useful.

We are used to giving checkpoint inhibitors. Now, many of us are giving them in colorectal cancer. Admittedly, with MSI-high disease, this is not very common, and is, perhaps, overstated in the literature. We assume that it’s somewhere in the 4% range for patients with metastatic disease. The use of checkpoint inhibitors in colorectal cancer for MSI is really exclusively for the metastatic setting. So, we’re looking at about 4% of all-comers that have true MSI.

Some people report a little higher. Some people report a little less. But, we know that as patients progress through colon cancer, it’s a little less likely to have MSI-high status. When we look at toxicities of these drugs, again, there’s not much to distinguish between nivolumab and pembrolizumab. There’s toxicities that are typical for any immunotherapy drug, which include fatigue, of course. There are the immune-related side effects, which are also fairly indistinguishable between nivolumab and pembrolizumab.  These include the typical ones, such as thyroiditis, which can occur with possible elevations in AST (aspartate aminotransferase) and ALT (alanine aminotransferase).

Then, there are some very rare but dangerous side effects, which include pneumonitis, pancreatitis, which has now been increasingly reported, and hyperglycemia. All of these events seem to be somehow related to autoimmune types of side effects. When recognized early, they can be treated. Some management strategies are required when continuing those drugs.

Transcript Edited for Clarity 
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Transcript: 

Andrea Cercek, MD: Options for patients in the third-line setting depend a bit on their molecular genomics. In patients who are MSI-high, we have approved therapies— Keytruda (pembrolizumab) and nivolumab. Often, if they have progressed after first-line and second-line therapy and have not been exposed to immunotherapy, that’s what we would consider. In our patients who are all–RAS wild-type, we think about anti-EGFR therapy cetuximab or panitumumab with or without irinotecan.  

In patients who are RAS-mutated, which is roughly 50% of our patients, the options include a clinical trial with either targeted agents or immunotherapy combinations. The large majority of our patients are MSS (microsatellite stable), and do not benefit from single-agent immunotherapy. In this case, we look for clinical trials. There are several ongoing trials that are looking at combinations—immunotherapy plus targeted agents, plus a type of stimulus that might stimulate the immune response. Or, of course, we have our standard approved therapies for refractory disease—Stivarga (regorafenib) and Lonsurf (trifluridine/tipiracil).
For many patients, it’s really about maintaining quality of life. A lot of our decisions include deciding what will give the best quality of life. Of course, we also consider duration to be incredibly important. But, it really is important that patients suffer as few side effects as possible, and are able to live a good quality of life for whatever the duration might be, at that point.

Tanios Bekaii-Saab, MD, FACP: We have 2 options for our patients with refractory metastatic colorectal cancer, assuming that we don’t have a clinical trial available that’s specific for colon cancer. Oftentimes, you think about clinical trials as phase I, nonspecific. I think all of these trials have their roles. But, both TAS-102 and regorafenib are part of our standard. Both would be considered as standard of care treatment options. The question is, how do you choose one versus the other?

There is no data that compares one versus the other. We do not have randomized trials that inform and teach us about which one to start with. We have some data here and there, and some more emerging data from ASCO’s 2018 Gastrointestinal Cancers Symposium, that gives us a hint about some kind of sequencing.

The RECOURSE trial looked at TAS-102 versus best supportive care. A little less than 20% of patients received regorafenib before they received TAS-102, and the benefit of TAS-102 was not compromised by prior exposure to regorafenib. We know that it’s a subset analysis, so it’s taken with a grain of salt.

We also know of a study with regorafenib from Asia that had patients with less pre-exposure to EGFR and VEGF inhibitors. That study showed that regorafenib may actually have a larger level of efficacy in patients who are less preexposed.

There’s also a study from ASCO’s 2018 Gastrointestinal Cancers Symposium that looked at treating patients with regorafenib in earlier lines of therapy. It was a phase II study, but the results looked somewhat better than those demonstrated in the historical CORRECT trial. So, all of these are hints.

Then, we have the REVERCE trial, also presented at ASCO’s 2018 Gastrointestinal Cancers Symposium, that suggested that the sequence of regorafenib before cetuximab, rather than the other way around—starting with cetuximab, and waiting on cetuximab to fail before going to regorafenib— produced a close to 6-month survival benefit. This was highly, statistically significant.

So, when we take all of this data and put it together, it becomes clear that it’s important to expose patients to as many lines of therapy as possible, as indicated, first. It’s also very important to consider regorafenib as an option for patients at the time for which it’s indicated, but not wait too long or far too long in the therapy, when you’re likely to lose benefit. That’s what we saw in the REVERCE trial. It was very interesting. The loss of benefit was clearer as you got into lower lines of therapies.

Zev A. Wainberg, MD: When patients are found to be MSI-high in colon cancer, we have 2 options that are approved for patients in the refractory setting—nivolumab and pembrolizumab. Both are FDA approved, and both have been studied extensively. At this year’s meeting, we saw some data with nivolumab. It showed long-term survival numbers, which are quite impressive. With pembrolizumab, we’ve seen that data before. It’s already published in several journals.

So, fundamentally, you have 2 options. From my perspective, it’s hard to distinguish between the two. They both have fairly equivalent response rates and fairly equivalent toxicity profiles. We find it reassuring, as oncologists, when 2 drugs really have very similar clinical activity. The decision between nivolumab and pembrolizumab, in this setting, in my opinion, is fairly arbitrary. It’s based on features that are outside of the data, perhaps. It is based more on individual practitioner preference and experience with those agents. So, it’s good to have 2 options. We happen to have 2 FDA-approved drugs for that indication. Both nivolumab and pembrolizumab are active and useful.

We are used to giving checkpoint inhibitors. Now, many of us are giving them in colorectal cancer. Admittedly, with MSI-high disease, this is not very common, and is, perhaps, overstated in the literature. We assume that it’s somewhere in the 4% range for patients with metastatic disease. The use of checkpoint inhibitors in colorectal cancer for MSI is really exclusively for the metastatic setting. So, we’re looking at about 4% of all-comers that have true MSI.

Some people report a little higher. Some people report a little less. But, we know that as patients progress through colon cancer, it’s a little less likely to have MSI-high status. When we look at toxicities of these drugs, again, there’s not much to distinguish between nivolumab and pembrolizumab. There’s toxicities that are typical for any immunotherapy drug, which include fatigue, of course. There are the immune-related side effects, which are also fairly indistinguishable between nivolumab and pembrolizumab.  These include the typical ones, such as thyroiditis, which can occur with possible elevations in AST (aspartate aminotransferase) and ALT (alanine aminotransferase).

Then, there are some very rare but dangerous side effects, which include pneumonitis, pancreatitis, which has now been increasingly reported, and hyperglycemia. All of these events seem to be somehow related to autoimmune types of side effects. When recognized early, they can be treated. Some management strategies are required when continuing those drugs.

Transcript Edited for Clarity 
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Community Practice Connections™: New Frontiers in Immuno-Oncology for Microsatellite Instability-High CancersAug 29, 20182.0
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