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Biomarkers and Novel Approaches in CRC

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: Friday, Apr 06, 2018



Transcript: 

Tanios Bekaii-Saab, MD, FACP: We are learning much more about subsets, but we still have a long way to go in understanding the various subsets.

Right now, we do understand the importance of RAS mutations. We’re learning a lot more about BRAF mutations. We have studies targeting the BRAF pathway. BRAF, EGFR, and MEK inhibitors plus or minus chemotherapy are trying to improve the really bad outcomes that we see with BRAF-mutated tumors.

We also are seeing more and more studies addressing HER2 amplification. A subgroup of patients, 4% of patients with colon cancer, have HER2 amplifications. That group does not seem to respond well to EGFR inhibitors. But dual HER2 inhibition seems to produce some significant responses. There are trials underway in that group. We have MSI–high patients with significant responses to PD-1, PD-L1 inhibitors. Perhaps there is a role for CTLA-4? I’m not clear on that yet. And we’re starting to look at even smaller and smaller proportions of patients with colon cancer. In those that have FGFR, MET, or PIK3CA, we are trying to understand how these different baskets are prognostically driven and whether we can use them as predictive biomarkers for target therapies.

So, I think the landscape is changing quite significantly. And then, the CMS classification, itself, is starting to make its segue into mainstream clinical practice. There’s the BRAF-like group, for example, that will likely benefit the most from some form of immunotherapy; perhaps not PD-1 inhibitors directly, because we know those are not active in MSS cases, but likely some form of PD-1 plus another immunotherapy agent or a combination of other biologics and immunotherapeutics.

Andrea Cercek, MD: Some of the more important biomarkers that we’ve learned a lot about are the MSI-high hypermutated patients that benefit from immunotherapy. We’ve known about BRAF. There are now a number of studies in BRAF that are clearly showing a benefit with combination BRAF inhibitors, anti-EGFR therapy, as well as MEK inhibitors or irinotecan.

Beyond that, HER2 is one of the more exciting emerging markers. In HER2-amplified tumors, there appears to be a signal with anti-HER2 therapy in colorectal cancer. That accounts for approximately 3% to 4% of all metastatic colorectal cancer patients.

Zev A. Wainberg, MD: In the next few years, I think we will see efforts with additional biomarkers for later lines of colon cancer therapy—and even earlier lines. Besides microsatellite instability, which I think is a very clear biomarker for benefit of checkpoint inhibitors, there are others that are being looked at very aggressively. HER2, which is infrequent, only occurs in perhaps 1% to 2% of KRAS wild-type colon cancer. This may be a useful biomarker. In early studies, such as the HERACLES trial with trastuzumab and lapatinib, benefit has been shown in that group of patients. Studies have now been taken to the next level through Cooperative Group settings. They are trying to look at KRAS wild-type HER2 patients to see if there’s benefit to an anti-HER2 drug.

Additional studies are also being done in other biomarker subsets. This includes looking at the CMS classifications, CMS 1 through 4, and trying to see if any individual CMS subtype might be sensitive to an immunotherapeutic strategy, for example, or to additional strategies. At ASCO’s 2018 Gastrointestinal Cancers Symposium, we’ve seen some longer-term data with the combination of MEK inhibition and PD-L1 inhibition with atezolizumab; that may be a subset of patients. And there’s a lot of interest in a group of drugs that are CEA bispecific antibodies, looking at which subsets of those patients might get benefit as well. So, in the next few years, we are hopeful and optimistic that a new series of biomarkers will emerge that will allow us to treat these patients in a more directive fashion.

Transcript Edited for Clarity 
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Transcript: 

Tanios Bekaii-Saab, MD, FACP: We are learning much more about subsets, but we still have a long way to go in understanding the various subsets.

Right now, we do understand the importance of RAS mutations. We’re learning a lot more about BRAF mutations. We have studies targeting the BRAF pathway. BRAF, EGFR, and MEK inhibitors plus or minus chemotherapy are trying to improve the really bad outcomes that we see with BRAF-mutated tumors.

We also are seeing more and more studies addressing HER2 amplification. A subgroup of patients, 4% of patients with colon cancer, have HER2 amplifications. That group does not seem to respond well to EGFR inhibitors. But dual HER2 inhibition seems to produce some significant responses. There are trials underway in that group. We have MSI–high patients with significant responses to PD-1, PD-L1 inhibitors. Perhaps there is a role for CTLA-4? I’m not clear on that yet. And we’re starting to look at even smaller and smaller proportions of patients with colon cancer. In those that have FGFR, MET, or PIK3CA, we are trying to understand how these different baskets are prognostically driven and whether we can use them as predictive biomarkers for target therapies.

So, I think the landscape is changing quite significantly. And then, the CMS classification, itself, is starting to make its segue into mainstream clinical practice. There’s the BRAF-like group, for example, that will likely benefit the most from some form of immunotherapy; perhaps not PD-1 inhibitors directly, because we know those are not active in MSS cases, but likely some form of PD-1 plus another immunotherapy agent or a combination of other biologics and immunotherapeutics.

Andrea Cercek, MD: Some of the more important biomarkers that we’ve learned a lot about are the MSI-high hypermutated patients that benefit from immunotherapy. We’ve known about BRAF. There are now a number of studies in BRAF that are clearly showing a benefit with combination BRAF inhibitors, anti-EGFR therapy, as well as MEK inhibitors or irinotecan.

Beyond that, HER2 is one of the more exciting emerging markers. In HER2-amplified tumors, there appears to be a signal with anti-HER2 therapy in colorectal cancer. That accounts for approximately 3% to 4% of all metastatic colorectal cancer patients.

Zev A. Wainberg, MD: In the next few years, I think we will see efforts with additional biomarkers for later lines of colon cancer therapy—and even earlier lines. Besides microsatellite instability, which I think is a very clear biomarker for benefit of checkpoint inhibitors, there are others that are being looked at very aggressively. HER2, which is infrequent, only occurs in perhaps 1% to 2% of KRAS wild-type colon cancer. This may be a useful biomarker. In early studies, such as the HERACLES trial with trastuzumab and lapatinib, benefit has been shown in that group of patients. Studies have now been taken to the next level through Cooperative Group settings. They are trying to look at KRAS wild-type HER2 patients to see if there’s benefit to an anti-HER2 drug.

Additional studies are also being done in other biomarker subsets. This includes looking at the CMS classifications, CMS 1 through 4, and trying to see if any individual CMS subtype might be sensitive to an immunotherapeutic strategy, for example, or to additional strategies. At ASCO’s 2018 Gastrointestinal Cancers Symposium, we’ve seen some longer-term data with the combination of MEK inhibition and PD-L1 inhibition with atezolizumab; that may be a subset of patients. And there’s a lot of interest in a group of drugs that are CEA bispecific antibodies, looking at which subsets of those patients might get benefit as well. So, in the next few years, we are hopeful and optimistic that a new series of biomarkers will emerge that will allow us to treat these patients in a more directive fashion.

Transcript Edited for Clarity 
View Conference Coverage
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TitleExpiration DateCME Credits
Community Practice Connections™: New Frontiers in Immuno-Oncology for Microsatellite Instability-High CancersAug 29, 20182.0
Community Practice Connections™: 1st Annual School of Nursing Oncology™Oct 31, 20181.5
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