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Future Directions for Later-Line Therapy in 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: 

Scott Kopetz, MD: There’s still a lot of progress that we need to make in metastatic CRC [colorectal cancer]. Certainly, we have an increased understanding of how to sequence our available therapies, but I think what we see for targeted therapies is a challenge of durability—the tumors are adapting, finding ways to grow despite this treatment. We need to figure out how we can understand those adaptive mechanisms, how we can short-circuit them, and how we can sequence therapies to get best results. It may be that intermittent rechallenge efforts in the targeted therapies setting may be beneficial, but also a number of targeted therapies, next-generation set of drugs, are in development.

For immunotherapy, the challenge is how do we get beyond MSI [microsatellite instability] high? I think the clear evidence of activity is a challenge in trying to think about how we extend that benefit to microsatellite-stable [MSS] populations. Aside from the REGO-NIVO [regorafenib-nivolumab] study and maybe a smattering of other smaller and less promising results, there has not been a clear signal on the direction to go. We really need to think about how we can target the 2 different subgroups of colorectal cancer: the immune desert—with no sign of any immune engagement where you need to do vaccine strategies, T-cell or perhaps bispecific T-cell engaging strategies, oncolytic viruses may be beneficial—or the immune-excluded subgroup of colorectal cancer, where it’s about improving the local tumor microenvironment to get better responses with checkpoint inhibition. Here, it may be that targeting MDSCs [myeloid-derived suppressor cells], targeting TGF beta and other stromal and immune-excluding phenotype, is what we need to be doing to move forward.

Axel Grothey, MD: One of the holy grails of metastatic colorectal cancer therapy would be to make MSS colorectal cancers immunogenic. We’ve tried various ways, and we have failed. The most intriguing combination I’ve seen recently is a combination of regorafenib and nivolumab. There were surprising data actually presented at the 2019 ASCO [American Society of Clinical Oncology] Annual Meeting tucked away in a drug development poster, where Japanese investigators combined 25 patients with gastric cancer and 25 patients with metastatic colorectal cancer. In the 25 patients with colorectal cancer, 24 of them were MSS—clearly not microsatellite-instable tumors. The combination of regorafenib at mainly 80 mg/day plus nivolumab in standard doses showed a response rate of 35%, 36%, which has never been seen before.

We still have to see whether these data can hold up—let’s say in Western population, expanded population—and eventually potentially run a phase III study, to identify whether this holds up in a randomized trial. But these were the most intriguing data I’ve seen so far to make MSS tumors respond to augmented immune therapy. This combination of a kinase inhibitor plus an immune checkpoint inhibitor is actually something that has shown before to be active.

There’s a lenvatinib-pembrolizumab combination approved for MSS endometrial cancers that has strong efficacy. We’ve seen recent data that are tumor agnostic—this combination of lenvatinib plus pembrolizumab actually makes sense. We’ve seen recent data of a combination of bevacizumab-atezolizumab in HCC [hepatocellular carcinoma] first line. The idea of a VEGF inhibitor plus an immune checkpoint inhibitor, opens the door for various combinations we can test in different tumors.

Marwan Fakih, MD: We have made a lot of progress in the management of metastatic colorectal cancer. The future is bright. I think we’re going to continue a path toward subpopulations of colorectal cancer. We’ve clearly defined now the BRAF population, the HER2 [human epidermal growth factor receptor 2] amplification. We have a little more work to do. How do we target HER2 mutations, for example? How do we target MEK1 mutations? There is no doubt in my mind that we still have to work on I/O [immuno-oncology] combinations. There have been some signals with tyrosine kinase inhibitors with regorafenib in combination with nivolumab in patients with microsatellite stability from a Japanese patient population. We need to follow that signal. But where we’re going to be in 2 to 3 years from now is more in a position where we’re better defining what small populations with metastatic colorectal cancer benefit more from targeted therapy. If there is another small subpopulation that responds from immunotherapy that is microsatellite stable, how do we define that population?

That’s where I see our field moving in the coming 2 to 3 years. We certainly need to develop new mechanisms in targeting colorectal cancer. Cellular therapies are going to be coming up as well, and these include modified T-cell infusions that are engineered to fight colorectal cancer. There is some work being done on CAR [chimeric antigen receptor] T cells but, it’s still in its infancy. There is also some more work being done on bispecific antibodies. I would expect more data coming from those studies that would lead us hopefully to the next generation of large randomized phase II and phase III studies.

Transcript Edited for Clarity
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Transcript: 

Scott Kopetz, MD: There’s still a lot of progress that we need to make in metastatic CRC [colorectal cancer]. Certainly, we have an increased understanding of how to sequence our available therapies, but I think what we see for targeted therapies is a challenge of durability—the tumors are adapting, finding ways to grow despite this treatment. We need to figure out how we can understand those adaptive mechanisms, how we can short-circuit them, and how we can sequence therapies to get best results. It may be that intermittent rechallenge efforts in the targeted therapies setting may be beneficial, but also a number of targeted therapies, next-generation set of drugs, are in development.

For immunotherapy, the challenge is how do we get beyond MSI [microsatellite instability] high? I think the clear evidence of activity is a challenge in trying to think about how we extend that benefit to microsatellite-stable [MSS] populations. Aside from the REGO-NIVO [regorafenib-nivolumab] study and maybe a smattering of other smaller and less promising results, there has not been a clear signal on the direction to go. We really need to think about how we can target the 2 different subgroups of colorectal cancer: the immune desert—with no sign of any immune engagement where you need to do vaccine strategies, T-cell or perhaps bispecific T-cell engaging strategies, oncolytic viruses may be beneficial—or the immune-excluded subgroup of colorectal cancer, where it’s about improving the local tumor microenvironment to get better responses with checkpoint inhibition. Here, it may be that targeting MDSCs [myeloid-derived suppressor cells], targeting TGF beta and other stromal and immune-excluding phenotype, is what we need to be doing to move forward.

Axel Grothey, MD: One of the holy grails of metastatic colorectal cancer therapy would be to make MSS colorectal cancers immunogenic. We’ve tried various ways, and we have failed. The most intriguing combination I’ve seen recently is a combination of regorafenib and nivolumab. There were surprising data actually presented at the 2019 ASCO [American Society of Clinical Oncology] Annual Meeting tucked away in a drug development poster, where Japanese investigators combined 25 patients with gastric cancer and 25 patients with metastatic colorectal cancer. In the 25 patients with colorectal cancer, 24 of them were MSS—clearly not microsatellite-instable tumors. The combination of regorafenib at mainly 80 mg/day plus nivolumab in standard doses showed a response rate of 35%, 36%, which has never been seen before.

We still have to see whether these data can hold up—let’s say in Western population, expanded population—and eventually potentially run a phase III study, to identify whether this holds up in a randomized trial. But these were the most intriguing data I’ve seen so far to make MSS tumors respond to augmented immune therapy. This combination of a kinase inhibitor plus an immune checkpoint inhibitor is actually something that has shown before to be active.

There’s a lenvatinib-pembrolizumab combination approved for MSS endometrial cancers that has strong efficacy. We’ve seen recent data that are tumor agnostic—this combination of lenvatinib plus pembrolizumab actually makes sense. We’ve seen recent data of a combination of bevacizumab-atezolizumab in HCC [hepatocellular carcinoma] first line. The idea of a VEGF inhibitor plus an immune checkpoint inhibitor, opens the door for various combinations we can test in different tumors.

Marwan Fakih, MD: We have made a lot of progress in the management of metastatic colorectal cancer. The future is bright. I think we’re going to continue a path toward subpopulations of colorectal cancer. We’ve clearly defined now the BRAF population, the HER2 [human epidermal growth factor receptor 2] amplification. We have a little more work to do. How do we target HER2 mutations, for example? How do we target MEK1 mutations? There is no doubt in my mind that we still have to work on I/O [immuno-oncology] combinations. There have been some signals with tyrosine kinase inhibitors with regorafenib in combination with nivolumab in patients with microsatellite stability from a Japanese patient population. We need to follow that signal. But where we’re going to be in 2 to 3 years from now is more in a position where we’re better defining what small populations with metastatic colorectal cancer benefit more from targeted therapy. If there is another small subpopulation that responds from immunotherapy that is microsatellite stable, how do we define that population?

That’s where I see our field moving in the coming 2 to 3 years. We certainly need to develop new mechanisms in targeting colorectal cancer. Cellular therapies are going to be coming up as well, and these include modified T-cell infusions that are engineered to fight colorectal cancer. There is some work being done on CAR [chimeric antigen receptor] T cells but, it’s still in its infancy. There is also some more work being done on bispecific antibodies. I would expect more data coming from those studies that would lead us hopefully to the next generation of large randomized phase II and phase III studies.

Transcript Edited for Clarity
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