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Promising Novel Agents and Treatments

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Published: Wednesday, Aug 21, 2019



Transcript:

Tanios Bekaii-Saab, MD:
In addition to immune therapy, there are certainly some emerging targets that are very important in metastatic colorectal cancer [mCRC]. We recently heard about the BEACON trial, a study essentially looking at a group of patients with BRAF V600E mutations. That’s about 5%, in some reports up to 8%, but I think it’s closer to 5% to 8% of patients typically occurring on the left side. So you have a RAS wild-type tumor with a BRAF V600E mutation. Those tumors tend to behave incredibly badly, and they do not respond well to chemotherapy. Those are the patients where we think FOLFOXIRI [irinotecan, oxaliplatin, fluorouracil, and folinate (leucovorin calcium)] perhaps plays a role in the first line plus bevacizumab, mind you, based on the subset analysis from another study. That’s all the data we had, but we know that those patients survive an average of 10 to 12 months, which is one-third of what you would expect for the average colorectal cancer patient, so really bad actors.

And so we’ve tried for many years to toy around with the idea that we can target RAF. It was done in melanoma very successfully, even with single-agent vemurafenib, we have an 80% to 90% response rate. The first studies with single-agent vemurafenib or others did not have much activity—5% or less—and they did not hold for more than a couple of months for most of these responses. So it was frustrating, but it appears that the biology of colon cancer is a little bit different, that EGFR may become more relevant and then hitting both RAF and MEK may actually make sense, and we know that from melanoma. But the EGFR angle is through a loop mechanism that makes EGFR relevant again. So a triple blockade for blocking MEK, blocking RAF, and blocking EGFR would make sense without chemotherapy.

So encorafenib, binimetinib, and cetuximab were taken in this BEACON trial versus FOLFIRI [fluorouracil, folinate, and irinotecanplus] cetuximab versus the doublet. But primarily what was reported on right now is that the study was positive. That’s a phase III study in which essentially the triple agent had a 26% response rate versus 1.4% for the FOLFIRI/cetuximab, a huge difference. And the survival was more than 3 months on average between the 2. So that establishes a new standard for us. It’s already making its way, if it’s not now on the guidelines.

We had another study from SWOG Cancer Research Network that was included in the guidelines, based on the phase II randomized. That’s a phase III study. Those are level 1 data, solid data, and that’s kind of transformed the landscape of how we treat patients with BRAF V600E mutations. And in all frankness, we—and this is underway—we should start thinking about taking this to the first line because of the bad biology of this disease.

The other target of interest that’s emerging is HER2. So HER2-amplified tumors relatively behave better than the BRAF-mutated, but they don’t respond to EGFR inhibitors, even in the setting of RAS wild-type. So there are multiple strategies that are being developed. One of them is a study with an agent called tucatinib, which is an oral agent that is very specific for HER2, and trastuzumab. We have some data that will be presented at ESMO [European Society for Medical Oncology]. We know some promising data from lapatinib plus trastuzumab. We also know of some promising data from pertuzumab plus trastuzumab in colon cancer as well. So that will become, one day, I think, one of the ways we’re going to transform the treatment of HER2-mutated cancers.

And then the last target of interest that’s very clinically relevant, although it’s almost like throwing a fish line into a big ocean hoping to catch a big fish, that’s the NTRK fusion. It’s only in about 0.3% to 0.7% of colon cancers, but if you find it, the response to larotrectinib is significant. These patients respond incredibly well, and some of these responses can be quite prolonged. The unfortunate thing is that there are very few of those. It gets frustrating and sometimes you may miss them even on a report. Now they’re being reported more consistently with some reports. I think that as long as we continue to consistently genotype all these tumors, we will be able to capture most of these alterations early on and be able to plan to either include the patients in trials, provide the standard of care, exclude some agents like EGFR inhibitors, or even think about immune therapy or an NTRK inhibitor like larotrectinib.

Fortunato Ciardiello, MD, PhD: I will not say that there is a single novel agent that is promising. What I would say is that it’s promising that if we get more information, especially with these new molecular diagnostic tools such as next-generation sequencing, before we start treatment of metastatic disease, then we will have a more clear picture of what the disease is and the clinical characteristics of the patient we have to treat. And then we can use our best therapeutic weapons in the best combination and the best sequence. And I think this is the most important thing. So molecular genotyping and molecular characterization will help really to personalize the treatment according to medicine in oncology.

Axel Grothey, MD: With all we’ve seen in recent years, I think this is a very exciting time to be involved in clinical research and in clinical development of agents and treatment options in colorectal cancer. We’ve seen new agents come about as well as new treatment options. We decipher biology—the interaction with the immune system—so we’ve definitely made improvements. And improvements right now mainly benefiting certain subgroups of patients. We talked about MSI [microsatellite instability]-high tumors, BRAF V600E-mutant tumors, and HER2-positive tumors. And hopefully this approach of profiling and using biology to guide our treatment will eventually help even more patients. And the Holy Grail, of course, would be to make immunotherapy work for a larger number of patients. Find markers for patients that could respond to immunotherapy perhaps in augmented immunotherapy with a little twist, kicking the immune system into gear, making tumors more immunogenic. That, I think, is the future, and I’ve honestly never been more excited about where we are right now, where we’ll go, than at this point in time.


Transcript Edited for Clarity
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Transcript:

Tanios Bekaii-Saab, MD:
In addition to immune therapy, there are certainly some emerging targets that are very important in metastatic colorectal cancer [mCRC]. We recently heard about the BEACON trial, a study essentially looking at a group of patients with BRAF V600E mutations. That’s about 5%, in some reports up to 8%, but I think it’s closer to 5% to 8% of patients typically occurring on the left side. So you have a RAS wild-type tumor with a BRAF V600E mutation. Those tumors tend to behave incredibly badly, and they do not respond well to chemotherapy. Those are the patients where we think FOLFOXIRI [irinotecan, oxaliplatin, fluorouracil, and folinate (leucovorin calcium)] perhaps plays a role in the first line plus bevacizumab, mind you, based on the subset analysis from another study. That’s all the data we had, but we know that those patients survive an average of 10 to 12 months, which is one-third of what you would expect for the average colorectal cancer patient, so really bad actors.

And so we’ve tried for many years to toy around with the idea that we can target RAF. It was done in melanoma very successfully, even with single-agent vemurafenib, we have an 80% to 90% response rate. The first studies with single-agent vemurafenib or others did not have much activity—5% or less—and they did not hold for more than a couple of months for most of these responses. So it was frustrating, but it appears that the biology of colon cancer is a little bit different, that EGFR may become more relevant and then hitting both RAF and MEK may actually make sense, and we know that from melanoma. But the EGFR angle is through a loop mechanism that makes EGFR relevant again. So a triple blockade for blocking MEK, blocking RAF, and blocking EGFR would make sense without chemotherapy.

So encorafenib, binimetinib, and cetuximab were taken in this BEACON trial versus FOLFIRI [fluorouracil, folinate, and irinotecanplus] cetuximab versus the doublet. But primarily what was reported on right now is that the study was positive. That’s a phase III study in which essentially the triple agent had a 26% response rate versus 1.4% for the FOLFIRI/cetuximab, a huge difference. And the survival was more than 3 months on average between the 2. So that establishes a new standard for us. It’s already making its way, if it’s not now on the guidelines.

We had another study from SWOG Cancer Research Network that was included in the guidelines, based on the phase II randomized. That’s a phase III study. Those are level 1 data, solid data, and that’s kind of transformed the landscape of how we treat patients with BRAF V600E mutations. And in all frankness, we—and this is underway—we should start thinking about taking this to the first line because of the bad biology of this disease.

The other target of interest that’s emerging is HER2. So HER2-amplified tumors relatively behave better than the BRAF-mutated, but they don’t respond to EGFR inhibitors, even in the setting of RAS wild-type. So there are multiple strategies that are being developed. One of them is a study with an agent called tucatinib, which is an oral agent that is very specific for HER2, and trastuzumab. We have some data that will be presented at ESMO [European Society for Medical Oncology]. We know some promising data from lapatinib plus trastuzumab. We also know of some promising data from pertuzumab plus trastuzumab in colon cancer as well. So that will become, one day, I think, one of the ways we’re going to transform the treatment of HER2-mutated cancers.

And then the last target of interest that’s very clinically relevant, although it’s almost like throwing a fish line into a big ocean hoping to catch a big fish, that’s the NTRK fusion. It’s only in about 0.3% to 0.7% of colon cancers, but if you find it, the response to larotrectinib is significant. These patients respond incredibly well, and some of these responses can be quite prolonged. The unfortunate thing is that there are very few of those. It gets frustrating and sometimes you may miss them even on a report. Now they’re being reported more consistently with some reports. I think that as long as we continue to consistently genotype all these tumors, we will be able to capture most of these alterations early on and be able to plan to either include the patients in trials, provide the standard of care, exclude some agents like EGFR inhibitors, or even think about immune therapy or an NTRK inhibitor like larotrectinib.

Fortunato Ciardiello, MD, PhD: I will not say that there is a single novel agent that is promising. What I would say is that it’s promising that if we get more information, especially with these new molecular diagnostic tools such as next-generation sequencing, before we start treatment of metastatic disease, then we will have a more clear picture of what the disease is and the clinical characteristics of the patient we have to treat. And then we can use our best therapeutic weapons in the best combination and the best sequence. And I think this is the most important thing. So molecular genotyping and molecular characterization will help really to personalize the treatment according to medicine in oncology.

Axel Grothey, MD: With all we’ve seen in recent years, I think this is a very exciting time to be involved in clinical research and in clinical development of agents and treatment options in colorectal cancer. We’ve seen new agents come about as well as new treatment options. We decipher biology—the interaction with the immune system—so we’ve definitely made improvements. And improvements right now mainly benefiting certain subgroups of patients. We talked about MSI [microsatellite instability]-high tumors, BRAF V600E-mutant tumors, and HER2-positive tumors. And hopefully this approach of profiling and using biology to guide our treatment will eventually help even more patients. And the Holy Grail, of course, would be to make immunotherapy work for a larger number of patients. Find markers for patients that could respond to immunotherapy perhaps in augmented immunotherapy with a little twist, kicking the immune system into gear, making tumors more immunogenic. That, I think, is the future, and I’ve honestly never been more excited about where we are right now, where we’ll go, than at this point in time.


Transcript Edited for Clarity
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