Current Perspectives on the Use of Targeted Therapies in Colorectal Cancer
Current Perspectives on the Use of Targeted Therapies in Colorectal Cancer Slide 1 Narrator: Targeted therapies are emerging as the standard of care in metastatic colorectal cancer. Dr. Alan Venook discusses some of the current principles of treating metastatic CRC and the role of targeted therapies, such as bevacizumab, cetuximab, and panitumumab, in the context of other therapies.
Slide 2 Dr. Venook: Targeted therapies is a term used for therapies that we think aim at the biology and physiology of the cancer cell rather than classic chemotherapy, which kills rapidly dividing cells. So, targeted therapies presume to work on different mechanism[s] than conventional chemotherapy. [An] example of a targeted therapy would be something targeting the epidermal growth factor receptor, either cetuximab or panitumumab, each of which appear to bind the epidermal growth factor receptor on the cancer cell surface. By binding, theoretically, it prevents the activation of that receptor. And the activation of that receptor leads to a number of events in the cancer cell, including unregulated growth and metastasis, and development of blood vessels. Bevacizumab would also be considered a targeted therapy. It's an antibody that binds circulating vascular endothelial growth factor. It targets VEGF, but exactly why inhibiting VEGF works so well in cancer is not clear. It may affect new blood vessel development; it may affect interstitial pressure in the tumor and enhance chemotherapy delivery. And, I think it's important to realize that bevacizumab, while atargeted therapy, really works almost exclusively in combinationwith chemotherapy.
Slide 3 Narrator: Dr. Venook explains that bevacizumab has recently been approved for use in first- and second-line treatment of metastatic CRC in combination with chemotherapy. First-line patients are appropriately treated with bevacizumab plus chemotherapy, while patients who are bevacizumab-naïve in first-line treatment would appropriately be offered the agent in combination with chemotherapy as second-line treatment. Dr. Venook: There are any number of studies that show that bevacizumab improves the efficacy of chemotherapy. The classic [is the] Hurwitz trial, which looked at bevacizumab in combination with the bolus irinotecan/5-FU/leucovorin, which was the standard treatment at the time the study was designed. Subsequent studies have looked at bevacizumab with FOLFIRI, or modified bolus IFL, that's the BICC-C trial. FOLFOX with bevacizumab, that's E3200, which is a second-line study in patients who failed irinotecan/5-FU/leucovorin first-line. The TREE-2 study, which looked at a number of combinations of oxaliplatin and fluoropyrimidines, including capecitabine, and appears to show bevacizumab adds to efficacy of each of those combinations. And then the 5-FU/leucovorin/bevacizumab studies done at the same time as the IFL/bevacizumab studies, but in patients who were not eligible for more aggressive therapy. Every one of these studies shows that bevacizumab adds to the efficacy in terms of response rate and appears to add in efficacy in terms of progression-free survival. So, there's compelling evidence that bevacizumab in the colorectal cancer patient is additive to all other therapies that are conventionally used. In fact, there's phase 2 data that suggest that bevacizumab is additive to irinotecan and cetuximab as a combination. So, across the board, bevacizumab adds efficacy.
Slide 4 Dr. Venook: Now, there is a major question that's unanswered in bevacizumab, and that is how long to treat patients with bevacizumab. The data supports first-line use and second-line use, but it doesn't tell us or guide us in the patient who fails first-line bevacizumab in terms of whether to continue or not to continue subsequent bevacizumab.Will bevacizumab provide added efficacy even if you've already seen it over the first line? There is a national study, a SWOG study, that's been designed to get at that, to determine if continuing bevacizumab is more effective than not continuing it. But that is simply an unknown at this point. This is relevant, because bevacizumab, while not having many of the side effects of conventional chemotherapy, does have some side effects: a risk of stroke, of myocardial infarction, or coagulation problems. It's not zero. And certainly, prolonged use may increase those risks, although that, too, is not known. So, lots to be learned about bevacizumab. But it does appear to be interactive in a positive way with virtually every therapy in patients with colorectal cancer. Slide 5 Dr. Venook: Other antiangiogenesis agents are of course waiting to be developed given the validity of targeting VEGF. It remains to be seen, though, which one of these will prove to be effective. So, multitargeted kinase inhibitors have been tested, and mostly in patients with advanced disease and in combination with chemotherapy. The most well known of these is PTK787. Now, vatalanib, which was tested in both untreated and second-line patients with colorectal cancer in combination with chemotherapy, really did not appear to have the same additive efficacy impact that bevacizumab had in similarly designed studies. It may have been a dosing phenomenon of the PTK drug. It may have been the way the studies were designed. But that, frankly, has been a little bit disappointing. Sunitinib, which is approved for GI stromal tumor and renal cell, is another multitargeted kinase inhibitor targeting VEGF, and at least by itself has really no particular activity in colon cancer. Another very promising treatment, for example, is VEGF-Trap, which is similarly designed to collect circulating VEGF and decrease its ability to interact at the cancer site. I should say that many targeted therapies interact across many different kinases. And so, there are a whole host of drugs targeting primarily the epidermal growth factor receptor, which may also target VEGF to some extent. Slide 6 Narrator: The EGFR inhibitor cetuximab has also been approved for patients with CRC who have failed an irinotecan-based regimen or who are intolerant of irinotecan, says Dr. Venook. Dr. Venook: It's currently being tested in front-line and in combination with other therapies. The real controversy is predicting who will or who won't benefit from cetuximab. The conventional wisdom has been that only patients whose tumors overexpress the epidermal growth factor receptor on immunohistochemistry should be treated with cetuximab. But there are some series of patients suggesting that the likelihood of benefit from cetuximab is the same whether or not the tumors overexpress the epidermal growth factor receptor. So, this is a controversy. It's also controversial, the right dosing of cetuximab, which is currently a weekly dosing regimen. And of course, its first-line role is being studied in a number of international trials. Panitumumab is different from cetuximab in that it's an entirely human molecule. It has a lesser incidence of infusion reactions. In fact, they are very rare compared to a couple of percent of patients who have infusion reactions to cetuximab. Panitumumab also is dosed on an every-other-week basis. But other than those differences in schedule and perhaps safety, the fact that panitumumab doesn't require premedication, they really look to be interchangeable. Slide 7 Dr. Venook: The challenge in the current management of patients with advanced colorectal cancer is in strategically planning how you will use all of these agents. It may very well be that the sequence is less important than exposing patients to each of these potentially effective treatments. Our approach is to really size up the patient, determine their suitability for aggressive therapy, look at other comorbidities, and to make treatment decisions with all that information available. So, the average patient without comorbidities would start with either a FOLFOX or FOLFIRI chemotherapy backbone with bevacizumab and, at the time of progression, would switch to the other chemotherapy. On the other hand, a patient who's diabetic with neuropathy may better not be treated with oxaliplatin. A patient who has got resectable liver metastases should get some minimal amount of chemotherapy, probably with bevacizumab or cetuximab, with the plan of stopping the bevacizumab 6 to 8 weeks prior to definitive surgery, if the metastatic disease is resectable. So, the take-home message is that it is no longer a one-size-fits-all, and you need to think of all of these possible outcomes when making treatment decisions in these patients.
Slide 2 Dr. Venook: Targeted therapies is a term used for therapies that we think aim at the biology and physiology of the cancer cell rather than classic chemotherapy, which kills rapidly dividing cells. So, targeted therapies presume to work on different mechanism[s] than conventional chemotherapy. [An] example of a targeted therapy would be something targeting the epidermal growth factor receptor, either cetuximab or panitumumab, each of which appear to bind the epidermal growth factor receptor on the cancer cell surface. By binding, theoretically, it prevents the activation of that receptor. And the activation of that receptor leads to a number of events in the cancer cell, including unregulated growth and metastasis, and development of blood vessels. Bevacizumab would also be considered a targeted therapy. It's an antibody that binds circulating vascular endothelial growth factor. It targets VEGF, but exactly why inhibiting VEGF works so well in cancer is not clear. It may affect new blood vessel development; it may affect interstitial pressure in the tumor and enhance chemotherapy delivery. And, I think it's important to realize that bevacizumab, while atargeted therapy, really works almost exclusively in combinationwith chemotherapy.
Slide 3 Narrator: Dr. Venook explains that bevacizumab has recently been approved for use in first- and second-line treatment of metastatic CRC in combination with chemotherapy. First-line patients are appropriately treated with bevacizumab plus chemotherapy, while patients who are bevacizumab-naïve in first-line treatment would appropriately be offered the agent in combination with chemotherapy as second-line treatment. Dr. Venook: There are any number of studies that show that bevacizumab improves the efficacy of chemotherapy. The classic [is the] Hurwitz trial, which looked at bevacizumab in combination with the bolus irinotecan/5-FU/leucovorin, which was the standard treatment at the time the study was designed. Subsequent studies have looked at bevacizumab with FOLFIRI, or modified bolus IFL, that's the BICC-C trial. FOLFOX with bevacizumab, that's E3200, which is a second-line study in patients who failed irinotecan/5-FU/leucovorin first-line. The TREE-2 study, which looked at a number of combinations of oxaliplatin and fluoropyrimidines, including capecitabine, and appears to show bevacizumab adds to efficacy of each of those combinations. And then the 5-FU/leucovorin/bevacizumab studies done at the same time as the IFL/bevacizumab studies, but in patients who were not eligible for more aggressive therapy. Every one of these studies shows that bevacizumab adds to the efficacy in terms of response rate and appears to add in efficacy in terms of progression-free survival. So, there's compelling evidence that bevacizumab in the colorectal cancer patient is additive to all other therapies that are conventionally used. In fact, there's phase 2 data that suggest that bevacizumab is additive to irinotecan and cetuximab as a combination. So, across the board, bevacizumab adds efficacy.
Slide 4 Dr. Venook: Now, there is a major question that's unanswered in bevacizumab, and that is how long to treat patients with bevacizumab. The data supports first-line use and second-line use, but it doesn't tell us or guide us in the patient who fails first-line bevacizumab in terms of whether to continue or not to continue subsequent bevacizumab.Will bevacizumab provide added efficacy even if you've already seen it over the first line? There is a national study, a SWOG study, that's been designed to get at that, to determine if continuing bevacizumab is more effective than not continuing it. But that is simply an unknown at this point. This is relevant, because bevacizumab, while not having many of the side effects of conventional chemotherapy, does have some side effects: a risk of stroke, of myocardial infarction, or coagulation problems. It's not zero. And certainly, prolonged use may increase those risks, although that, too, is not known. So, lots to be learned about bevacizumab. But it does appear to be interactive in a positive way with virtually every therapy in patients with colorectal cancer. Slide 5 Dr. Venook: Other antiangiogenesis agents are of course waiting to be developed given the validity of targeting VEGF. It remains to be seen, though, which one of these will prove to be effective. So, multitargeted kinase inhibitors have been tested, and mostly in patients with advanced disease and in combination with chemotherapy. The most well known of these is PTK787. Now, vatalanib, which was tested in both untreated and second-line patients with colorectal cancer in combination with chemotherapy, really did not appear to have the same additive efficacy impact that bevacizumab had in similarly designed studies. It may have been a dosing phenomenon of the PTK drug. It may have been the way the studies were designed. But that, frankly, has been a little bit disappointing. Sunitinib, which is approved for GI stromal tumor and renal cell, is another multitargeted kinase inhibitor targeting VEGF, and at least by itself has really no particular activity in colon cancer. Another very promising treatment, for example, is VEGF-Trap, which is similarly designed to collect circulating VEGF and decrease its ability to interact at the cancer site. I should say that many targeted therapies interact across many different kinases. And so, there are a whole host of drugs targeting primarily the epidermal growth factor receptor, which may also target VEGF to some extent. Slide 6 Narrator: The EGFR inhibitor cetuximab has also been approved for patients with CRC who have failed an irinotecan-based regimen or who are intolerant of irinotecan, says Dr. Venook. Dr. Venook: It's currently being tested in front-line and in combination with other therapies. The real controversy is predicting who will or who won't benefit from cetuximab. The conventional wisdom has been that only patients whose tumors overexpress the epidermal growth factor receptor on immunohistochemistry should be treated with cetuximab. But there are some series of patients suggesting that the likelihood of benefit from cetuximab is the same whether or not the tumors overexpress the epidermal growth factor receptor. So, this is a controversy. It's also controversial, the right dosing of cetuximab, which is currently a weekly dosing regimen. And of course, its first-line role is being studied in a number of international trials. Panitumumab is different from cetuximab in that it's an entirely human molecule. It has a lesser incidence of infusion reactions. In fact, they are very rare compared to a couple of percent of patients who have infusion reactions to cetuximab. Panitumumab also is dosed on an every-other-week basis. But other than those differences in schedule and perhaps safety, the fact that panitumumab doesn't require premedication, they really look to be interchangeable. Slide 7 Dr. Venook: The challenge in the current management of patients with advanced colorectal cancer is in strategically planning how you will use all of these agents. It may very well be that the sequence is less important than exposing patients to each of these potentially effective treatments. Our approach is to really size up the patient, determine their suitability for aggressive therapy, look at other comorbidities, and to make treatment decisions with all that information available. So, the average patient without comorbidities would start with either a FOLFOX or FOLFIRI chemotherapy backbone with bevacizumab and, at the time of progression, would switch to the other chemotherapy. On the other hand, a patient who's diabetic with neuropathy may better not be treated with oxaliplatin. A patient who has got resectable liver metastases should get some minimal amount of chemotherapy, probably with bevacizumab or cetuximab, with the plan of stopping the bevacizumab 6 to 8 weeks prior to definitive surgery, if the metastatic disease is resectable. So, the take-home message is that it is no longer a one-size-fits-all, and you need to think of all of these possible outcomes when making treatment decisions in these patients.
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