Skin cancer is the most common form of cancer worldwide. It is usually caused by excessive exposure to sunlight or other sources of ultraviolet light, such as tanning beds. The rarest but deadliest form of skin cancer is melanoma, which is aggressive and can spread rapidly if not detected and treated early.
Newer targeted treatments like immunotherapy have emerged in recent years and appear to be not only more effective than conventional therapy but also better tolerated, because unlike chemotherapy and radiation, these newer approaches are designed to kill cancer cells without damaging healthy ones.
In this fascinating segment, Igor Puzanov, MD, MSCI, FACP, Chief of Melanoma, Director of the Early Phase Clinical Trials Program, discusses the latest advances and the new combination treatment for advanced Melanoma.
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New Combination Treatment for Advanced Melanoma
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Learn more about Igor Puzanov, MD
Igor Puzanov, MD
Igor Puzanov, MD is a Clinical Professor of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Professor of Medicine and Director of Early Phase Clinical Trials Program in the Department of Medicine at Roswell Park Comprehensive Cancer Center.Learn more about Igor Puzanov, MD
Transcription:
New Combination Treatment for Advanced Melanoma
Bill Klaproth (Host): Simple surgery remains the primary treatment for most types of skin cancer, but a new immunotherapy combination treatment is showing promise. And there to talk with us about new combination treatment for advanced melanoma is Dr. Igor Puzanov, Chief of Melanoma and Director of the Early Phase Clinical Trials Program at Roswell Park Comprehensive Cancer Center. Dr. Puzanov, thank you for being on with me. I appreciate it. So, let me ask you this. At what point does simple surgery not work for skin cancer?
Dr. Igor Puzanov, MD, MSCI, FACP (Guest): Wow, that’s a loaded question because if you consider the adjuvant therapy as well, i.e. therapy for microscopic disease which is left behind at the later stages of melanoma; I would say probably from a late stage II, definitely end stage III and for sure end stage IV because even patients with deep ulcerated melanoma stage II-C, stage III which means lymph nodes involved; they do have high risk of recurrence of their melanoma, spread, metastatic disease and death. So, actually systemic therapy is recommended in those patients as well even with invisible cancer and of course stage IV patients, they do have visible cancer and unless you can remove all the metastases in some limited cases; you will need systemic therapy.
Bill: So, when you talk about systemic therapy; is that immunotherapy?
Dr. Puzanov: Systemic therapy can be immunotherapy, but also can be targeted therapy, targeted to certain mutations we know present in melanoma such as BRAS mutation or CKIT mutation or other mutations as well which are under development, but I wouldn’t want to leave our listeners with the idea that immunotherapy is the only treatment for melanoma, actually. We have targeted therapies that are well established as well.
Bill: So, when do you use immunotherapy? Who is a good candidate for that?
Dr. Puzanov: So, for immunotherapy, here right now a good candidate is patients with unresectable stage IV melanoma and also patients whose tumors have been removed i.e. stage III melanoma patients, you know all visible tumor removed where we try to prevent recurrence.
Bill: And so, why is immunotherapy so effective for metastatic melanoma?
Dr. Puzanov: That is actually effective both for metastatic and as an adjuvant therapy. We now know that because there are like several trials reported recently. So, basically, immunotherapy in general is effective to kill melanoma. Melanoma actually harbors a lot of genetic changes which we call mutations and it seems like the more complicated, uglier the tumor looks like; actually our immune system once you break the tumor protection has easier time to clear it up. In the old days, the patients with these uglier tumors died earlier but now that we actually have the immunotherapy; those patients respond better because you have more targets so to see for your immune system to kill the cancer, you just have to break the tumor defenses.
Bill: So, let’s talk about the clinical trialing and can you talk to us about Masterkey 265?
Dr. Puzanov: Sure, it’s a first oncolytic virus called talimogene laherparepvec T-VEC in combination with pembrolizumab you know Keytruda which is known as the drug which helped former President Carter and it is a Phase III clinical trial, you know it of course started as a Phase I and it is a simple idea you combine oncolytic virus which is injected to some of the tumors, it doesn’t have to be all the tumors. And you prime the immune system and then you actually come with Keytruda to kind of seal the deal and we now know it was published in one of the best scientific journals in the world, called Cell last year, that when you combine Keytruda with the T-VEC with the virus you know, inject it; you actually have about 65% of patients who will have shrinkage of their tumors and most of these shrinkages are ongoing, most of these responses. So, that’s Phase I-B, it is like the first 20 patients. But then you have like several hundred patients now randomized to either Keytruda alone or Keytruda with the oncolytic virus and this is the trial you just mentioned. We are awaiting its closure and then we are awaiting its results because if they turn out to be positive; i.e. the combination is better than Keytruda alone, then obviously it will be a win for our patients and for everybody.
Bill: So, this is very exciting. So why is this so promising to you?
Dr. Puzanov: Well you know, it is promising because there is a percentage of patients where the immunotherapy, what we call the checkpoint inhibitor such as OPDIVO, Keytruda you know people know from TV ads and literature, where they don’t work. Because they actually don’t work if you do not have your immune cells ready to kill in the tumors. Think about Keytruda and OPDIVO as a brake on a brake. While if there is no car, there is no brake on brake helping you because if you have empty tumor which is invisible to your immune system, that tumor is growing, killing you slowly, yet your immune system is oblivious and is not sending any cells, any lymphocytes to kill that tumor. If there are no lymphocytes in that tumor, your Keytruda cannot work. Because it’s trying to improve killing of the lymphocytes but there are no lymphocytes. So, the T-VEC actually drives the lymphocytes into the tumor. It gets them there. It inflames the tumor. These cells get in there and now actually the Keytruda can help break the spell because there are some soldiers ready to kill. So, this is the exciting part. This is really what we need to do for all of the tumors, you know get the immune system in and then make it kill. Because if you can do that, you can cure people potentially.
Bill: So, that’s kind of the one two punch, then of this new combination treatment.
Dr. Puzanov: That is right. You need both because if you use T-VEC alone, it does have effect and we published that in Journal of Clinical Immunology Oncology in 2016, but it actually helps mostly patients with kind of lower burden of their disease, you know kind of earlier stages III-B, III-C, lymph nodes involved, skin involved, some lung involvement, but not necessarily when the cancer spreads into the bones, liver, multiple organs. That is too much to ask for simple injection into the tumor, but once you add Keytruda, well you have best of both worlds. You prime the system, you prime the pump so to speak and then you bring in the big gun and we can help more patients. But mind you, it’s still not 100%. We still have ways to go.
Bill: So, I’m just thinking of the process as you talk about this. How does the immunotherapy process work, this new combination? Is it two injections or how does the patient go through the treatment process?
Dr. Puzanov: So, the T-VEC is actually a modified virus, you know herpes simplex virus which was modified so it cannot infect the whole body. It can only multiply in the tumor. It is weakened. And you have to inject it you know with a needle into some of the patient’s tumors. So, they have to have be somehow accessible. And of course, accessibility can mean it’s on the skin, it can be deeper. You can even use ultrasound if you have that skill. You can use ultrasound and you can inject deeper lesions. And that is kind of the T-VEC part. It is given every two weeks and then Keytruda is given in the vein. It’s a simple infusion like everybody is knowledgeable about getting an infusion of fluid. This is an infusion of fluid with the antibody called Keytruda in it. So Keytruda is a standardly easy to give. You know T-VEC you have to be skilled in injections and you have to have certain precautions because it is modified – genetically modified virus. It actually also produces the immune system stimulation through something called GMCSF so it’s like making itself visible once injected into tumor and you have to follow rules on how to dispose of it, how to inject it and go through the training. So, T-VEC injections are typically done in more specialized centers which see more of these patients and have volume enough to develop the expertise. Because also it is stored in minus 80 degrees Celsius tanks and there are a few logistical issues one has to be able to work out. But once you know how to do it, it is very easy. I do it myself and we recently actually did a video which is available on our Roswell Park.org webpage where you can see me injecting one of my patients and talking through the process there. So, it is not a very difficult, if I can do it, anybody can do it with the proper training.
Bill: Dr. Puzanov, should people locally or regionally ask about being included in this trial?
Dr. Puzanov: In general, I think it’s a very good idea if you get cancer to number one, think about clinical trials because that may be actually available only before you even started any treatment and there may be clinical trials out there these days which have very effective and can be alternatives to standard of care therapy and one other thing to think about clinical trials is that it’s like additional gun. If you have three guns as a standard of care and there are two more trials you can sneak in for the patients, well that is five guns and five guns is always better than three guns. Or more bullets is better than less bullets. So, I always tell the patient before you jump, before you do anything, see if you have at least a little bit of time, one to two weeks, get a consultation at a comprehensive cancer center, kind of see what is available either locally or even regionally depends on how people can travel and also how aggressive the cancer is and everything. But before you jump, educate yourself because truth to be told, little bit of delay really doesn’t change the outcome of the cancer. Two weeks here, two weeks there don’t change anything if it is going to work, it is going to work but once you start certain treatment, you may realize I am not eligible for something I would have liked to try but now I already had my treatment and I cannot. So, I think it’s a good idea to actually ask about clinical trials before you commit to a treatment and get like a second opinion, a quick second opinion to actually understand the situation, what’s available from the usual sources, standard of care; what is available through more research sources and how to put all of it together.
Bill: As always, you are a wealth of knowledge Dr. Puzanov. Thank you so much for your time today. We appreciate it. For more information visit www.roswellpark.org. Just go to www.roswellpark.org. You’re listening to Cancer Talk with Roswell Park Comprehensive Cancer Center. I’m Bill Klaproth. Thanks for listening.
New Combination Treatment for Advanced Melanoma
Bill Klaproth (Host): Simple surgery remains the primary treatment for most types of skin cancer, but a new immunotherapy combination treatment is showing promise. And there to talk with us about new combination treatment for advanced melanoma is Dr. Igor Puzanov, Chief of Melanoma and Director of the Early Phase Clinical Trials Program at Roswell Park Comprehensive Cancer Center. Dr. Puzanov, thank you for being on with me. I appreciate it. So, let me ask you this. At what point does simple surgery not work for skin cancer?
Dr. Igor Puzanov, MD, MSCI, FACP (Guest): Wow, that’s a loaded question because if you consider the adjuvant therapy as well, i.e. therapy for microscopic disease which is left behind at the later stages of melanoma; I would say probably from a late stage II, definitely end stage III and for sure end stage IV because even patients with deep ulcerated melanoma stage II-C, stage III which means lymph nodes involved; they do have high risk of recurrence of their melanoma, spread, metastatic disease and death. So, actually systemic therapy is recommended in those patients as well even with invisible cancer and of course stage IV patients, they do have visible cancer and unless you can remove all the metastases in some limited cases; you will need systemic therapy.
Bill: So, when you talk about systemic therapy; is that immunotherapy?
Dr. Puzanov: Systemic therapy can be immunotherapy, but also can be targeted therapy, targeted to certain mutations we know present in melanoma such as BRAS mutation or CKIT mutation or other mutations as well which are under development, but I wouldn’t want to leave our listeners with the idea that immunotherapy is the only treatment for melanoma, actually. We have targeted therapies that are well established as well.
Bill: So, when do you use immunotherapy? Who is a good candidate for that?
Dr. Puzanov: So, for immunotherapy, here right now a good candidate is patients with unresectable stage IV melanoma and also patients whose tumors have been removed i.e. stage III melanoma patients, you know all visible tumor removed where we try to prevent recurrence.
Bill: And so, why is immunotherapy so effective for metastatic melanoma?
Dr. Puzanov: That is actually effective both for metastatic and as an adjuvant therapy. We now know that because there are like several trials reported recently. So, basically, immunotherapy in general is effective to kill melanoma. Melanoma actually harbors a lot of genetic changes which we call mutations and it seems like the more complicated, uglier the tumor looks like; actually our immune system once you break the tumor protection has easier time to clear it up. In the old days, the patients with these uglier tumors died earlier but now that we actually have the immunotherapy; those patients respond better because you have more targets so to see for your immune system to kill the cancer, you just have to break the tumor defenses.
Bill: So, let’s talk about the clinical trialing and can you talk to us about Masterkey 265?
Dr. Puzanov: Sure, it’s a first oncolytic virus called talimogene laherparepvec T-VEC in combination with pembrolizumab you know Keytruda which is known as the drug which helped former President Carter and it is a Phase III clinical trial, you know it of course started as a Phase I and it is a simple idea you combine oncolytic virus which is injected to some of the tumors, it doesn’t have to be all the tumors. And you prime the immune system and then you actually come with Keytruda to kind of seal the deal and we now know it was published in one of the best scientific journals in the world, called Cell last year, that when you combine Keytruda with the T-VEC with the virus you know, inject it; you actually have about 65% of patients who will have shrinkage of their tumors and most of these shrinkages are ongoing, most of these responses. So, that’s Phase I-B, it is like the first 20 patients. But then you have like several hundred patients now randomized to either Keytruda alone or Keytruda with the oncolytic virus and this is the trial you just mentioned. We are awaiting its closure and then we are awaiting its results because if they turn out to be positive; i.e. the combination is better than Keytruda alone, then obviously it will be a win for our patients and for everybody.
Bill: So, this is very exciting. So why is this so promising to you?
Dr. Puzanov: Well you know, it is promising because there is a percentage of patients where the immunotherapy, what we call the checkpoint inhibitor such as OPDIVO, Keytruda you know people know from TV ads and literature, where they don’t work. Because they actually don’t work if you do not have your immune cells ready to kill in the tumors. Think about Keytruda and OPDIVO as a brake on a brake. While if there is no car, there is no brake on brake helping you because if you have empty tumor which is invisible to your immune system, that tumor is growing, killing you slowly, yet your immune system is oblivious and is not sending any cells, any lymphocytes to kill that tumor. If there are no lymphocytes in that tumor, your Keytruda cannot work. Because it’s trying to improve killing of the lymphocytes but there are no lymphocytes. So, the T-VEC actually drives the lymphocytes into the tumor. It gets them there. It inflames the tumor. These cells get in there and now actually the Keytruda can help break the spell because there are some soldiers ready to kill. So, this is the exciting part. This is really what we need to do for all of the tumors, you know get the immune system in and then make it kill. Because if you can do that, you can cure people potentially.
Bill: So, that’s kind of the one two punch, then of this new combination treatment.
Dr. Puzanov: That is right. You need both because if you use T-VEC alone, it does have effect and we published that in Journal of Clinical Immunology Oncology in 2016, but it actually helps mostly patients with kind of lower burden of their disease, you know kind of earlier stages III-B, III-C, lymph nodes involved, skin involved, some lung involvement, but not necessarily when the cancer spreads into the bones, liver, multiple organs. That is too much to ask for simple injection into the tumor, but once you add Keytruda, well you have best of both worlds. You prime the system, you prime the pump so to speak and then you bring in the big gun and we can help more patients. But mind you, it’s still not 100%. We still have ways to go.
Bill: So, I’m just thinking of the process as you talk about this. How does the immunotherapy process work, this new combination? Is it two injections or how does the patient go through the treatment process?
Dr. Puzanov: So, the T-VEC is actually a modified virus, you know herpes simplex virus which was modified so it cannot infect the whole body. It can only multiply in the tumor. It is weakened. And you have to inject it you know with a needle into some of the patient’s tumors. So, they have to have be somehow accessible. And of course, accessibility can mean it’s on the skin, it can be deeper. You can even use ultrasound if you have that skill. You can use ultrasound and you can inject deeper lesions. And that is kind of the T-VEC part. It is given every two weeks and then Keytruda is given in the vein. It’s a simple infusion like everybody is knowledgeable about getting an infusion of fluid. This is an infusion of fluid with the antibody called Keytruda in it. So Keytruda is a standardly easy to give. You know T-VEC you have to be skilled in injections and you have to have certain precautions because it is modified – genetically modified virus. It actually also produces the immune system stimulation through something called GMCSF so it’s like making itself visible once injected into tumor and you have to follow rules on how to dispose of it, how to inject it and go through the training. So, T-VEC injections are typically done in more specialized centers which see more of these patients and have volume enough to develop the expertise. Because also it is stored in minus 80 degrees Celsius tanks and there are a few logistical issues one has to be able to work out. But once you know how to do it, it is very easy. I do it myself and we recently actually did a video which is available on our Roswell Park.org webpage where you can see me injecting one of my patients and talking through the process there. So, it is not a very difficult, if I can do it, anybody can do it with the proper training.
Bill: Dr. Puzanov, should people locally or regionally ask about being included in this trial?
Dr. Puzanov: In general, I think it’s a very good idea if you get cancer to number one, think about clinical trials because that may be actually available only before you even started any treatment and there may be clinical trials out there these days which have very effective and can be alternatives to standard of care therapy and one other thing to think about clinical trials is that it’s like additional gun. If you have three guns as a standard of care and there are two more trials you can sneak in for the patients, well that is five guns and five guns is always better than three guns. Or more bullets is better than less bullets. So, I always tell the patient before you jump, before you do anything, see if you have at least a little bit of time, one to two weeks, get a consultation at a comprehensive cancer center, kind of see what is available either locally or even regionally depends on how people can travel and also how aggressive the cancer is and everything. But before you jump, educate yourself because truth to be told, little bit of delay really doesn’t change the outcome of the cancer. Two weeks here, two weeks there don’t change anything if it is going to work, it is going to work but once you start certain treatment, you may realize I am not eligible for something I would have liked to try but now I already had my treatment and I cannot. So, I think it’s a good idea to actually ask about clinical trials before you commit to a treatment and get like a second opinion, a quick second opinion to actually understand the situation, what’s available from the usual sources, standard of care; what is available through more research sources and how to put all of it together.
Bill: As always, you are a wealth of knowledge Dr. Puzanov. Thank you so much for your time today. We appreciate it. For more information visit www.roswellpark.org. Just go to www.roswellpark.org. You’re listening to Cancer Talk with Roswell Park Comprehensive Cancer Center. I’m Bill Klaproth. Thanks for listening.