Patient Selection and Sequencing of Therapies in the New Melanoma Landscape

Transcription

1 Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: Released: 03/02/2015 Valid until: 05/06/2016 Time needed to complete: 15 minutes ReachMD info@reachmd.com (866) Patient Selection and Sequencing of Therapies in the New Melanoma Landscape Narrator Welcome to CME on ReachMD. This expert interview is: Patient Selection and Sequencing of Therapies in the New Melanoma Landscape, discusses the issues related to treating patients with either stage IV disease or advanced unresectable stage III disease, and how these new therapies play a role in the management of these patients. Your host is Merrick I. Ross, MD, Professor, Charles M. McBride Distinguished Professorship in Surgical Oncology, Chief, Melanoma Section, Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center Houston, TX. Dr. Ross will speak with Patrick Hwu, MD, Department Chair 2018 ReachMD Page 1 of 9

2 Department of Melanoma Medical Oncology, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center, Houston, TX Dr. Hwu has no relationship to report. Dr. Ross is on the speakers bureau and receives honoraria from Merck and GSK. This activity is supported by independent educational grants from Genentech USA, Inc., Merck, Prometheus Laboratories, Inc. and Provectus Biopharmaceuticals. After listening to this educational activity, participants should be better able to: Discuss the mechanism of action and clinical evidence of currently approved as well as emerging therapies for the treatment of melanoma patients. Evaluate the most recent recommendations for the use of approved strategies for melanoma treatment. Hello, My name is Merrick Ross, and I'm a surgical oncologist at MD Anderson Cancer Center, and in today s discussion, we re going to be addressing issues related to patient selection and sequencing of therapies for melanoma. As everyone knows, there's been kind of a revolution of therapies that are available now for melanoma, particularly in the advance disease setting. We re going to discuss mostly about issues related to treating patients with either stage IV disease or advanced unresectable stage III disease, and how these new therapies play a role in the management of these patients. So I'm going to be interviewing Dr. Patrick Hwu as the chief of our medical oncology group here at MD Anderson Cancer Center. Good evening Patrick, are you doing okay? Yes, wonderful, and thanks Merrick for inviting me ReachMD Page 2 of 9

3 So we ll start off with the monoclonal antibody pembrolizumab, which is an anti-pd-1 molecule, and could you, Patrick, tell us a little background about its approval and how it s being used currently and what you think the future for the use of pembrolizumab? This is a very exciting advance in our therapeutic ability to treat melanoma patients. Our immune system can be very dangerous to us, so our immune system naturally has brakes to stop reactions. For example, if you get the flu virus, your immune system will take off and you need something like a brake on the immune cells such as the PD-1 molecule. So anti-pd-1 though is an antibody that takes the brake off the immune system, and we need this when we have cancer and we re trying to stimulate the immune response to kill the tumor. So, as a medical oncologist, how do we decide when to use the anti-pd-1 molecules versus starting with ipilimumab, in today s particular melanoma treatment landscape? So, in general, we want to start with immunotherapies if we have the time. And the reason for this is every patient, their desire is to have a long-term durable response, and our immune systems have memory and so our immune cells can live a long time. So we usually start with immune therapy, and there are a number of immune therapies we can start with. One is the antibody ipilimumab. It s called anti-ctla-4, and the other is anti-pd-1, or pembrolizumab. So either can be used. The FDA approval for pembrolizumab was in patients whose tumor did not respond to ipilimumab therapy, however pembrolizumab has a bit higher of a response rate and fewer side effects, in my opinion, and so should also be considered up-front, and the studies show that it also works very well up-front prior to previous ipilimumab as well. So what about the combination of ipilimumab and another anti-pd-1 molecule called nivolumab? So this combination has been tested in a phase 1, and I think in a phase 2 study as well, and also probably 2018 ReachMD Page 3 of 9

4 has completed a phase 3 randomization to ipilimumab alone versus the anti-pd-1 drug, or the combination. Do we know where the results of that trial stand? Yes. So the combination of taking the brakes off of two molecules, CTLA-4 as well as PD-1, if you do that at the same time, that actually causes much higher response rates and they re also durable in patients with advanced melanoma. That was done in a fairly small study, but now there's a randomized study that is just awaiting for events of the ipilimumab by itself or the anti-pd-1 antibody Nivolumab by itself, or the combination and so when we get those results, we ll really see if the combination is better, but it really looks like, on the phase 2 studies, that the combination is going to be very potent. Can you tell us what the toxicity profile is of the combination versus either therapy alone or as monotherapy? So, anti-pd-1 antibodies, are fairly well tolerated. The major side effect is lung inflammation, pneumonitis, which can be severe in very rare cases. The main toxicity of ipilimumab by itself is diarrhea, hepatitis and hypophysitis, which is inflammation of the pituitary gland. Together, you do get increased side effects, especially diarrhea, which can be serious. It really is caused by colitis, so it has to be treated fairly rapidly when it does occur. So, you mentioned before that generally speaking, you would start with immune therapy, but what if the patient had had a B-RAF mutation? When would you consider using targeted therapy first in the stage IV setting, versus immunotherapy? So, in general, when a patient has a B-RAF mutation, it s nice that there's an option to use a B-RAF inhibitor, which has a high response rate and is also well-tolerated, and it s just an oral medication as well, so it s convenient, also. The challenge is that the durability is not so good, and with a B-RAF inhibitor by itself, it s about 7 months or so, average durability of response. It s a few months longer if you had added the MEK 2018 ReachMD Page 4 of 9

5 inhibitor. So is there any situation now where you would use monotherapy with B-RAF inhibition alone, or would you always use the combination of the B-RAF inhibitor plus the MEK inhibitor? The majority of times, if we re going to use the targeted therapies, it s the combination of the B-RAF inhibitor plus the MEK inhibitor because, interestingly, the two drugs by themselves are better tolerated than either drug by themselves. That s really not seen in the majority of chemotherapies, I can tell you, but because of that, we use it together and also the durability of response is better when the two are given together. However, if you were going to give this with immunotherapy, and that s the cutting edge, it s possible that the MEK inhibitor may inhibit the immune response. We still have to really look at this more carefully, but that MAP kinase pathway is important for an immune cell. So right now, the standard of care is not to combine the immunotherapy with the targeted therapy at the same time, so when would you decide now to use the targeted therapy first as opposed to the immune therapy? We almost always start with immunotherapy if we have time, because of the durability. But if the tumor is really growing rapidly, which is an extremely challenging situation for us to treat, then we would start with the targeted therapy, and then hopefully then work in the immunotherapy at some point. So what if the tumor was rapidly growing but the patient did not have a B-RAF mutation? What would be other options to use in that setting? Now that s a challenging situation. So, if the patient had a N-RAS mutation, there are other clinical trials that we can try, such as a combination of a MEK inhibitor and a CDK-4 inhibitor, which is showing some response. Otherwise we can try some of our old standby, such as chemotherapy or biochemotherapy, which, both of those can work fairly rapidly when they work, but again, usually the 2018 ReachMD Page 5 of 9

6 responses are not durable. So when you mentioned bio-chemotherapy, you mean the combination of cisplatin-based chemotherapy with IL-2 and interferon, is that correct? Yes, that s exactly right. So you mentioned the concept about a patient being N-RAS or having N-RAS mutation, what kind of progress have we made in those patients who are N-RAS positive? So based on a mouse model by Linda Chen, it looks like that combination of a MEK inhibitor plus a CDK-4 inhibitor may be effective in tumors that have that mutation, and it does look like that has shown some response in early clinical trials. So you mentioned earlier that the sequence of targeted therapy first, particularly when using a MEK inhibitor followed by immune therapy, may not be the best approach, but rather maybe immune therapy first and then followed by targeted therapy. There are a number of studies that are looking at that sequencing to see if targeted plus immune is better than immune plus targeted, or vice versa. The challenge with that is that sometimes when someone fails targeted therapy, it s hard to get them off that therapy because the tumor starts growing fairly rapidly in order to give you time to start the immunotherapy. That is what the challenge is. So that s why, in general, I start with the immunotherapy. So if you were just tuning into this discussion, you're listening to Project Oncology on ReachMD, the channel for medical professionals. Again, I'm your host, Dr. Merrick Ross, I'm a surgical oncologist at MD Anderson Cancer Center, and I'm speaking with the chief of our Medical Oncology Group at MD Anderson, Dr. Patrick Hwu, regarding the patient selection and sequencing of therapies for the new 2018 ReachMD Page 6 of 9

7 melanoma landscape. Patrick, can you give us some comments about what you think is the most challenging patient situation to treat overall for patients who have advanced metastatic melanoma? Yes. So the challenge, despite having six new drugs FDA approved in the last three years, is that still some patients fail everything, so that we have to do much, much better than we re doing right now still. More and more we re seeing patients at a tertiary center like MD Anderson that have failed ipilimumab, pembrolizumab, B-RAF inhibitors, chemotherapy and then the question is, what do you there? So, the pipeline is rich with new agents, but still, that s the most challenging situation in all, and oftentimes, we ll use many combinations of things like a chemotherapy, and as you know, as our collaborator many times, surgical metastasectomies. So now that you ve brought that up, about the role for surgery at stage IV disease, we re seeing a lot of patients who may have mixed responses where many of the sites are responding very well to the immune therapy or the targeted therapy, but there is one clone of cells that seems to be progressing while the other ones are actually regressing. Do you see a significant role for surgical resection in that setting? I think it s an excellent point and excellent time for surgical intervention. I think as our systemic therapies improve so that we can take care of micro-metastases, the role of surgical metastesectomy will increase. And I think we re seeing that. So what about the role for harvesting T cells from tumors that we resect, and to use those patents as a potential therapeutic option. I know in Europe there are some studies that are looking at multi-center trials to study the role for this adoptive type of therapy and certainly we ve a lot of experience at MD Anderson Cancer Center, and often at the Moffitt Cancer Center. Thanks for bringing that up, Merrick. In every tumor, there are immune cells trying to kill that tumor, so obviously not doing a good enough job because the tumor is growing, so we ve learned to take those 2018 ReachMD Page 7 of 9

8 tumors out and grow up the lymphocytes, the immune cells in those tumors, to very large numbers to billions, and then re-infuse those cells back to the patient. That s called T cell therapy. And that T cell therapy can have fairly high response rates, up to around 50 percent in some patients, and so, it is laborious and that s why it s only available at the National Cancer Institute, MD Anderson and Moffitt, and a few other places in America, as well as a few centers in Europe and Israel, because it is so labor intensive to do this. However, I think it s a good option for patients, especially if they have not responded to anti CTLA-4 or anti-pd-1 therapy. So before we finish, I d like to readdress the issue where you said that one of the biggest challenges is trying to figure out ways to have more durable responses and I think the best way to do that is probably to look at certain biomarkers. And I think one of the approaches to do that is to look at some neoadjuvant approaches in patients who have more earlier stage disease or they have advanced stage III disease that s actually where surgery would be the primary mode of therapy initially, followed by adjuvant therapy. So this may be an opportunity to look at markers within the tumor that can predict responses to certain therapies. I think it is an outstanding possibility and maybe our best chance of avoiding the challenging situation I talked about, a very resistant disease, if you can try to hit the tumor hard up-front, in a neoadjuvant setting. In fact, Merrick, you ve been involved in some of these trials and are really leading the way here. Why don t you talk about some of the studies that you have ongoing for neoadjuvant therapy. So, it s for patients who have resectable stage III disease where the standard of care would be surgery up-front, followed by adjuvant therapy. The adjuvant therapy part is a little bit complicated because, as you know, most of our therapies that are available in the adjuvant setting are really only modestly effective and are relatively toxic. We re still waiting for the adjuvant trial results using the targeted therapies and we re looking forward to an adjuvant therapy trial looking at Pembrolizumab. But in the meantime, we have the opportunity to learn about some of these therapies and why patients may become resistant to the B-RAF therapies, if they're B-RAF mutant, and why some patients may not respond to the immunotherapeutic agents. And the best way to find that out is to get tumor samples before, during, and then after treatment. We have patients who have B-RAF mutations, we have a randomized phase 2 trial of up-front surgery versus the B-RAF / MEK combination up-front with that 2018 ReachMD Page 8 of 9

9 therapy first for 8 weeks, and then followed by surgery, and there's clearly an opportunity to get surgical biopsies before, during, and after treatment. Then we would compare the outcome of those patients who received up-front surgery first. The other approach is for patients who do not have a B-RAF mutation, and we re looking at this combination of ipilimumab and PD-1 and actually randomizing patients to that combination versus the PD-1 therapy alone, and we re looking forward to starting that clinical trial in the near future. Again, looking at biomarkers obtained from the tumor tissue. So I think we re pretty much out of time. I think we ve covered most of the issues. Thank you again, Patrick, for participating in this discussion. I think it s a very exciting future, because the pipeline of new agents, as well, is very exciting. I appreciate you including me on this call. NARRATOR CLOSE This segment of Project Oncology on ReachMD is brought to you by Prova Education. To receive your free CME credit or to download this segment, go to ReachMD-dot-com-forward slash-projectoncology or go to the ReachMD medical radio app on your iphone, ipod ReachMD Page 9 of 9