Melanoma and Immunotherapy with Dr. Jedd Wolchok
In 2011, the FDA approved ipilimumab (Yervoy®) for the treatment of metastatic melanoma. This landmark immunotherapy approval has forever changed the way this skin cancer is treated—and is helping to increase the survival rate for patients with metastatic melanoma. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on melanoma and immunotherapy to educate and empower patients, caregivers, and advocates.
Jedd D. Wolchok, M.D., Ph.D., medical oncologist and chief of immuno-oncology service at Memorial Sloan Kettering Cancer Center, led the session on immunotherapy for melanoma, discussing progress made and what’s on the horizon to bring the benefits of immunotherapy to more cancer patients.
Dr. Wolchok opened the session with an introduction to immunotherapy for melanoma. He noted that while melanoma is one of the rare types of skin cancer in the U.S., it causes the most skin cancer-related deaths. Melanoma is relatively less responsive to conventional cancer treatment approaches, such as chemotherapy or radiation therapy. However, over the past decade the approval of immune checkpoint inhibitors like ipilimumab have significantly increased survival rates. He reflected, “The feeling of hope as a result of that is palpable. I see it in my waiting room, as people now run into each other more often.”
During the audience Q&A, Dr. Wolchok addressed common concerns from patients and caregivers in the audience. In response to a question about promising clinical trials, he drew attention to a type of immunotherapy called tumor-infiltrating lymphocyte (TIL) therapy that is becoming increasingly available to patients. TILs are a type of immune cell that can recognize and kill cancer cells. He explained that TIL therapy involves a three-week process of removing the tumor, isolating and growing TILs, and then reinfusing them into the body where they attack and destroy tumor cells.
The conversation moved on to common side effects of immunotherapy. Dr. Wolchok echoed Dr. Leena Gandhi’s guidance during the lung cancer and immunotherapy breakout session, emphasizing that side effects of immunotherapy are unlike chemotherapy or any other form of anti-cancer therapy. The most common side effect is inflammation of internal organs that might lead a rash, diarrhea, fatigue, and elevation of liver enzymes that may affect the endocrine glands of the body. For some immune checkpoint inhibitors, worsening of existing autoimmune diseases may occur. Most side effects can be treated with short courses of immune-suppressing drugs like steroids. Dr. Wolchok emphasized that more serious or potentially life-threatening side effects can be prevented with early detection.
He wrapped up the session reflecting on how advances in melanoma have affected cancer outcomes on a more global scale. He explained, “The lessons that we learn studying one can perhaps be the basis for therapeutic improvement for others.”
MELANOMA AND IMMUNOTHERAPY SESSION TRANSCRIPT
Tamron Hall: Welcome back, and for those of you joining us for the first time, welcome to the first ever Cancer Research Institute Virtual Immunotherapy Patient Summit. Let’s jump in on our session on melanoma, a type of skin cancer. I’m excited to be joined by Dr. Jedd Wolchok, an immunotherapy pioneer who helped bring the first FDA approved immunotherapy to melanoma patients. He joins us from Memorial Sloan Kettering Cancer Center in New York City, where he serves as the chief of melanoma and immunotherapeutics service. He’s also an associate director of the Cancer Research Institute Scientific Advisory Council. Brian Brewer, from the Cancer Research Institute, will be sharing your questions with Dr. Wolchok, so please be sure to put them in the Q&A box. Dr. Wolchok, Thank you for being with us today.
Dr. Jedd Wolchok: Thank you very much, Tamron. Welcome to all of the attendees of the CRI Patient Summit. We’re really happy to have you today. I am Jedd Wolchok, and I am the chief of immunotherapeutics at Memorial Sloan Kettering. I’d like to begin with an introduction to immunotherapy for melanoma. Just to quickly review, melanoma is one of several different kinds of skin cancers. As many of you know, skin cancer is the most common kind of cancer in people in the US. The two most common kinds are basal cell carcinoma and squamous cell carcinoma. Those are highly curable with surgery alone and very rarely require any other medication for treatment. Thankfully, recently, for more advanced cases of squamous cell carcinoma, we now know that immunotherapy, a drug called cemiplimab, has been approved by the US FDA for treatment of that disease.
Melanoma is one of the rare kinds of skin cancer, along with Merkel cell carcinoma and Kaposi’s sarcoma. Melanoma is in some people related to sunlight exposure. As opposed to basal cell cancer and squamous cell cancer, where the death rate is very low, melanoma is actually the highest cause of skin cancer related death in the United States. I think we have had a lot of interest in using melanoma as a model for immunotherapy. There are a lot of historical reasons for this, but one is that melanoma is relatively less sensitive to more conventional approaches to cancer treatment, such as chemotherapy or radiation therapy, and so it was a subject for immunology researchers for several decades.
Can I have the next slide, please? There are now, because of this historical interest in using the immune system as a therapeutic modality for melanoma, there are now numerous different immune modulators approved for the treatment of melanoma, and we’ll go through these very quickly. In addition, one type of immune therapy, called an oncolytic virus therapy, has been approved for melanoma, specifically for melanomas that can be injected on the skin, so metastases to the skin, or easily felt lymph nodes or other areas underneath the skin.
The immune modulators that have been approved for melanoma sort of historically include the interferons and interleukin-2. Interferons and interleukin-2 are in the class of medicines called cytokines, which are our hormones that the immune system uses to activate itself. Interferons were the mainstay of therapy for people with stage two and three melanoma for most of the 80s and early 90s, when there was a delay in time to progression shown after surgery when the use of interferon was started. Interleukin-2 is a growth factor for an important kind of immune cell, which I know you’ve heard about already, called the T cell. Interleukin-2 was actually discovered in the 80s, and it was quickly used to try to treat cancer, really based upon the pioneering efforts of Dr. Steven Rosenberg and the group at the National Institutes of Health.
Interleukin-2 was shown to have activity in mainly two cancers, kidney cancer and melanoma. What we now know is that a small, but real, number of people with very advanced melanoma can in fact be cured with interleukin-2. The challenge with the medicine is that that number is lower than we want it to be. It’s probably about 3% to 5% of people that have a very durable response from it, and it can have very severe side effects, which restricts its use to people who are relatively healthy.
The most recent addition to the immunotherapy agents used to treat melanoma include what are called the checkpoint blocking antibodies. These are medicines that really interfere with the molecular breaks that keep the immune system under control. In general, the breaks that we’re interfering with are two pathways, one called the CTLA-4 pathway and the other called the PD-1 pathway. There are a variety of PD-1 or PD-L1 blocking medicines that have been approved for use either alone or in combination with other treatments for melanoma. Then there are the CTLA-4 blocking drug, ipilimumab, which Tamron mentioned at the beginning.
I was one of the investigators that led a trial that really was responsible for making ipilimumab the first medicine to show an overall survival benefit in patients with melanoma. In fact, one of the courageous volunteers for that clinical trial could very well be in the audience today, and that is Ms. Sharon Belvin, who was treated as a part of this, one of the initial clinical trials of ipilimumab now over 16 years ago. She was treated for a total of three months. She had a complete remission, which is ongoing. She’s had two wonderful children since then. She’s gone on to become a triathlete and an advocate for immunotherapy. We’re of course extremely happy to have seen her restoration of full health, and we’re extremely grateful to her for the time and effort that she has given to the cause of immunotherapy and specifically to the efforts of the Cancer Research Institute to widen awareness about this form of anti-cancer therapy. For me, as a clinician and investigator, having outcomes in early clinical trials that include what we saw in people like Sharon, that is really the best kind of motivation to continue to work diligently in this field to find new and better treatments to offer to our patients.
Brian Brewer: All right. Well, thanks for that brief introduction, Jedd. Always good to see you. Since it’s hard to believe how far the field has come since that first FDA approval in 2011 of the first checkpoint blockade, since that time, how has standard of care changed for melanoma patients?
Dr. Jedd Wolchok: Melanoma patients really have now had access to medicines like ipilimumab, as you said, Brian, since 2011. The feeling of hope as a result of that is palpable. I see it in my waiting room, as people now run into each other more often. They’re living for long periods of time and encouraging each other, talking about new treatment modalities. Of course, we first saw that there was the possibility of long-term disease control with drugs like ipilimumab, which gave rise to the PD-1 blocking drugs. Then that gave rise to combinations of those medicines together.
In addition, we now know that these immunotherapies can be combined with some of the other approaches to melanoma therapy, which include the targeted therapies. As you know, melanoma is characterized in about half of people with a mutation, a genetic error in a gene called BRAF, B-R-A-F. Around the same time that ipilimumab was approved, inhibitors of BRAF and MEK, another member of the pathway that BRAF sits in, also showed very high activity in melanoma. So, now we see multiple different treatment options for people with newly diagnosed advanced melanoma.
We see single agent checkpoint blockade with either CTLA-4 or PD-1 pathway blockade. We see combined CTLA4 plus PD-1 blockade. We see very recently the FDA approval of a PD-L1 blocking antibody along with a BRAF and MEK inhibitor. We’ve also seen activity of one of the oncolytic viruses, T-VEC, in patients with melanoma. There are actually clinical trials, which we’re waiting for the readout from, that have looked at the combination of T-VEC with immunotherapy, specifically with PD-1 blockade, to see what additional activity that yields.
Brian Brewer: Well, thanks for touching on BRAF. We had just gotten a question in from one of our viewers about it and its significance in melanoma and specifically in immunotherapy treatments, so I think you addressed that, unless there’s anything else you want to say about BRAF.
Dr. Jedd Wolchok: I actually would just add one thing that the patients in my own practice often ask, and that is, if a patient has a tumor with a BRAF mutation, is that something that they would need to worry more or less about, specifically in terms of their family’s propensity to develop melanoma? I think it’s important to recognize that the BRAF mutation is only found in the melanoma cells. It is not found in the normal cells in the body, and so it is not passed along through families. We definitely do see families in which melanoma occurs in multiple generations. That is, I would say, the vast minority of people, but BRAF is not something that people need to worry about in terms of transmitting that to their relatives. What I try to tell people is that having a BRAF mutation is neither a good thing nor a bad thing in terms of the prognosis of the melanoma, but rather it is just a signal that we use about whether or not to offer a particular class of therapies.
Brian Brewer: Okay. Thanks for that. You mentioned a combination, a clinical trial combining an oncolytic virus with checkpoint blockade. Now that melanoma is treated with checkpoint blockade as part of the standard of care, are there other exciting clinical trials that you’re looking at right now or that have some near-term impact for more patients or melanoma patients?
Dr. Jedd Wolchok: Yeah. I think that the clinical trial landscape in melanoma has been very rich, and we’re very grateful for that. A few trials that I’ll just mention that hopefully we’ll be reading out soon or that I think are important for the field, one is a trial that’s looking at a type of immune therapy called tumor infiltrating lymphocyte therapy, or TIL therapy. This is a kind of treatment which was previously only offered at a very select few hospitals in the country. It’s really based upon some work originally done at the surgery branch of the National Cancer Institute, where a tumor is removed by a surgeon and then the immune cells are separated away from the tumor cells. The immune cells are grown in the laboratory for several weeks and then re-infused, like a transfusion, into the patient after the patient receives pretty high doses of chemotherapy to make what is called immunologic space for that infusion of immune cells.
In this way, it’s a method to try and improve the number of immune cells, specifically T cells, that recognize a tumor in an individual patient. There has, until now, again, this has only been offered at a select few places, but now there are some commercial entities which are attempting to try and offer this through centralized manufacturing of the tumor infiltrating lymphocytes and then read disparate redistribution of the patient specific drug, if you will, back to the patient’s home hospital, where the patient can receive this treatment. We are eagerly awaiting the results of a clinical trial that is ongoing right now.
It takes about three weeks to manufacture the TIL. During that time, the patient is not receiving other treatment. Toward the end of that three to four weeks, the patient’s admitted to the hospital, given chemotherapy. Then they receive the TIL. Then they receive one of the immune modulators that I mentioned before, interleukin-2, to try to help those cells expand.
Another clinical trial that we’re very interested in, it’s actually a class of clinical trials, which are called neoadjuvant clinical trials. These are studies that are done in patients who have a metastasis, say a lymph node that could be removed surgically, where we wonder whether giving people some immune therapy before that surgery is done might improve their outcome, make the tumor smaller, make the surgery easier, and in the ideal situation cause the entire tumor to be killed by the immune system.
What we’ve now seen is that there have been somewhat have been called pathologic complete responses seen with immunotherapy offered just once or twice before a planned surgery. When the surgeon goes in and he or she removes the tumor, sends it to the pathologist, the pathologist has given some great news, saying, “Hey. Guess what? Yes, there was a mass there, but it was nothing but a lot of activated immune cells. There were no living tumor cells there.” That’s really the best possible news that we could receive.
This idea about whether this could be a way to change our standards of care about when we offer surgery, what we do before surgery, because I think it’s a natural inclination that we, as humans, have that … If somebody says, “You have cancer, and we can remove it,” the next question is, “Well, how fast can you get that removed from my body?” We’ve tried to offer surgery as quickly as possible, but now we’re wondering whether it might be advantageous to the patient to perhaps wait a few weeks for that surgery and use the immune system as a tool to treat the disease during that period of time. That’s another class of trials which are ongoing right now that we’re quite interested in.
Another class of studies looks at what are called intratumoral injections. This gets to I think one of the questions, Brian, that you circulated in advance that had to do with the difference between hot and cold tumors. Hot and cold is sort of a cheeky vocabulary that we immunotherapists use to talk about a hot tumor, which is just full of immune cells and just raring to go or a cold tumor, where the immune system really has been ignoring that tumor. If you look at the tumor itself under the microscope, it’s nothing but cancer cells and not much else.
What we know is that the currently available immune therapies work best in people who have hot tumors, where the tumor itself, the mass, yes, has cancer cells in it, but also has immune cells that are somehow being kept in check by one of these checkpoint mechanisms that we spoke about earlier, one of these molecular breaks. All we need to do is disable those breaks and let the immune cells that are sitting there poised and ready do their thing and kill the tumor cell. The hot tumor is really the best setup. The cold tumors are ones where you have to do some extra work as a clinician to get the patient’s immune system to heat up that tumor.
By injecting that tumor with either an oncolytic virus or a class of chemicals called TLR lignans or toll-like receptor lignans, these are actually synthetic versions of things that are found in bacteria or viruses to trick the immune system into thinking that there are bacteria or viruses in the tumor and heat it up by putting immune cells in. We now have several clinical trials ongoing looking at whether the combination of an intratumoral injection with a checkpoint blocking antibody, like a PD-1 or PD-L1 blocking antibody is better than the antibody by itself.
Brian Brewer: Our next question coming in … And those of you who are watching, please feel free to leave your questions in the Q&A. We’ll try to get to as many of them as we can today … is how long does it take a person to know that an immunotherapy is working?
Dr. Jedd Wolchok: This is a very important question and one that I don’t have a simple answer to, except that it really varies. There are some people where we can see, because they have tumors on or under the skin, resolution of quite large masses within the first say three weeks of treatment. There are other people where we know that the response or the reduction in size of the tumor may not happen for at least three months. This is a lesson that we learned quite early on in the clinical trials of ipilimumab.
Actually, we found out that you needed to perhaps delay the assessment of the anti-tumor response beyond even three months in some people, because these tumors can actually in some people enlarge in size before they eventually decrease in size, not necessarily because there are more cancer cells, because as the immune cells begin to infiltrate the tumor, they make the tumors appear larger. We don’t yet have standard scans available that can differentiate between tumor cells and immune cells. There are clinical trials of some of these what are called immuno PET scans being done at Memorial Sloan Kettering and other places right now to try to look at that, but I think that we need to have a very open mind about when the benefit of immunotherapy can best be observed.
Brian Brewer: The other side of that question then is how long does an immunotherapy regimen typically last in melanoma?
Dr. Jedd Wolchok: I think the aligned answer is that it varies from person to person, because there are some folks who may get just one or two doses of say the combination of ipilimumab and nivolumab. They may have a significant toxicity from that, but they may have a very dramatic anti-tumor response, and it may be impossible for them to receive additional therapy, but we don’t know whether they need additional therapy. I think this is a very important point of patient and family education that we introduced early on, that the goal is not to get as much medicine for as long as possible into an individual person. The goal is to make the tumor go away and have the least possible side effects. Once you have observed that the immune system has caused a potentially life-threatening side effect, then that may be a signal that the medicine has done its job or maybe done a little bit more than its job and it’s time to stop.
Unlike things like chemotherapy or targeted therapy, where the medicines are directly interfering with the tumor cell’s ability to divide, immunotherapies are actually acting in a much more indirect way. They are causing the immune system to be more activated. Once that happens, we are not sure that you need to continue with the administration of these medicines. It’s a very important question. Actually, one of my colleagues, Dr. Geoff Gibney at Georgetown, just launched a clinical trial in the Eastern Cooperative Oncology Group, or ECOG-ACRIN, which I am very honored to serve as the melanoma committee chair for, called the PET-Stop Trial, which basically uses early PET scans as a decision point as to whether or not you need to continue immunotherapy. We really need to do clinical trials like this to determine what are the best indicators of when to stop treatment? Because perhaps we can do it before someone has a side effect.
Brian Brewer: Well, speaking of side effects, that’s always a common question we get. What are some of the more common side effects, and how do you deal with them?
Dr. Jedd Wolchok: Thankfully, some of the other speakers… Dr. Gandhi did a really good job of introducing this, but the side effects of immunotherapy are unlike chemotherapy or other forms of anti-cancer therapy. They represent inflammation of normal organs. Some of the more common ones with the medicines that we use to treat melanoma include rash, diarrhea, elevation of some of the liver function tests, which is not something that a patient would feel, but something that we would detect, a slowing down of function of some of the endocrine glands in the body, such as the thyroid or the pituitary gland. For some of the PD-1 blocking drugs, the worsening of pre-existing arthritis is not uncommon. Fatigue is pretty common. There is a long list of even rarer events. Thankfully, most of these are reversible by either stopping treatment or giving a short course of immune suppressing medicines, like corticosteroids.
There are other side effects, which are more permanent, such as the damage to the endocrine organ, so some people will end up having to take a thyroid hormone replacement or pituitary hormone replacement. Type one diabetes has occurred in about 1% of people, and this obviously leads to insulin dependence. Then very rarely, but importantly, we’ve seen the development of potentially fatal side effects. These include inflammation of the heart and lungs. With early detection of the side effects, we have been able to control them, but in some people, especially with the heart inflammation or the myocarditis, the number of people who die from that side effect reaches about nearly 50% of the people who develop symptoms from it. Now, thankfully, that is a side effect that occurs in one in thousands, but it is still something that we are very eager to learn why it is that a very small, but real, number of people have this side effect, how we might know that ahead of time, so we could be extra cautious, and what we need to do to perhaps intervene even sooner.
Brian Brewer: Another question we’ve received is, is there an optimal point at which a person should receive an immunotherapy? This is related to the stage of disease.
Dr. Jedd Wolchok: It’s a terrific question. This is probably the most common question that I answer in my outpatient practice every week. We see a large number of people who come to us for what is called adjuvant therapy, which basically means the person has had surgery. They are usually for stage three or four melanoma. They have had all the disease that can be seen on a scan or felt on their body removed, and yet because of how many lymph nodes were involved or how deep the primary tumor was, they are at a higher or lower risk of recurrence. We now know that there are various options for treatment that might be received to lower that risk of recurrence.
Right now, for people with stage three melanoma, and this is melanoma that has spread to sites in the skin distant from the primary or lymph nodes in the area where the primary tumor was, or stage four melanoma, so if the distant metastasis has been removed, those people can receive a CTLA-4 blockade with ipilimumab, or they can receive a PD-1 blockade with either nivolumab or pembrolizumab, or they can actually also receive BRAF and MEK inhibitors if the tumor has a BRAF mutation. For that indication, dabrafenib and trametinib is the pair that’s used.
Now, there has recently been a clinical trial, which just completed accrual in stage two melanoma, so people in whom the tumor is moderately deep in the skin, but there were no lymph nodes involved. The question that was asked is, giving those people the option to receive PD-1 blockade, is that something that will delay recurrence or prevent recurrence? The question that we have to grapple with is we still do not know whether offering people treatment in this setting is better, worse, or the same as offering them the same treatment if they should have a recurrence in the future. As a clinician, I take this question really seriously, because we’re treating people not for a recurrence that we know they have, but rather for a calculated risk of recurrence. If I see a hundred people with stage three melanoma, maybe half of them will have a recurrence. The other half won’t. If I’ve given them all adjuvant therapy, then half of them will only have the possibility of having side effects and not have any possibility of having a clinical benefit in terms of melanoma, because they weren’t going to have a recurrence anyhow.
I think that one major goal for our own research program and many others is using ultra-sensitive methods for detecting minimal residual disease. I mean, right now we do scans, but can we do blood-based analysis looking for what’s called circulating tumor DNA in people’s blood as a very sensitive way to detect really minute amounts of cancer in people after surgery, so we know the difference between minimal residual disease and no evidence of disease, and so therefore we could offer adjuvant therapy to people who we know need it, rather than a large population in whom some need it and some don’t.
Brian Brewer: We are almost out of time, and there are still so many more questions. We will try to get to them after today’s events if we hadn’t. This one is a one that you’ve gotten before, Dr. Wolchok, about diet and exercise. This person actually has heard the word microbiome, so how are those two things related?
Dr. Jedd Wolchok: This is a really important question, and there are some ongoing clinical trials looking at the connection between the microbiome, which is the population of bacteria that, if we’re talking about the intestinal microbiome, that lives in our colons and the immune tone in our bodies and how that interplays with immunotherapy. There are some very impressive pre-clinical studies with some early clinical signals that have been published over the past few years.
The answer that we now know is that it’s best not to try to manipulate your own microbiome by taking probiotics. There was some recent data published by the outstanding group at MD Anderson showing that in fact those people do worse with immunotherapy if they try to manipulate their own microbiome with probiotics. I always advise people that exercise and a balanced diet could do nothing but help them in terms of their quality of life, so I’m a big proponent of that.
Brian Brewer: Wonderful. Just to close, how has immunotherapy transformed your outlook on treating patients with melanoma and cancer in general?
Dr. Jedd Wolchok: I’ve been a believer from the start, but I have now seen the power of immunotherapy to have a major impact on the outcomes from metastatic melanoma. When I first started practicing on the faculty at Memorial Sloan Kettering in the year 2000, the median survival of people with melanoma was about six months. Now, actually, the median survival of the population of people who are in the clinical trial of ipilimumab and nivolumab, the CheckMate 067 Trial, with five years of follow-up the median survival hasn’t been reached yet for the people who started with the combination, meaning that the average person is living longer than five years. Yes, we have more work to do, but the amount of hope that I have seen generated among our own population of patients and us, the clinical team, it’s tremendous. The waiting room is a very hopeful place.
I am just so grateful to have been here in this field at this time. I’m very grateful to the CRI for their visionary commitment to this field of immunotherapy. Actually, I really believe that the lessons that we’ve learned trying to find better treatments for melanoma has affected cancer outcomes on a more global scale. You know, just last night I got an alert on my phone from the AACR that I believe the FDA approved the combination therapy of ipilimumab and nivolumab to treat mesothelioma. It made me, as one small worker ant in the field, very, very happy to see that the work that we originally did in a few dozen courageous people who volunteered for the phase one trial of ipilimumab and nivolumab for melanoma, that initial group of people can now feel as if their dedication impacted cancer outcomes and treatment availability not just for melanoma, but for melanoma, for kidney cancer, for the rare kinds of colorectal cancer due to MSI high status or mismatch repair deficiency, to non-small cell lung cancer, to hepatocellular cancer, primary liver cancer, and now to mesothelioma.
I think that we are seeing that, yes, it’s important to study the biology of individual diseases, but there are common threads, like the interaction between the immune system and the cancer cells, that can be shared among different kinds of cancer of different origins. and that the lessons that we learn studying one can perhaps be the basis for therapeutic improvement for others.
Brian Brewer: Well, thank you so much, Dr. Wolchok. That was a fantastic way to wrap up. I know this is going to be helpful for a lot of people who are watching today and will continue to be able to watch in the future, so thank you again for being with us.
Dr. Jedd Wolchok: Thank you, Brian. Always a pleasure.
Tamron Hall: Thank you, Dr. Wolchok, for that informative and helpful conversation about melanoma and immunotherapy. As we wrap up day two of the first CRI Virtual Immunotherapy Patient Summit, I would like to thank all of you for attending and participating. We hope that today was an empowering experience for you, and we look forward to hearing from you in our follow-up survey. We would also like to, again, thank our sponsors for their generous support. We want to thank our hosts institutions for their support, as well as the incredible immunotherapy experts who joined us over the past two days.
We will be sharing all of today’s slides, video recordings, as well as the CRI Resource Guide, which includes valuable information from the virtual summit partners, as well as CRI’s free Immunotherapy Clinical Trial Finder Service. Finally, I’m excited to tell you that we will be inviting you to register for day three of the summit, which takes place on Saturday, December 5th. During this free program, we will hear from top doctors in bladder, blood, colorectal, head and neck, kidney, and pancreatic cancers. We encourage you to register right away to reserve your spot and join us for another afternoon of learning and networking. I’m Tamron Hall, and it was my pleasure to be your host for this important event. Thank you. Stay safe and enjoy the rest of your day.