Hi! I am Dr. Sandy Liu. I am a medical oncologist and the Medical Director of the UCLA Kidney Cancer Program at the Institute of Urologic Oncology and the Johnson Comprehensive Cancer Program at UCLA. Today I am going to talk about Metastatic Renal Cell Cancer in 2019: Aiming to Cure with Aggressive Systemic and Multi-Modal Therapy. So, for my talk, I’m going to talk about– oh, sorry– this is having problems–I’m going to go over the background, specifically talking about statistics and the risk factors for who gets kidney cancer, I’m going to talk about the histology, clear cell versus non-clear cell, the risk stratification, for when I see a patient for the first time in clinic, how do I determine if they’re favorable, intermediate, or poor risk, and make treatment decisions based on that, and for the majority of my talk, I’m going to go over treatment because the landscape is continuing evolving at a very fast pace, and treatment becomes more complex and now more personalized than ever, and the last part I want to touch on is a subset of patients who have oligometastatic disease, in those who have limited sites of disease who may be amenable to a multi-modal therapy. So here at UCLA, we have our Kidney Cancer Program, and we aim to search for a cure through a multidisciplinary approach to treat kidney cancer. So, here’s the problem. Kidney cancer is the eighth most common cancer in men and women in 2019. An estimated 74,000 men and women get kidney cancer, and among those, 16% are diagnosed with stage 4 disease, which has metastasized, and the 5-year survival really depends on the stage of disease. So if you have localized disease, the 5-year survival is 93%. It goes down when cancer has spread to surrounding tissues or regional lymph nodes to 70%. When it spreads beyond the kidney and the lymph node, even with an abundance of effective therapies in 2019, the 5-year overall survival is a dismal 12%. So, how can we do better? Well, we need to have a better understanding of the disease. We need to have biomarkers to guide treatment, a novel combination of approaches to treatment, as well as a multi-modal therapy because ultimately, patients want to be cured of their disease. They want to live longer, have a good quality of life with limited toxicity. So, who gets kidney cancer? There’s hereditary and non-hereditary risk factors. Hereditary risk factors comprise about 5-10% of all kidney cancer cases, and the most common is von Hippel-Lindau, or VHL, hereditary leiomyomatosis and RCC, and Birt-Hogg-Dube. At UCLA, we are a recognized VHL clinical cancer center, and my colleague Dr. Brian Shuck, who is a urologic oncologist as well as the Director of the Kidney Cancer Program, is an expert on these hereditary familial cancer syndromes, and he has built a robust program here for these patients. The non-hereditary risk factors include smoking, gender–men are 2-3 times as more likely to get kidney cancer as women, African-American, older age –the median age of diagnosis is around 64 years old, high blood pressure, obesity, and chronic kidney disease. So, I want to go over the histopathologic features. Clear cell is the most common variety, about 70%-80%. Non-clear cell has about 15 or more subtypes, but the most common is papillary, chromophobe, collecting duct, and unclassified. I do want to mention sarcomatoid or rhabdoid features that can be associated with any of the above histology and is a harbinger for prognosis just because of its aggressiveness and its resistance to treatment. So, risk stratification. Advanced kidney cancer has a highly clinical variable behavior. Presentation can vary from an incidental detection to being very highly symptomatic due to the disease burden. Some patients, however, with limited metastatic disease can be managed with observation. Sometimes we watch these patients for months and even years before starting systemic therapy, and we always consider patient and tumor factors when selecting therapy, such as the patient’s multiple medical problems. There are symptoms of disease, there are sites of disease, their performance status, as well as the histology. Our stratification really aims to get the patient the most appropriate therapy for their disease. So, how do we risk stratify these patients? Well, it’s based on 2 clinical and 4 laboratory parameters, and it’s using the IMDC criteria. So, the two clinical parameters is the performance status of the patient, the time from diagnosis to treatment of less than a year, and laboratory parameters, which includes a low hemoglobin, a high neutrophil count, a high platelet count, and a high corrected calcium serum. So if you have no risk factors, you’re in the favorable risk. If you have 1-2 risk factors, you’re in the intermediate risk, and if you have more than 3 factors, you’re in the poor risk. I should note that about 75% to 80% of patients that are newly diagnosed fall into the intermediate and poor risk category, and in a large study in 2009, they looked at more than 500 patients treated with targeted agents and found that patients with favorable risk have a 43-month overall survival. Those with intermediate risk have a 23-month overall survival, and those with poor risk have about an eight-month overall survival. Now, this was in 2009. Because our therapies are so good, patients are living longer, even in the poor risk category. So, what are the goals of treatment? And the goals may be different for each patient, but the ultimate goal for us as well as for the patient is to live longer with the best quality of life for those patients with active sites of these disease. There are several modalities that we can do to help treat these diseases, and they include medical treatments to shrink and destroy the active site of disease, cervical treatment, which helps to remove the site of disease by surgical resection, as well as ablative techniques, either radiation or using heat or ice to locally destroy the active site of disease. Generally, for most patients with multiple sites of disease, the mainstay of treatment has been medical or systemic therapy. So, here’s a timeline of approvals. Before 2005, the only FDA-approved therapy to treat kidney cancer was high-dose IL-2 and interferon alpha. Since 2005, we’ve seen an explosion of therapies. Currently, there’s 13 available systemic treatment agents. Most of them are targeted agents. However, 2015 was when immunotherapy Nivolumab got approved in the second-line setting for advanced kidney cancer, and 2018 was a tremendous year. It was a game-changer because the combination immunotherapy of Ipilimumab and Nivolumab really allowed these patients to live longer and have a better quality of life. Most recently, we’ve had the combination of a targeted agent as well as immunotherapy recently approved, and I’m going to go over these in later detail. So, I want to talk about high-dose IL-2. This was the first FDA-approved drug and the only agent we know with long term remission of over 10 years. High-dose IL-2 has a rich history in UCLA. Our kidney cancer program founder, Dr. Ari Belldegrun worked with Dr. Steve Rosenberg at the NIH, who developed high-dose IL-2, and Dr. Belldegrun brought high-dose IL-2 back to UCLA, ran his clinical trials until it got approved in 1992. Since then, he’s built a very strong collaborative high dose IL-2 program. We have a lot of experience, treated many patients, and a portion of them were actually cured, and it was considered one of the most experienced sites in the West Coast. As I mentioned, high dose IL-2 can cure about 3%-7%, but it’s in highly selected patients. As you can see down here in the graph, those who benefited the most from high dose IL-2 were the favorable risk patients, and high-dose IL-2–the management can be very challenging. It is highly toxic, and it must be given in the intensive care unit. As of right now, high dose of IL-2 has been largely replaced by immunotherapy, given its even higher cure rates with limited toxicity. So, kidney cancer is a highly angiogenic cancer. It likes to form new vessels in order to feed and help the cancer grow and spread. So, the tumor secretes a protein called VEGF. VEGF actually is bound to a receptor on the blood vessel. When VEGF binds to the VEGF receptor, it likes to form new blood vessels so it can feed itself and help it grow and metastasize. So, the premise of these VEGF targeted agents is really to block off the VEGF receptors, so VEGF cannot bind and cannot form new blood vessels to feed the cancer, and we’ve seen an improved survival with these targeted agents, and as you can see, all of the risk groups–favorable, intermediate, and poor–have benefited from these targeted agents. So, the first targeted agent I want to go over is sunitinib. This was the first targeted agent to be approved in the first-line setting and it was compared with interferon alpha and showed a benefit in progression-free survival. So when I mean progression-free survival, it means how long can the patients stay on therapy and how well their disease is controlled, and it’s shown that sunitinib had a progression-free survival of 11 months compared to interferon alpha of 5. Sunitinib also had a better response rate of 31% compared to only 6% with interferon alpha, so this has changed the landscape, shifting from high-dose IL-2 to targeted therapy, and sunitinib is used to compare how well immunotherapy works. The second targeted agent I want to go over is cabozantinib. It is approved in the first as well as in the second-line, and it was improved in the first-line based on the CABOSUN study. It compared cabozantinib versus sunitinib, and it showed a improvement in progression-free survival of 8.2 months with cabozantinib versus 5.6 months with sunitinib, and it also had a better response rate. Patients’ tumors were shrinking on the scan by 46% compared to 18% with sunitinib. So for the first time, cabozantinib was the only targeted agent to actually outperform sunitinib, and because of these data, it was approved for intermediate and high risk patients in the first-line setting. Cabozantinib was also looked at in the second-line and beyond setting, and it was compared with everolimus. Everolimus is another targeted agent that targets the mTOR pathway. Cabozantinib has shown an improvement in, again, progression-free survival response rate, and patients were living longer on cabozantinib. So based on this data, it’s approved for the second-line and beyond. The last targeted agent that I want to mention is axitnib. Axitnib is a highly selective oral potent VEGF receptor. It is currently approved in the second-line setting but does have activity in the first-line, and given its well tolerability, it has been combined with immunotherapy with pretty impressive results, and I’m going to go over those results in my later slide. So now, we’re entering the future of reaching for a cure in kidney cancer with immunotherapy. So, T-cell is part of the immune system, and we need the immune system active to go and attack the cancer cells. PD-1 and CTLA-4 are expressed on these immune T-cells, and when they’re bound to their receptors, they turn off and shut down the immune system. So, tumor cells likes to utilize this pathway, and they can try to masquerade themselves as normal cells, so basically shield themselves, from the immune system so they cannot recognize the cancer. And when we block these PD-1 and PDL and CTLA, we unleash the immune system. We unmask the cancer cells. So now, when an immune system does its surveillance, it can recognize and go in and attack the cancer cells. So, immunotherapy was first approved in 2015 with nivolumab. Nivolumab is a PD-1 inhibitor, and it was studied in the second-line setting, which showed an overall survival advantage, so patients live longer when they got immunotherapy in the second-line setting. But this was a game changer, when immunotherapy combination nivolumab and ipilimumab, which is a CTLA-4 inhibitor, was approved for these newly diagnosed patients, and for these newly diagnosed patients, when they received this combination, they were able to live longer and decrease their risk of death in the intermediate and poor risk patients. And more impressive is the response rate. At a 30 month follow-up, about 11% had their disease completely eradicated. “They had their disease cured” in the intermediate and poor risk. In the favorable risk, we see the complete response rate of 8%, which is also very impressive. Not only that, immunotherapy improves quality of life. As you can see here, it had an improvement in health-related quality of life compared to sunitinib. So overall, these immunotherapies–they do have their side effects, but generally it’s manageable and well-tolerated. So in essence, immunotherapy improves survival with an excellent quality of life with impressive responses, and the responses are commonly long-lasting. So even if patients discontinue therapy prematurely due to side effects, we’re still able to see responses of therapy. But the impressive responses–they only occur in about 40% of the patients, with only 10% cured. So we still have a long way to go, and we still don’t know how to predict efficacy. We don’t know who will have their response and who will not. So now, we’re really entering the dawn of a new treatment era with the combination of an anti-PD1 and a VEGF pathway blockade. So, the combination of a targeted therapy and immunotherapy really boosts responses. So it’s well studied that these VEGF targeted agents act synergistically with immunotherapy, and they really enhance the immune response. So, pembrolizumab and axitnib was the first combination therapy approved just recently in April. Pembrolizumab is an anti-PD1 antibody, which by itself has some anti-tumor activity, and axitnib we know is a highly potent VEGF targeted agent. It’s approved in the second-line setting, but it also has activity in the first-line setting. So, the combination of pembrolizumab and axitnib really demonstrated a high overall response rate, a progression-free survival, and an overall survival. And this was done in the KEYNOTE-426 study design, and what they found was the combination actually lowered the risk of death by about 47%, and the benefit of the combination was seen across all sub groups, including favorable, intermediate, and poor risk, and it didn’t matter if you were PDL-1 or PD-1 negative or positive, all the subgroups benefited and also had an improvement in progression-free survival. Patients on average stayed on therapy for about 15 months. Additionally, there was impressive response rates. The combination had a response rate upwards till 60%, whereas sunitinib was only 35%, and about 6% of patients are cured with this combination therapy. The second combination therapy I want to go over is avelumab and axitnib. And this was recently approved just last month in May. Avelumab is a anti-PDL1 antibody, again, has shown activity as a single agent in the first-line setting, and the combination of axitnib and avelumab has, again, demonstrated a high overall response rate as well as progression-free survival. So this is the study design, it’s JAVELIN 101, very similar to the pembrolizumab and axitnib study design, and again, it showed that the progression-free survival benefitted across all risk groups, the favorable, intermediate, and poor. The response rates also favored the combination in all risk groups. So now, I want to shift gears and talk about non-clear cell. So, this is a heterogeneous group, and it comprises about 15% to 20% of cases. Unfortunately for non-clear cell, FDA-approved therapies are lacking, and treatment guidelines now suggest enrolling these patients in clinical trials or use VEGF targeted therapies. S,o these patients have a significant unmet need for a safe and effective treatment options. Sarcomatoid histology, likewise– it comprises about 10% to 20% of patients. They can coexist with any subtype histology, and we know that patients with non-clear cell or sarcomatoid differentiation have inferior survival. And sarcomatoid usually expresses PDL-1 with an immune signature because we know that these tumors are usually inflamed, and we know they respond better to immunotherapy. So, this study, Immotion 151, looked at patients with non-clear cell as well as sarcomatoid histology, and they randomized these patients to a PDL-1 inhibitor atezolizumab as well as bevacizumab, which is a VEGF monoclonal antibody, and what they found was pretty impressive response rates for the overall patient population. The response rate was 34%, and specifically, the non-clear cell patient had a 26% response rate, and it was even higher if they had a sarcomatoid histology. Now, what is the role of the surgery in the primary tumor? So, removing the primary tumor has really been the mainstay of initial management in newly diagnosed advanced kidney cancer. More recently, new data has suggested that not all patients will benefit from this approach tree upfront. It’s really for those fit, healthy patients that can withstand surgery and are able to afford to delay systemic therapy that we take them to surgery right away. Now, because we have such good systemic therapies, surgery can be delayed until their disease responds to the treatment and then we can take them to surgery. We all know that long-term responders generally do well when they have their kidneys removed. So, what is the role of local treatment of limited sites, also known as oligmometastatic disease? So, the rationale for treatment of metastases is twofold. One is for palliation, to control pain and to alleviate oncologic emergencies, such as spinal cord compression to stabilize fractures and prevent seizures. The second rationale is the potential for improving oncologic outcomes. It may confer a survival benefit, and at some times it can delay and avoid a sometimes toxic systemic therapy. Consolidated surgery, or metastasectomy, can be used in a variety of ways. One is to consider surgical resection, or we can consider radiation or ablation to treat these local sites of disease. And we asked for all of these patients with oligometastatic disease. We always consider the pace of this disease and the period of surveillance before going on to local treatments. So, metastasectomy, based on a large series of studies, was the significant predictor of survival. If you have a complete resection, the 5-year survival goes upwards to 50%. If patients do not have resection of their metastatic sites, the 5-year survival is 12%. Lastly, I want to emphasize the integration of care. Kidney cancer is only getting more complex. We have better systemic therapies, we have new technologies for surgery, and the use of precision medicine. So, really, care cannot take place in isolation. We need a multi-modality treatment team that improves patient satisfaction and outcome. At UCLA, we have a comprehensive Kidney Cancer Program. We take an individualized approach and present each patient during our multidisciplinary case conference to determine the best treatment approach for each patient. We know that there is a movement towards centralization of kidney cancer care in many countries, and it was recently reported in the European urology journal that supports data that high volume care centers has improved outcome versus centers that are in isolation. So, in summary, the standard first-line therapy is rapidly changing. We’ll likely have many new treatment options for our patients, and that’s really exciting yet complicated. We know that combining targeted agents as well as immunotherapy improved clinical outcomes, and it’s now the standard of care, and patients with non-clear cell and sarcomatoid histology now have hope because the combination of atezolizumab and bevicuzumab really improved the progression and overall response rate. And for oligometastatic disease, we use a multi-modality treatment combined with systemic therapy to improve the cure rate. So, our goal for every newly diagnosed patient is cure. Therefore, regimens with the highest chance of cure/durable response, balance that with acceptable toxicity and time off treatment, should be prioritized, and this immunotherapy-based regimens offer the best chance of achieving those patient goals, whether it’s immunotherapy combinations with one another or immunotherapy combinations with a VEGF-targeted therapies. So, what are the next steps? So, unfortunately for those patients who progress on first-line therapy, we still don’t know what the optimal management of these patients are. So, we need new biomarkers to help us sort out who should get what therapy and who will respond. We need to develop novel imaging modalities to predict response and resistance to therapy, and we need to expand our ability to analyze treated tissue samples. So, we have a long way to go. There’s still many unanswered questions. So, please consider enrolling in our clinical trials. We have several clinical trials and every line of therapy and more information. Please visit our website. Thank you for joining this webinar. Do you have any questions from the audience? “Dr. Liu, how do you know if I’m responding to chemo or immunotherapy?” Well, that’s a very good question. There are several things I assess when I see a patient in clinic. First, how they’re feeling–if they have pain, you know, before treatment and well, after they started treatment, their pain gets better, then I know the treatment is working. So, subjectively, I look at the patient and they seem to be to be doing well. Their fatigue is improving. Their pain is improving. They’re gaining weight. Another way I assess response to therapy is scans. So, while a patient’s on our therapy, I scan them, typically every three months, to assess for response, whether it’s stable disease or their tumor is shrinking, those are all successes in our treatment. So, the second question is “Can a pregnant mother take this treatment? Will any of this go into breast milk?” So, that’s a very good question. In targeted therapies, it’s been studied that we want to avoid– there is a potential for harm in pregnant women and for nursing mothers, so we generally avoid giving targeted therapies to pregnant women as well as nursing mothers. Immunotherapy has not been extensively studied– generally I do like to avoid immunotherapy to pregnant women and nursing mothers because it is an antibody, and it potentially can be transferred in breast milk. “Is surgery always curative? How do you make sure the disease does not come back?” That’s another great question. So, after surgery–surgery, for the most part, if it’s localized to the kidney, is curative. However, a third of the time, the disease can come back, and we make sure that the disease doesn’t come back by doing surveillance imaging. We typically like to do it every 3-6 months. If the cancer likes to come back, it likes to come back in the first 2-5 years, and there are FDA-approved targeted agents, sunitinib, that has been approved for high-risk patients to make sure the cancer doesn’t come back, although it can be toxic. There is another clinical trial that we have at UCLA that is an immunotherapy clinical trial that helps, you know, that looks at patients who had a curative resection, and we give them immunotherapy to see if we can lower the risk of their cancer coming back. “Is targeted therapy going to make me sick?” So, that’s another great question. We know the side effects of targeted therapies, and if we can manage those side effects in a timely manner, generally, I can make patients stay on therapy longer. However, when it was targeted therapy compared to immunotherapy, immunotherapy generally did better than the targeted therapy. So, yes, the targeted therapy can make you sick. We know how to manage those side effects to prevent, you know, the symptoms from getting worse. But the immunotherapy definitely has a better side effect profile. Any other questions? Thank you for joining this webinar. We would like you to check out our kidney program and like to see you in clinic. If you have any questions, I would like to meet all of you. Thank you very much.