 So the last last talk this morning before our panel discussion is by Kevin Scher Kevin did his training at UCLA most recently at City of Ope Joined Cedars-Sanai Samulation Cancer Center where he's a medical oncologist With a focus on many cancers including GU malignancies Hi everyone So as dr. Figlin said I'm a medical oncologist here in the urologic oncology group and my main office is at tower oncology, which is just a few blocks away So I'm going to talk about adjuvant therapy and the treatment of renal cell carcinoma today But before I get started, I just want to make a distinction between localized disease and metastatic disease So localized disease is disease that has confined solely to the kidney at presentation Whereas metastatic disease refers to disease that has spread beyond the kidney So when we talk about adjuvant therapy, this only applies for patients who present with localized disease and the standard of care therapy currently for patients who present with localized disease is Surgical intervention with a nephrectomy followed by routine observation alone and surveillance with frequency T scans and Multiple physician visits and monitoring Currently There are no therapeutic interventions that are standard of care post surgical intervention because none to date have proven benefit however, we're hopeful that this will change in the future as new Studies are completed and may show that some of these therapies that we've talked about so far today May actually also prove benefit in the adjuvant setting okay So just taking a step back so adjuvant therapy refers to any therapeutic Intervention that's delivered after definitive treatment for a cancer and the goal of adjuvant therapy is to reduce the risk of cancer recurrences So in kidney cancer, we're talking about the definitive intervention is surgical intervention and so post nephrectomy We can start to think about what treatments do we have available that might help to prevent recurrences? And those include cytotoxic agents which are traditional chemotherapy drugs Immunotherapy which are drugs as you may have heard already that modulate the immune system And and tar and make your own immune system fight the cancer cells Tyrosine kinase inhibitors which target specific mutations in the cancer and vaccines which you'll hear more about later as well We do know that adjuvant therapies in general are most effective among higher risk populations and this makes sense because Patients who are at low risk of recurrence are going to receive little benefit from receiving additional therapy after surgical intervention and as was just discussed higher risk populations are based on number of factors Including the size of the tumor whether nodes are involved What the tumor looks like under the microscope as well as the performance status of the patient? So what's the rationale for adjuvant therapy? So once the disease is resected surgically? We're never sure that we've gotten all of it and there may be Micrometastatic disease that is still in the body or even circulating tumor cells and the goal of adjuvant therapy is to eradicate any remaining disease that isn't grossly visualized and This concept sort of gained favor in the 70s when scientists discovered That under the microscope that the number of viable cells that are undergoing active cell replication are inversely related to the population size So in other words in smaller tumors the cells are more rapidly divided and all of our known therapies Target actively dividing cells So therefore treatment may be more effective when you're targeting small volume disease or Micrometastatic disease versus large volume disease, which is one of the rationales for adjuvant therapy We know that adjuvant therapy is successful in other disease types We've seen survival advantages with the use of adjuvant therapy in other cancers like breast colon rectal Etc. And this is common Standard of care practice in these disease types is that after definitive surgical treatment? We still give additional therapy to prevent recurrences so this slide just looks at above the the date are the Therapies that are actively that were actively used in the treatment of metastatic disease So in the 80s and 90s IL-2 interferon and then high-dose IL-2 were actively utilized in the metastatic setting in The 2000s and beyond we've started to use these tyrosine kinase inhibitors or targeted therapies that actually address specific mutations in the cancer the reason I And actually one of them is missing at the end exit nib which was more recently approved the reason I show this slide though is to point out that as Therapies are popularized in the metastatic are used in the metastatic setting We then start to evaluate whether these same therapies may be useful in the adjuvant settings So when we used IL-2 interferon high-dose IL-2 in the 80s 90s And then we started to study in adjuvant clinical trials in the late 90s early 2000s whether we can use these immune therapies in the adjuvant setting to help prevent recurrences The same goes for the targeted agents So now in 2010 and beyond we've started clinical trials to utilize these accepted Therapies in the metastatic setting now in the adjuvant setting So these are the historical reported adjuvant trials and kidney cancer There are 14 or so trials. These are the largest ones and you know, they they Done throughout the late 80s early 90s and even into 2000 looking at interferon high-dose IL-2 tumor vaccines as well as some older chemotherapy agents and Unfortunately out of these 14 trials 13 of them were negative Meaning that none of them showed benefit For intervention after definitive surgical treatment Except for one, which is if I can figure out how to There we go in 2004 this autologous tumor vaccine trial Was positive and showed a progression-free survival advantage for patients in the adjuvant setting So I'm going to talk about this trial in a little bit more depth So They enrolled about 560 patients throughout Germany 55 sites in Germany and they looked at patients who had tumors that were greater than Two-and-a-half centimeters That's an older staging system or who had node positivity and these patients were randomized before they underwent surgery They were randomized to either receive the vaccine or receive no treatment Each of these patients received the ones that got the vaccine got six interdermal applications of the vaccine at four-week intervals and 177 patients ended up receiving the vaccine and this is an autologous vaccine So it's prepared from the patient's actual tumor It's prepared the specimen is harvested the vaccine is created and then The vaccine is delivered to the patient with the goal towards priming the immune system to fight the cancer cells and So as I mentioned, this was a positive trial And it showed at the five-year mark in patients who received the vaccine 77.4 percent of the patients who received the vaccine were alive without disease Versus 67.8 percent of patients who did not receive the vaccine So this was statistically significant and it showed that there that this vaccine was helpful in preventing recurrences Unfortunately, the vaccine was difficult very difficult to prepare and and cost prohibitive And so no further work has been done with this particular vaccine Although there are multiple clinical trials underway now in the metastatic setting using vaccines And hopefully if they prove benefit in the metastatic setting will again see trials in the adjuvant setting with other vaccines So this turns to the to the trials that are currently underway in the adjuvant setting and there are six major trials All of these trials are utilizing different agents They're utilizing different periods of treatment time So some are looking at one year some are looking at three year and others also Excuse me, so they all also have slightly different inclusion criteria So while they're all hoping to enroll higher risk patients as those are the patients where we think we can Effect the most change They there's the eligible eligibility criteria are all slightly different So we'll have difficulty interpreting the data when it all comes to fruition. So the issue oops the assure trial The assure trial is looking at Sioux 10 versus seraphim versus placebo All for one year of therapy the atlas trial is exit nib versus placebo for three years The s-track trial of Sioux 10 versus placebo for a year The everest trial is everolimus for a year versus placebo That trials interesting because it's the only one of this group that's looking at the mTOR inhibitor class of drugs Whereas the other drugs are all looking at veg F pathway inhibitors The protect trial is looking at Pozopinib for a year versus placebo and the source trial seraphim for a year versus seraphim for three years Versus placebo and as you see so three of these are no longer recruiting Three are still recruiting and the everest trial is underway here at Cedars and we are participants still enrolling patients in that trial The two on the corners are the ones that are most likely to present results sooner And I believe assure hopefully should report some conclusions later this year So I'm just going to talk a bit about the everest trial real quickly because that's the trial that we have underway here So this is looking at patients who are as I said higher risk patients Intermediate high-risk group or very high-risk group and that's based on the size of the tumors as well as the grade of the tumor under the microscope And patients undergo nephrectomy. They're stratified based on pathologic stage histologic subtype and performance status and then randomized to either receive everolimus for one year fifty four weeks or placebo and the follow-up on this trial is 10 years So estimated enrollment is about 1200 patients the study was started in April of 2011 Will complete in October 2021 hopefully and as I said it's open here at Cedars So once we have the results of all these trials it will likely be a challenge interpreting all of these results And we can imagine three scenarios of in terms of the results Potentially all of the trials will be positive all will be negative or more likely there will be heterogeneous results and so if all are oops if all are positive or Heterogeneous results will be left with trying to understand how do we prioritize these agents which agent might be better for each individual and it will also become a question if we use one of these agents in the Adjuvant setting if the patient progresses and becomes metastatic We will have a question as to whether we go back to the initial drug or we try a different drug or try a different class of drug So these are all questions that will arise as these results come in The other question will be about duration of therapy So while some of the trials are looking at a year versus three years Depending upon the results. We may be left wondering is a year better than three Do we really know if that's true? So that's another issue that we will have to think about and also patient selection as I mentioned all the trials Attempts to enroll higher risk patients, but the inclusion criteria are slightly different And so we'll really have to parse the data when it comes back Especially if there are heterogeneous results to try and understand which subtypes or which classifications of patients actually received benefit if If the trials are all negative There are other approaches that are still underway and being considered such as moving vaccine trials into the adjuvant setting starting to think about using the newer immunomodulating agents as well as potentially identifying Targetable mutations in an individual's tumor so after resection We might be able to identify a marker in the blood or in the tumor That might show us that one of these drugs may be better than another for a particular patient So in conclusion, there's no current standard of care treatment post nephrectomy. So no adjuvant treatment currently Historical trials as I said have yielded negative results For interferon IL-2 chemotherapy with the exception of the vaccine trial that I discussed However newer trials are underway Examining the role of TKI's and hopefully we will have some new data within the next few years to help guide our treatment decisions and The treatment paradigm may drastically change in the next years as this trial data is published And again newer agents on the are on the horizon to add to our adjuvant armamentarium That's it. Thank you