Cancer Biomarkers

>> we'll get going and some announcements. we have the first lecture now, it's been archived and so, people can watch it on their computer. videocast.nih.gov any time. and you usually -- for the rest of the term two, days after the

lecture videocast.nih.gov -- the lecture will be archived so you can watch it any time as opposed to watching it monday 4-6. robbie got his md from the new jersey medical school and then completed internal medicine residency and then joined nci medical oncology branch as a

fellow in 2005 and currently has an appointment in the medical oncology branch in the laboratory of tumor immunology and biology. so, today is titled treatment of metastatic castration resistant prostate cancer. >> thank you dr. moody.

so prostate cancer is one of the big more frequent diseases with one out of eight men getting diagnosed. so, unfortunately, this is one of those things that you guys are in biomedical sciences and health care. this is the thing that people

always approach you with. i know somebody, my neighbor, my grandfather, my dad. so these are things that come up just even from conversational standpoint, unfortunately. today i'll be focusing, since we have an hour only, on kind of advanced prostate cancer.

from a scientific standpoint, that is probably what is more relevant for your interest. so, as opposed to starting out with an outline of what i will be talking about, i'll highlight what i'm not going to be talking about because these things can be addressed in the whole

separate lecture unto themselves. so the treatment of primary disease, newly diagnosed patients is primarily managed with surgery or radiation. for the most part, there are no randomized clinical data that shows which is better, which is

pretty confusing. so if cancer is localized in the prostate, it's actually difficult for patients because they can't come to me and i say this is better based on data. so, radiation is sometimes curative with potentially the use ofand jeb suppression

therapy. there is no randomized data that says which is most appropriate. the other aspect of prostate cancer i won't be talking about today is biochemical recurrent so these are the 20-40% of men who have surgery or radiation with the curative intent, then

unfortunately are not cured and just have a reoccurrence of disease that is measured by a rise in psa. these patients are traditionally observed or surveilled for a period of time until which they may be treated with antigen suppression.

so for a slide what i'm not going to be talking about, that was a lot of talking and i apologize. i want to highlight some of the nuances of these things. for the sake of the time that we do have today, i'd liked to focus on how we manage advanced

prostate cancer because that highlights some of the more salient scientific issues. so when we are talking about advanced prostate cancer, we are talking about a disease state that again is initially attempted to be cured with surgery or radiation when it is

diagnosed and also castration sensitive. in other words, it's still responsive to hormones and i'll come back to that. these are patients that are cured. for the 20-40% of men who i pointed out earlier, those

recurrent have a rising psa and this currently represents psa and tumor volume. those patients are treated with androgen suppression which is a way to contain the disease and then second line hormone unfortunately f they are not cured when it's localized, there

is a potential for it to become metastatic and spread to other parts of the body, most commonly bone but sometimes also lymph nodes and liver as well as lung. ultimately over time, the symptoms may increase and then they may lead to death. until really 2004, there were no

proven therapies that demonstrated the ability to improve survival in prostate cancer. that was metastatic and castration resistant. so 2004, chemotherapy with dose attacksil demonstrated for the first time we could extend the

lives of men with prostate now we tried for about the next six years to improve on that with a bunch of combination studies taking your favorite targeted molecular therapy and combining with docetaxel and they all filed. there was was lines of

investigation going on and we have five new therapies approved that were employed four different treatment modalities. so, the first one actually was no one ever talks about the current immunotherapy oncology revolution as having started a prostate cancer but it

kind-of-sorta did with a therapeutic cancer vaccine and that was approved in 2010 with data that i'll share with you. so i'll come back and share with you all the data for these approvals but almost as unexpected was a second chemotherapy was approved

demonstrating survival benefit which was also attacks 8 which was surprising but strange at least on first blurb why two work in prostate cancer and no other chemotherapies do. by the end of this talk i might postulate a reason for that. then there are two antiandrogen

therapies which i'll again get to the mechanism of action later, ab ratter own and ens lawsuita mide and they were for post-chemotherapy metastatic prostate cancer before they were approved for pre-chemotherapy so randomized phase iii trials were done in both populations

and in 2013, a radio isotope known as radium 223 was also approved. so you see how quickly we went from basically not having anything until 2004, but then from 2010 to 2014 the population i mean the treatment landscape got a lot more crowded.

so let's start with definitions. so i mentioned this a couple of times already. what is castration resistant prostate cancer? this is prostate cancer that is progressing despite castration levels of testosterone. this could manifest itself in a

rising psa or increasing legions on imaging. but this is important because biologically speaking, initially androgens drive proliferation of prostate cancer cells. so once you find out that the cancer cannot be cut out or radiated to oblivion, you have

to contain it and the best way to contain it initially is to decrease the global androgens of the body and basically deprive it of testosterone. primary proliferation signal. now over time through mechanisms i'll touch on later, the disease progresses despite the

castration levels of testosterone and so hence the term, castration resistant older literature may refer to this as hormone refractary since we think hormonal therapy still work in this population, it's probably a misnomer. this is an important point and

the for the people listening at home, anyone in the audience has questions, just interrupt me during my talk and i'm happy to answer it. this is an important characterization of the disease. but i already mentioned that there is two antiandrogen

therapies approved in castration resistant metastatic prostate so why is that the case? this has to do with the resistance mechanisms that basically develop in prostate cancer once you do androgen suppression therapy. and all of these are kind of a

mixed bag of things that are possible mechanisms of resistance. ar amplification, that ar is the androgen receptor. when you deprive the cancer of androgens, it wants to become more sensitive to what little there is so it upregulates the

number and quantity of the receptors. perhaps the most sinister thing is secondary production of androgen. so when you deprive the body of testosterone, what you do is basically do feedback inhibition, or gnhr agonist that

sends a signal to your testicles that basically there is enough testosterone, don't produce anymore. what the cancer cells can do in their own micro-environment then is produce their own androgen. and thereby oddo crin or paracrin fashion, potentially

fuel that proliferation. so basically you lower systemic testosterone but unfortunately, it's the androgens that are produced in the neighborhood or the micro-environment of the cancer cells that can still drive the disease. ligand-independent growth.

that means that you either have modifications in the androgen receptor or the androgen receptor pathway such that they are active despite the fact that there is no androgen signaling the proliferation signal to the cancer cells. and then there can be

intranuclear changes as well because as you can see, once the androgen receptor is activated, there are a series of cascade reactions that gets to the nucleus and interacts with the dna through androgen response elements leading to cellular proliferation.

i think the practice nuclear changes are among the ones least poorly or ones that are poorly understood at this patients, more receptor pathways. just drives home the point the androgen receptor pathway is how this disease is driven.

interestingly a little bit lower on this chart is dna repair. and this actually came out to be about 20% these pathways here. and i won't go into that today but there is strong interest now looking at harp inhibitors very important for brca mutations and other dna repair mutations.

there some thought that 20-30% of prostate cancers are fueled by this. they have received breakthrough designations from the fda. i won't talk about that this year, maybe if dr. moody invites me back next year, i'll have more definitive data.

we'll have to see how this 45 minute lecture goes. just something to be on your radar screen and before we get to the therapies, i think it's important to go through the rules of the game so to speak. this is actually something that is very, very tricky and that

is, how do you manage prostate cancer? how figure out if a therapy is working? they convened a group called the prostate cancer working group, pretty original name, around 2008 and published an another and mirrored what our prostate

cancer team under the direction of bill, was already doing, basically psa is a biomarker. so for everybody who wants to do a clinical trial with biomarkers, i think prostate cancer has one of the best ones in psa and guess what? everybody hates it.

so, just be aware. biomarkers come with a double-edged sword. the reason why it's difficult is because it's hard to know what to do with that information. until about the timeline that these guidelines came out, even though institutions like ours

were already breaking away from this, there was a sense that your ps sample going up, the treatment is not working. -- psa. once introduce were done in an innovative fashion that broke away from the guidelines, recommendations were that we

don't do this in any other cancer where we just look at serum markers in the absence of clinical progression symptoms or radio graphic progression. and essentially there are strong recommendations now and this is prostate cancer working group two.

last year was published prostate cancer working group 3 which followed up these recommendations. which are don't use psa as a read out of response to therapy when you have radio graphic imaging to follow. i'll tell you, i see a lot of

referrals. we have basically a tertiary type practice where we see a lot of referrals from the community. this is something i think a lot of issues still surround and it's not because they are bad doctors out there. i think a lot of it is because

going back to when you have biochemically recurrent disease, so if your psa starts to the come back after surgery or radiation and it proves you're not cured, essentially patients lock on to psa as being a indicator of their cancer. when you can't image the disease

and the only way to evaluate it is with psa, that's all have you to go on. so you're locked in on it. once you have imaging, you have to transition the patient to the fact that the imaging is more important. and i can tell you, it's a very

hard thing to do. patient stay locked on the psa. providers have to spend a half hour trying to explain to the patient even though they are on a therapy, and their psa is going up, that it is still working and then they ask, why does my psa go up?

and it's hard to answer that question. because yes, on some level it's not working as well as it was before, but radio graphically your disease is stable and that is the most important thing. patients kind of adopt the philosophy of no one ever died

with psa, which is true. it's radio graphic progression that unfortunately kills the patients. aiming it's very difficult. this is something that is important because almost all the clinical trials i'll show you in the coming slides used radio

graphic progression as their primary read out of progression. and for example, i seen patients who had rising psas for almost two years and stay on the same so what that implies -- it's not unique to me or our practice or our treatment. by stopping it earlier just

because of psa, you potentially short change the patient, the clinical benefit, continued clinical benefit of the therapy they are on. so a lot of talking on one slide but it's a big deal and i think it is something that is still not fully embraced by patients

or providers in the community. so, just something to highlight. and again, my last disclaimer before i start talking about therapies is, i'm going to list a lot of therapies and you're going to wonder which one -- and i'm going to put it in a way that maybe highlights what i

think is the appropriate sequence. but, you have to realize there are no clinical trial data yet available that defines how to use these six therapies we now have? we went from one therapy where it was pretty easy.

metastatic got chemo at some point. now we have 5 or 6 and it's not as clear. so, there are several trials that are ongoing and that probably will be several-year process if they yield data at all.

so in the absence of data, i will provide you with my opinion of what the sequence should be and i'll probably highlight that from the get-go, but realistically when practitioners evaluate these therapies with the patient, you have to factor in what the treatment is going

to bring to the table in terms of side effects and outcomes. and what the patient is bringing to the table in terms of their co-morbidities. so you'll see that some things don't work specifically with patients that have a seizure history or something like that.

also what they are bringing to the table in terms of symptoms or pace of the disease. if they have a high level of symptoms, and a high pace of disease, you're probably going to accept the therapy or be more accepting of the they were they has more side effects.

so what i'll do is go through each treatment and lay it out how i think patients are generally managed. again based on my opinion, but also i think some practice patterns and then i'll go through each individual drug, the data that led to their

approval and then in a big scary screen, i'll show you a bunch of side effects. not anything that anyone needs to memorize, just more that you understand this is what factors into that go or no-go for a given patient. so it's getting close to

dinnertime so i guess we can pretend like we are headed to a restaurant. i think that this is a reasonable way to put forth the treatment options in prostate and we start off with an appetizer, first course, second course and third course.

and i think that again, what you like to do is maybe sample the most appropriate things from each of the courses here, realizing that maybe in some patients, you may have to skip a course or realize that not everybody gets an appetizer. so, the first one i'll start off

with is with what i characterized here as the appetizer. now, this is -- remember these are all treatments for prostate cancer and cyp lou sell t is best role in early metastatic prostate cancer with minimal symptoms and basically

low volume and low pace of the disease. and i'll go over the data with you which is with substantial controversy in the field to this day. six years after this amount has been approved, there is still controversy on whether or not

this works. but that is why i made it an not everyone orders an what i also say is that it's not your main course. you're not just going to go to the restaurant and order this and then leave and think that everything will be okay.

so it is a different form of immunotherapy called a therapeutic cancer vaccine. so i know in these lecture series you'll hear a lot about immunotherapy in other form of checkpoint inhibitors because that's the majority that are this is the one in the minority

of vaccine and this is, in some ways very personalized. what they do is they basically take a patient's peripheral immune cells, ship them to a processing facility where for 24-48 hours those immune cells are exposed to a target androgen, pap, and a cytokine.

to stimulate the immune cells. this is kind of bootcamp for the immune system. after two days of bootcamp, they are shipped back to the doctor's office and infused into the patient. a full course of therapy consists of three invasions done

two weeks apart over a month. so basically, like an appetizer, you just get it and then you're done. and here is the phase iii trial again scrutinized beyond what you expect as a successful phase iii trial. patients were randomized to the

vaccine or placebo. there was a salve annual protocol which has been a point of controversy a little bit where they took some immune cells and reinfused them back in. the primary endpoint was survival.

that's based on a series of two phase iii studies previously done where in 2007 or 2008, where they basically had the primary endpoint being time to progression and those were negative studies. what they found in a smaller phase iii study was that the

patients who got the vaccine lived longer so they said, all right, we now understand how instead of doing 150 patient or 125 patient study, we are going to do a 500 patient study with survival as our end point and it was a positive study. so this is the second time in a

randomized study that this treatment improved survival in now, remember what we do in clinical trials? we are not smart enough to assess how it is going to impact the individual so what we do is assess basically the middle and assume that person is

representative of the general population and there are come up with numbers like median improvement and survival of 4.1 months. and this was substantial improvement and clinically meaningful and led to the fda approval.

but the fact that there was no short-term change in progression, everybody pretty much had progressive disease three months into this which is roughly two months after they finished therapy. and psa declines were rare. i seen actually pretty

interesting psa declines with this treatment but psa declines were rare and therefore to this day, partially because of the reliance i told but earlier, there was cob versey this data is fraud leapt and this treatment doesn't work. that is a whole lecture into

itself. i will tell you i don't pick and choose my phase iii data. if it is positive, i believe that the data is real. and again this is the second phase iii trial that demonstrated this saying the advantage.

so, and guess what? six years later to get other things. so generally speaking if i have a healthy patient who comes with one or two bone lesions and i think they have a few years to live and benefit from this, i recommend them to go on this

who should get this therapy? this study was enrolled about 15% of patients who already had chemotherapy but i would still use it in earlier stage disease because i think like a lot of immunotherapies works better if it has time. not surprisingly, what this

data, a subgroup analysis demonstrated that was if you had lower tumor burden in the measure of psa, you were more likely to have a better overall survival benefit. so basically this is months of survival based on psa quartiles and you see the improvements got

better as your psas were lower. things were slow in the beginning. small volume. when the immune system has the best chance so these are the patients i would recommend for. i won't go into a lot of detail.

a lot of criticism for how does this therapy work? data shows that basically there is immune specific activation of different components, antibodies, t-cell proliferation, correlating with these outcomes so there is data on that and again, i think it is

a reasonable thing. perhaps the best part of this therapy is the fact that it has very low side effects. this has not been -- this stroke issue concern is nothing really uncovered further in post-marketing. so i don't think it is a huge

deal but these chills, fatigue, fever, we see that a lot with immunotherapies. it's very well tolerated. three invasions over a month. it is expensive. -- 3 infusions over a month. unfortunately all new therapies are expensive.

but that was another kind of thing that this was labeled with. so that is sep louisil t. it's an appetizer. i would use it upfront as early as possible realizing that i'm going to go on and get something for my first course anyway.

so who are the patients who should be treated with these first course treatment options? these are patients with minimal to moderate symptoms. so unlike the appetizer group who i said low volume, minimal to no symptoms, these are patients who have minimal to

moderate disease and moderate symptoms and these are actually probably the combination of the most effective therapies as well as the best tolerated. and the two are enzalutamide and abiraterone. and they have minimal side effects and they do work well in

this early disease setting. the one difference is that if you order the abiraterone, you have to get a side of prednisone with that. so that is some added, if it's potatoes and your dinner concept is add extra carbs, in the patient there are potential

co-morbidities just from having prednisone. i will come back to why i listed prednisone first. so what is ens lawsuita mide. it's an -- enzalutamide? we had these therapies for a long time. they were developed in the 1980s

and early 1990s and this concept is if androgens basically drive the disease, why not develop a blocker for the androgen receptor? and they did that. we used them and the data in older agents, demonstrated subgroups that did well but no

clear benefit overall that it led to survival. so the group headed by charles sawyer at sloan-kettering about 10-12 years ago said you know what? we have better scientific technology now and i bet we can come up with a better ar

antagonist. that paid off with more than a billion dollars block buster drug here enzalutamide which had greater binding affinity than our older agents and then i talked earlier about how basically the androgen receptor translocates to the nucleus

leading to cellular this treatment enzalutamide prevents androgen receptor translocation of the nucleus and then within the nucleus, some dna binding and co-activator recruitment. so it has downstream attempts as well and that was a probably

part of the reason why we have much better clip call data and -- clinical data. unlike older agents, it doesn't have agonistic properties which i won't go into too much detail on. this treatment is worth 14 billion dollars because the

company that made it just sold itself for 14 billion dollars to pfizer like two weeks ago. apparently you can make money if you develop a good drug. here is the first of two trials that demonstrated the clinical efficacy, quite impressive with enzalutamide.

these were in a time when basically docetaxel was the approved therapy. so all these patients received docetaxel because when you develop a drug you go as late in the disease as you can because you get your payoff or endpoint quicker and then you get to sell

your drug for 14 billion dollars faster. so that is the first study they did. and what they saw here was in the 1200 patients treated, the overall survival benefit was about 18 and a half months versus 13 and a half months.

time to progression, mostly radio graphic here. again, was about a little over 8 months compared to three months and this led to basically the fda approving this drug in 2012. here is the kaplan-meier curve. they had also started a study in the prechemotherapy setting

where patients here had not received docetaxel and by 2014, this data was also positive. the progression-free survival was one year was basically 65% to 15%. the survival rates are not as robust as may be have expected. and there is a couple of reasons

potentially for that. but, you see it somehow is still 32 versus 30 months was statistically significant and this was approved then in the pre-chemotherapy setting as well in 2014. so some reasons this however all survival signal is not as strong

as one year survival progression. could be the fact that there were other available therapies and indeed some of these men may have gone on to get enzalutamide placebo arm. this is increasingly a compounding variable in trials.

it was probably easier to take an effective therapy and develop a phase iii trial that can prove that efficacy when you have one therapy in the treatment landscape they showed ed earlier now you have six, there is a debate as to whether or not you can show a survival advantage

i'll try to come back to that at the end. and it really is. fatigue is believe pro under rented although the pop% highlights a little bit. but for the most part, patients do very well. younger patients might feel

fatigue a little bit more. but this is a very well tolerated medication. all really other things are very minor. the one thing that is important and we seen this with other ar antagonist, there is some cns penetrants of this treatment

that somehow can impact patients with a risk for seizure. so if they are on seizure medications, maybe they had a receipt stroke which advanced age population is possible with prostate cancer or a history of seizures in general, this is not the best treatment for them.

so, in this setting, it would not be my preferred option. but in the absence of that, it actually would be my first recommended treatment for patients with moderate disease and moderate symptoms. i won't go into it too much but there is data that shows that

both enzalutamide and abiraterone improve symptoms as well as changing psa kinetics and progression. so abiraterone is the second option i listed and i listed it number 2 primarily because of the side effect profile and the fact that it requires

so that is why enzalutamide is my preferred presuming they can or don't have any seizure threshold issues. what is abiraterone? it impacts the other resistance mechanisms so enzalutamide works where the resistance mechanism is probably ar, upregulation

although it could impact this mechanism of resistance as well. and that is the fact that as we come better in our understanding of prostate cancer, we realize that there is the potential for these cancer cells themselves or other cell in the tumor micro-environment stroma to

basically biosynthesized their own androgens. this basically means through various enzymatic reactions, they can synthesize androgen in their tumor micro-environment and provide their own growth signal even when you globally suppress testosterone.

so basically, this amount called abiraterone -- agent, blocks two enzymes, which basically diminish these other cells from producing androgens. i will take a step back and say all these metastatic castration resistant prostate cancer patients and all these studies

being done include testosterone suppression in the background. i didn't mention that earlier. but that is because if we let testosterone return to normal, and they have all these other upregulated receptors or androgens in the tumor micro-environment the cancer

would do a lot worse. we do our best to suppress the global testosterone realizing we have to attack the tumor micro-environment. so this is the mechanism of abiraterone which is also developed in the mid or around 2005.

and this was not affectionately a brand new concept either. for historical purposes, there was a drug called -- [ indiscernible ] as you can tell it was developed as an antifungal in the early 80s and had impact in prostate cancer in some groups of

patients and was tested extensively. and there are a lot of -- it was unclear how it worked but it was thought that one of the prevailing opinions that was it worked through these enzymes on secondary androgen production from the adrenal glanced.

that was what was really thought. and we have become more enlightened in the last decade. again this was -- coug are biopharmaceutical in england said, we can build a better mouse trap. so they did.

so it goes to show sometimes older ideas can be improved upon and we seen that with these two drugs. so much like enzalutamide, the abiraterone company did two studies again in the phase iii setting in the post-chemotherapy celting and one of the

pre-chemotherapy setting and randomized patients to either abiraterone with prednisone or prednisone alone. it's important to realize that prednisone in this setting is required to mine myself some of the side effects. when you -- minimize -- when the

inhibit the hydroxylase, you get up regulation of cortizone which can lead to swelling and electrolyte abnormalities. and so basically, the prednisone helps to mitigate the side effects. it's not just an artifact of clinical trial design as it is

with docetaxel but that is the role of prednisone here. and the end result of this study was again a 14 a 4-month improvement in survival. you can't compare these numbers across studies. i think all we know is that in this study, this treatment

improved survival and this also led to fda approval. as we saw with enzalutamide it delayed time to psa progression by four months and we see that the majority of patients had other responses by imaging or psa relative to placebo and again, there were other read

outs of success here but really survival was paraannouncement and that's what led to the approval -- paramount. so this is the second phase iii study. patients were randomized again. prednisone in the control group or abiraterone plus prednisone.

a median survival of 33.4 verse 23.4 months. this was approved before enzalutamide so that could explain why the survival signal was preserved a little bit more. a lot of the enzalutamide patients probably got abiraterone at some point.

so, that brings us to our list of toxicities with abiraterone. some of this is partially bauds of the prednisone that goes along with it. hypoglycemia, because of the cortisol affects there can be edema and hypertension. it's a side effect profile not

because i have any real affection for ens lawsuita mide but it's a side effect profile which is why i favor enzalutamide over abiraterone. that becomes very important when we move forward and realize new data that come out in the last few years and that is

highlighting the fact that the mechanisms of resistance for abiraterone and enzalutamide or lap. so there is cross-resistance to these two therapies and therefore you might not be able to order two agents from the first course because they may

not work well sequentially. so probably what will happen is you'll use one and you get a diminished benefited if at all from the second. and i'll go over that data in a second. but, the reason why i favor enzalutamide is if one they were

le work for two years and the other will work for three months, it's probably better if that patient is not on prednisone for two years. and also the other side effects. because of the data i'm about to share with you, other countries like australia and canada will

only pay their government health care only pays for enzalutamide or abiraterone because the data suggests that responses rates to the other treatments are 20% or less. so what is that related to? it's related to what has been highlighted in this new england

article here but probably a broader phenomenon and that's the fact that there are what are called androgen receptors spliced variants. so one of the mechanisms by which the prostate cancer can resist treatment is by basically altering the androgen receptor

and basically having an androgen receptor pathway that has no receptor. so that is a stit weptly active pathway that in the past at some point relied on testosterone to bind into the receptor and led to intracellular cascade that led to cellular proliferation.

but these variate pathways often have a receptor or no ligand binding domain and so they are active in the absence of any androgens. and what johns hopkins demonstrate said that in patients who have previous abiraterone, as you can see

here, they were less likely to respond and had rising psas after enzalutamide. if this were or these patients didn't have previous abiraterone as you can see with most, they would have likely had a much more pronounced anti-tumor affect.

similarly, patients who had previous enzalutamide didn't respond to abiraterone as well either. and what they found is that in this paper at least, they focused on one of these variants called androgen receptor variant 7 and there was a very strong

correlation between the presence of this variant and a lack of response. so that goes back to the fact that there is basically clinical evidence that suggests that when you use these therapies sequentially, whichever one you use second, probably as a

response rate of 20% as opposed to one that is much, much higher. so it seems like very good therapies for the most part, we may not be able to use them sequentially. there are studies going on to see if there is any benefit to

the use them together and when that date at is available with you, i'll be happy to fill you so, then we talk about our second course. so these are patients who have as opposed to the first course where it was minimal to moderate symptoms, these are patients

with moderate to substantial symptoms. and you'll see the toxicity with chemotherapy is much higher. but, in this case, it's worth it because essentially you get a better impact on symptoms. enzalutamide and abiraterone did studies that demonstrated if you

had moderate pain you get improvement but no data that shows extensive pain gives you therapy the way chemo does. if the disease is moving quickly it's best to use chemotherapy. so people who think we shouldn't knock down trees or something like that because that's where

we have the cure for cancer, not enneastyle off base. docetaxel is derived from paclitaxel derived from the u tree so don't tear down adds many rain forests i guess. my bug on that. but it's important to realize that tax us were thought to work

by inhibiting microtubule assembly which was thought to basically have an important role in mitosis and if you have a lot of cellular proliferation from cancer growth, you have a lot of mitosis and therefore we thought that if you're not letting the microtubules take part and

you're freezing them, the cancer cells can't police officer skate you have less mitosis. the reality is that perhaps something that come across in the last decade to suggest that maybe it is really all about the androgen receptor in prostate seems like we forgot about that

for a while. microtubule impact is actually not on mitosis or proliferation but think of microtubules as a train track by which the androgen receptor or the variants travel from the cellular binding domain to the nucleus and if you impair that,

you lose that cellular, intracellular cascade signaling. so again, just all comes back to the androgen receptor with chemotherapy and prostate and that could explain why with all the chemotherapies available, it's two tax owns that work in prostate cancers

and no other therapies. this study was published in 2004, a landmark study. first time we demonstrated the ability of survival in advanced they investigated two doses, one weekly and one every 3 weeks. and basically they compared it to mitosanatron and prednisone.

i won't go into this data but they were approved in the 1990s by the fda for prostate cancer treatment based on pallation. so no survival benefit just improved symptoms. here is the end result of the study basically, they found three weekly docetaxel was

better than two weekly -- i'm sorry. bern mitosanatron and basically that became a new standard of care. the median survival were 18.9 months versus 16.4 months. so a couple of things about that.

these values fluctuated over the years. some studies before abiraterone and enzalutamide were done suggested this was over 20 months but now it's coming down a little bit and maybe closer to 10-15 months. but the one thing that i think

principle that gets highlight bide this, i can't tell you how many patient groups i talked to over the last decade where patients are like, see, that's why i'm never getting chemotherapy. because i'm not getting all the side effects for just a 2 1/2

month improvement in survival. trust me, it usually there is a lot of hand raise being that. and then, i had a lot of patients come to my clinic and say i'm not getting chemo for this and the wife is like, i want you to live. he's like i'm not going to do

it. then you highlight the fact that there is an aspect of this trial you should take into account, and there was a crossover. the patients on the might sant ran were able to crossover and get tokes taxel at progression. so any time you have a

crossover, your long term outcomes like survival underestimate the benefit. and indeed, when you look back at historical trials with just might sanatron, the overall survival was closer to 10 in that context, you realize that yes, the patients initially

randomized lived 16.4 months but a substantial number of them actually probably got docetaxel as well. this is that post-treatment contamination aspect. so usually when i mention this in the office, the wife hits the husband and then he kind of gets

in trouble and then he is more inclined to do chemotherapy. just another concept to understand how to interpret clinical data. now here is the toxicity which i'm not going to minimize. it's chemotherapy so there is but despite all this, i'll tell

you that i treated men in their 90s and they still lived productive lives. for the most part these side effects are i would say for the most part more annoying than life altering for patients in the context of the fatigue and some of the risk of infections

with neutropenia and things. really worse in the first week of the three-week cycle and then patients recover. we have trials at our institution here where we treated patients on and off, stopping for breaks and things for 50, 100 cycles every three

weeks. so this is a reasonable and tolerated therapy. in this trial they only gave it for 10 cycles and that is still how a lot of people use it. but we have decided based on our data here that it is worthwhile to continue it as long as the

patient is tolerating it. despite this long list of infections, i think it is a worth while therapy when the disease burden high and when they progressed out of earlier therapies or when their symptoms are high. the big side effects are the

neutropenia which can lead to infections and then neuropathy. numbness and tingling we see. a lot of the other things are more chronic and kind of slowly developing over time. so that brings us to the next item on our second course here and that is radium 223.

in prostate cancer we don't just a bunch of chemotherapies. we have antiandrogen, immunotherapies and chemotherapy and radium 223 is a infusional radiopharmaceutical therapy. the way this trial was done essentially is really not indicated for patients visceral

disease because radiopharmaceutical agent in this sense was targeting bone metastasis as you'll see. but one of the tricky parts is again, even though i like to brag about all these new therapies, and i kind of already shown you caution about using

psa, people who treat prostate cancer really prefer therapies that make the psa go down. that's a sad reality. we are talking about sep louisil t and radium. there is no immediate decline in psa. for that reason it's still

unclear how these therapies are being used. older radiopharmaceuticals and prostate cancer were approved for pallation only and so basically, that is kind of where radium fits in as a replacement because unlike those agents, this agent demonstrated a

also the advantages, also unlike those agents, those were beta emitting alpha particles and radium 223 is a alpha emitting radiopharmaceutical. i'm not going to pretend to understand the physics beyond what i'm showing you on the slide.

but what i do understand is that alpha particles are heavier so when they shoot off, the concoction that binds primarily to areas of high turn over in the bone, they don't shoot as far. so what that means is if you have an area of prostate cancer

in the bone, realizing that 90% of men with prostate cancer have bone mass, the most commonplace to go. when the alpha particle shoots off, it shoots off less than 100 micrometers. i don't know what that is but less than a beta particle and

because it's a smaller destruction radius, you're less likely to have a bystander affect of healthy hematologic cells like platelets and the white cells and red cells. those were the primary side effects we saw with other radiopharmaceuticals used in

this with the lower destruction radius with the alpha particle, we are seeing that a lot less. and this study was a little different than the other studies in that basically it allowed patients to be pre and post chemotherapy, require them to not have visceral disease.

couldn't have morning 3 centimeters of lymph node visceral is not lymph node. and the results of this study demonstrated no real dramatic short-term changes in psa. patients just lived longer which is what you want. so that based on these findings,

this amount was approved by the fda for patients with metastatic castration resistantes from daysicanter and so it is something we have. i have to say that i was at a meeting last week in new york where we are still trying to figure out how to best use this

therapy perhaps in combinations or other disease populations. importantly, i told you that this group of patients was more heterogenous and some received chemotherapy and some some had not and the reality is the survival benefit was seen in both subgroups.

so i think that is an important thing to understand. the palliative benefit was a little less clear in the post-chemotherapy subgroup but i don't think it was really powered for this. i wouldn't overinterpret that. generally speaking when you have

a positive trial, you can't pick it apart to find the date awe want to believe in. so i think there is clear data this works in both groups. even though you have a minimal destructive radius, you have a lot of lesions in the bone or near the bone marrow, you'll

have a lot of alpha particles flying around so you'll have bystander affect with anemia, leukopenia and thrombocytopenia. not as extensive as why saw in previous agents. it is a kelatively tolerated agents and for patient with substantial bone pain it can

bring relief. there was an article published in lancit oncology this summer which said you could use this safely with enzalutamide and abiraterone and in fact what i recommend in patients who have already had chemotherapy and perhaps abiraterone or

enzalutamide pre-chemo, i suggest patients get radium with whatever treatment they did have before if that makes since. so in other words if they haddence lawsuit mide in the first course maybe when they get to the radium standpoint they can get it with abiraterone.

so the third course is really docetaxel refractary patients. these are patients who already had chemotherapy of the i mentioned data where there is data where it shows survival benefit. the last agent i'll talk about is the capassa taxel.

that's a taxain that differs from docetaxel based on two hydroxyl groups being different. we talked about building a better mouse trap earlier? you can be cynical on this. they thought they would come up with capas i taxel which may be different and better and maybe

they can maintain that patent space. surprisingly, this trial came out of nowhere. they took this to parents that already had -- i'm sorry. they gave cabaz i taxel or mitotax anotron. this was not on anybody's radar

screen despite a paltry 2 1/2 month improvement in time to progression, there was a statistically significant abiraterone and enzalutamide. it is available. because of the side effects namely this trial saw about 5% of patients with

infection-related mortality. so that has been a constant thing that plagued this treatment. so not a lot of use of this again these patients are pretty sick and there is not a lot of ep newsasm after they progress to give them another

chemotherapy amount although it has a role and i think you can find a way to use that on the menu that we talked about. now there is updated data about cabaz i taxel that is very i mentioned the drug company that developed this was maybe looking to preserve their patent

space by the fact that docetaxel is going off patent in the near future so they did a randomized upfront study with docetaxel in patients getting advanced prostate cancer and then randomized them into their own drug. that study didn't show a

difference. so docetaxel is still the front line agent. they also looked at dose because again there was some thought that having a lower dose might be less milo suppressive, which is where the prize marry infection eat ollie is coming

from and 20y is just as good as 25. and so i don't think it will change things that much. phase iii trial didn't mandate growth factor use and that probably led to a safety signal that we are talking about. i already talked about the use

of these treatments after docetaxel. they have data that shows overall survival benefit and can all be used. ultimately, the goal is to really maximize quality of life for the patient while picking treatments that are relevant

from this menu and try to go through, that's what i try to do is try to figure out where these patients are. how can they get the benefit of each therapy at the appropriate time point? i wish there was an easier way to say that we knew which to use

when. the field is doing trials to evaluate that. until then hopefully there was logic and rational in the way i laid that out. there are other opinions but i think there are some slight variations but that ink it's a

pretty -- it's not a revolutionary thought process i'm presenting here. i think a lot of people would agree. i still have a few minutes and i want ta talk about some things that are changing how we do prostate cancer in earlier stage

you have this slide in your hand out. it's something about cost that always comes up. none of these drugs are cheap. a lot of people hang their hat on 35 grand a month. enzalutamide if you're on for a year, it costs a few times as

much. they are expensive. and that is something that will have to be addressed at some point just because they are not limitless resources but another sense of one thing the menu didn't have was prices and you hate going to a place that is

doesn't give prices on the menus. so i thought i'd give that you here. i know i would only talk to castration resistant prostate cancer but i want to talk about a different population of patients now.

this is patiented who are not so they are earlier stage patients who back in their doctor's office and don't know they have prostate cancer and basically find out they have metastatic prostate cancer. it's castration sensitive technically because they haven't

been exposed to androgen suppression so these are patients 3-4 years ago had radiation surgery, thought they were in good shape and came in and found out they had metastatic disease or didn't know they had prostate cancer at all and showed up with bone pain

and found out they had prostate so it's very different than the advanced populations i talked to where essentially they start off with local therapy and progress through to metastatic disease later o these are patients who are showing up here and from the get-go at this point, local

therapies with radiation and surgery wouldn't be curative. so interestingly in 2007, they did a study that randomized patients through the standard of care at that the time androgen suppression therapy versus six cycles of docetaxel approved in later stage disease.

you see that this is a remarkable probably because of the time lines, a 13 and a half almost a 5-year period. that's a substantial change in how we manage early metastatic disease where two years ago we would have only given androgen suppression therapy and now we

found out that sixes months of docetaxel can improve that. this is having implications how did to re-evaluate early stain looking at ways to improve on this and perhaps seeing if we can bring curative measures to patients who are diagnosed with maybe only one or two bone

lesions. that the is something that is being increasingly explored. i won't go over the subgroup analysis just in the interest of time. but i will tell you this was very well tolerated and i would sa say that if 88% of men who

got tolerated this therapy were basically tolerated well enough to get all six infusion system, that speaks to the tolerability, but just in the interest of time, i'll skip over the slides have you in the controversy of treating low volume. it's a nontoxic regimen so all

people regardless of the arbitrary volume designation should get it. thank you for your time today. i will say that just looking forward, because i know you are doing research, i still think there is a lot of room for improvement as you know.

none of these therapies are curative. so maybe taking these therapies earlier and minimal metastatic setting and seeing if we can combine them to get cure. that is one of the points and emphasis, better understandings of resistance mechanisms will

improve our understanding of how to treat them and then immunotherapy. there hasn't been a lot of progress. we do a lot of immunotherapy here and we are trying to work with others to advance the immunotherapy in prostate cancer

which has been left behind, i think. here is my e-mail. you'll get a lot of, unfortunately family, friends and neighbors and stuff who have prostate cancer questions. feel free to e-mail me if anything comes up.

follow me on twitter. i usually just tweet about prostate cancer and i don't tweet about what i had for dinner. that's enough the menu analogy for me now. hope you have an enjoyable dinner ahead.

one great lecture coming up after this. so thank you for your attention. [ applause ] yes? >> ah michael gottesman:. [ off mic ] >> so i'll repeat the question. i said psa isn't a great

biomarker of response yet i showed a response where it shows a initial read out of responsiveness of the tumor and i think the answer is, i think it does show some early benefit in terms of efficacy but it department show -- it's not a good indicator for duration of

so it tells us the direction you're going in but it's not the indicator of when you should switch therapies and a lot of the phase iii trials, basically with the exception of the docetaxel, did not use psa progression as their primary progression criteria.

they used radio graphic so my concern would be if you stopped the therapy based on 20% rise in psa, you're short changing the patient because you're curtailing the potential clinical benefit of getting treatments further n early studies it's a good indicator of

responsiveness of a treatment but i think in clinical management, radio graphic or clinical parameters are much more important. good question. >> that's where a lot of the information came from. that's a popular coreulative

study which is looking at the evolution of that resistance mechanism by sequencing ar. thank you for all staying awake. i know you have one more lecture to go so i'll get out of the way. >> okay. so i'm working onsetting up the

tumor board rotations and visiting the core facilities. i'll probably have something for you at the start of next week and then i'll be e-mailing everyone, and you can sign up for the activity that you would like. so our next speaker is from the

surgery branch, stephanie guav. a staff clinician an. she got her general surgery residency at columbia university followed by oncology fellowship at dana farber and brigham and her title is about immune checkpoint blockade. >> thank you.

so we're going to talk about immune checkpoint blockade and you might be wondering why is a surgeon talking about immune check point blockade and we'll get into that in a little bit. but it started with who is the best to look at a tumor and that's the one who can take it

that's why the surgery branch got into immunotherapy and immune check point blockade. it's a hot topic and any of you following cancer literature know a little bit about it. so what are we going to talk about? the basics of immunotherapy and

the mechanism of action of some of the early clip call experiences that we had here and how we discovered immune-related adverse events. we'll talk about checkpoint blockade in melanoma and those are three of the drugs we will talk about.

one of the channels of checkpoint blockade is pronouncing those medications so it is -- we are going to talk about check point blockade in other cancers and the experimental questions being answered today. the handouts you have are almost

exactly the slides you sigh but i have made a couple of changes for you. so we often talk about oncology and before 5 years ago, people individual shown,and it only would have been a 3 hill ard corticobut now we have 4. the first and the old cest

surgery. the first known operation for cancer was done in ancient egypt and it was documented on scroll that is they seen in hieroglyphics. it was taking out breast cancer. radiation came about in the late 1800's, early 1900s.

chemotherapy came about as a result of work done both here at the nci and dana-farber and now immunotherapy has joined as one of the four pillars of how to treat patients with cancer today. so a couple of different ways that capser immunotherapy works.

the first and most broad said a nonspecific stimulation of immune reactions so cells you already have within your body. can we stimulate them to go after your cancer? press on the gas to use a car metaphor, or are they already have the gas pressed but there

is a brake involved so you have to take off the brake and that's inhibiting the regulatory fact expose that's checkpoint blockade. another way is to teach the t-cells you already have how to find your tumor and that's what cancer vaccines are trying to do

and then a lot of what we do now in the surgery branch and many may have seen dr. rosenberg's work with this is to work on t-cells outside of the body and then give them back and that's adoptive immunotherapy. what we are going to talk about is the inhibition of regulatory

factors or check point blockade. so these are the cells of the immune system for those who aren't primarily immunologists. our marrow is responsible for making up all the cells in our blood com partment and some are blood cells, red cells, some are platelets which help us clot but

the vast majority of cells that get made are part of our milo site or granulocyte lineage. and the ones that we are going to focus on for adaptive immunity are the ones you see so we have t-cells which can basically be broken into cd4 cells which are helper cells,

and cd8 cells which are called killer cells. there are different kind of those but that is sort of where you need to be at the beginning. and then b-cells which make our antibodies. there are some other nonspecific things that help us both fight

sort of baseline infections innate immunity, things that happen really fast and go into play when you get stuck with a splitter. not things that go into play when you catch a flu. so when you catch a flu, this side gets activated.

when you get a splinter this side goes to work. we'll talk more about this because it's slower but it's the one that is a little bit more easy to educate. and checkpoint blockade primarily affects t-cells. so how is a t-cell born?

when these cells come out of your marrow they go to the thymuses. they got their nime t-cell because they are differentiated in the thymus. they go through a process where they are exposed to an antigen that may make them turn on.

and a couple of things can happen. they don't see any androgen at scall your body realizes that combination of genes isn't effective for that person and that t-cell dies because it's not needed. that's what we callander gee.

or it gets hit with the a signal so strong, say an androgen on every single cell in your body. if your blood-type a and it is seeing protein a and your thymus knows you don't want to destroy blood cells that have a on them, that's called negative selection.

so it sees such a strong stimulus that it kills that t-cell to prevent it from going on and causing harm. then there is that middle level where it gets just enough stimulation to get turned on but not too much, and that's positive selection, those are

the t-cells we live with and those are the t-cells that make up the repertoire. you can have most people would say you have a repertoire of 10 to the 7th different types of t-cell receptors in your body at any one time. you have about 10-12th

t-cells in your body. so t-cell activation happens in three steps. the first is what tells the t-cell that it found the right target and that's the specificity. so what has to happen there is that an antigen, some abnormal

protein in your body or abnormal protein that come in on a virus, has to get digested by the cell and it gets put out on to the surface of the cell in these components called mhc. now we can talk exactly about what mhl is but it's a white blood cell type just like your

red. you inherit from your parents. it makes the shape of a pocket that these antigens can sit in. so you have to have the right combination of mhc and antigen for this t-cell which is going to have a very specific protein shape in the folding here, to

see it. and that is called signal one. so your lock and key have to fit together or else nothing hearts. so it can happen in a cd8 phenoknop non-o goes in different processing for cd4. but the tcr has to find the antigen in the beginning.

so that is signal 1. the next signal is what tells that t-cell either to turp on or turn off. so this is the lock and key that we talked about here. so once that antigen fits in here, then the cell is going to look for another thing to click

if it clicks with cd28, it gets turned on and all these things start to happen. cells grow. they develop function. they survive and thrive and proliferate. if it clicks to one of these other inhibitory molecules,

ctla4, pd-1, there are a lot of pathways we still don't understand but it tends to shut the t-cell off. this is called signal 2. and what we calico-stimulatory molecules. signal 3 as you might imagine, now a lock and key, it is

clicked together because it will work but what kind of environment is it living in? what kind of cell will it turn into? when you're talking about a helper cell, it can turn into a bunch of cells. it can turn into type i, type

ii, th17, and a regulatory cell. all of these things help to keep things in checks and balances. you want to have a vigorous immune system to attack anything that comes in but you also want to not destroy your cells. if you think about autoimmune diseases.

type i diabetes. the body is attacking the cells in the bankerous that make insulin. ulcerative colitis, the body is attacking cells in the colon. because there is dysregulation of checks and balances. so signal 3 is the environment

the cellsure living in and it helps to develop the cells into the kind of cells they will be. but what we really are interested in from a cancer immunotherapy stand point is the role of the signal 2 checkpoints. so these checkpoints are what

help us promote self tolerance. if you have a t-cell that knows how to recognize your thyroid, if it has a brake on it, fine. it won't destroy your thyroid f that thyroid cell turns into thyroid cancer we want to find a way to take off that brake. same with melanoma.

if your t-cells can recognize your skin, you don't want it to destroy your skin on a regular every day basis. that's called vitiligo when you see people with white patches. but if that skin cell turns into a melanoma, we certainly want the t-cell to be able to go

after that and lift that brake. so what we are trying to do is brake tolerance. so when your body sees antigen, it is usually in the things that you grown up knowing about. lymph nodes, tonsils, all the place that is get swollen when you get a cold.

patches are very specific areas of immune cells that live in the gut. mucosa associated lymphoid tissue in the stomach. these immune checkpoints can limit the collateral damage. so say that splinter comes in and it starts to affect your

finger and all the cells that you need go there to try to get rid of that splinter to prevent the bacteria from coming in. you want that to shut down at some point so it doesn't just inflame and your whole finger turns rett. you want it just red enough to

get rid of the probe and go away and that is what the second part of the checkpoints can do. so these are two different way that is we can try to break the tolerance to self antigen and make our bodies figure out the cancer doesn't belong there. so the first way we do this is

with ctla4. this is work done by jim alisyn who has gotten a lot of press recently, most deservedly so, on his understanding of ctla4 and its role as a checkpoint so the cell you see in purple sell a t-cell. this is a t-cell that is

survived coming out of the thymus. it has a particular tcr, a particular lock that needs a particular key. and when it finds that antigen, what is happening is that it is putting ctla4 on the surface. so then this cell rather than

finding this t-cell and turping it on with cd28, it turns it off by hitting ctla4. so something that might have been working gets shut down. and gives it a negative signal so all the things that are happening in the nucleus to make this cell become an effector

cell gets stopped. so it has a dampening affect on any sort of downstream processing that happens and these cells called t-reg tory cells that keep everything in check, they always have ctla4 on the surface. second way that we can engage

this is when the t-cell leaves that lymph node and leaves that area where it first sees antigen and goes out to the tumor or out to the tissue. the tissue itself can put up the ligand called pdl1 or 2 and that engages pd-1 which again is a negative signal to the t-cell.

so if we can find a way to block this interaction, we can stop it from shutting down this t-cell. ordinary though is what you want. this is what keeps the immune response from destroying your finger when you get a splinter. when that is going after a cans

are, we don't want it to stop until the cancer is gone. so how does this work in cancer? there are some cancers, particularly some brain tumors, that just part of the dna change that is made them a cancer, they upregulate pdl1 on the surface of that cell present to block

any sort of immune response called constitutive oncogenic signaling. part of what makes it a cancer givers it that pdl1. is she cells in hodgkin's lymphoma dot same thing. the other thing that can happen is when we get a response, when

that t-cell find a tumor and know system how to kill it and starts killing it, the cell is a survival mechanism starts putting pdl1 on the surface to try to stoop it. so even if the cell department have any pdl1 on it to begin with, once the t-cell engages

and starts to kill and build that tumor micro-environment, it and other cells around it will start to upregulate pdl1 in the response to interferon gamma and start to shut down the t-cells. so we can find a way to block both of these, we might have a way to enhance a cancer

so where do we start with this? so we decided to start with tumors known to respond to other forms of immunotherapy. melanoma is a rare cancer but can be a deadly one when it gets advanced. only about 10,000 deaths per year in the united states.

what is important to remember because you will probably know someone if not yourself that had a melanoma, 95% of all melanoma is cured with the first incision. it's only when it gets to metastatic it gets to be deadly. if you have a mole you're

worried about, don't panic, go see a dermatologist. when it gets to be metastatic, you ohm he about a 16% chance of surviving five years up until recently. one of the first drugs found to cure, and we don't use that word often in cancer but could cure

patients was interleukin two. and that first drug where i said you step on the gas is try to rev up the immune cells in the body, when you give that drug to patients with metastatic melanoma, 4% will have all their cancer go away and stay away. we have followed this up to 40

years these patients are still alive. kidney cancer. surprisingly, is another one that responds to immunotherapy. this is a little bit more common than melanoma with just as dismal survival rate. it also has cured, dourable cure

10-20 year follow-up in about 7% of patients. so these were our first targets. we did these studies at the surgery branch in 2,000 one when it was first in human -- in 2001. so ctla4 gap as a phase i trial and we treated with a monoclonal

antibody plus a peptide vaccine. we had 14 patients, very small study for phase i because you're just wanting to see if you can give it safely. to our surprise, there were three responses. two of them had all of their disease go away and one had a

partial response. but what was interesting was that we started seeing toxicity. bad skin disease, colon disease, liver disease, and attacking the pituitary gland. so what you see here in figure a and b, this is a patient for those not used to looking at cat

scans, this is the lungs. the patient is laying flat with the feet coming towards you and the head going back into the screen. what shows up on the left side of the screen is the right side. what shows up on the right side is the left side.

so this is a tumor present in the periphery of the lung and you can see from the shape of the heart and everything else we are in sort of the same slice and that tumor is now completely gone. but what we were seeing, this is skin and we are seeing influx of

t-cells and destruction of the cortical layer between the skin. all these white areas in the skin shouldn't be there. you're seeing the same in colon. this is colon with a lot of inflammation and this is a specific stain for cd8 cells. so you got this influx of

lymphocytes into an area where there shouldn't be that many and this is a liver biopsy again with just an influx of lymphocytes. so the way you test any sort of chemotherapy that we had known up until this point is if you get toxicities in your phase i

and safety study, you stop and go back and you dose reduce. and so we used that same model going from 3 down to one milligram per kilogram. what we found was that unlike chemotherapy toxicities, if these patients were getting these other sort of side

effects, it meant that their immune system was getting turned on and so the chance of having a response was elevated if they had one of these side effects. so just for terminology, here ae is adverse event. grade iii drastically affects patient's lifestyle.

goes from 1-5. and in our patients with melanoma, if you had a grade iii or higher ae, you had a 36% chance of responding whereas if you didn't, you only had a 5% chance. more striking in kidney cancer if you had a greater than grade

iii ae, you had -- all responders showed some sort of side effect. so we realized we had to change the paradigm. it wasn't a dose reduce like you do for every sort of you wanted to push the toxities as long as you can as long as

you didn't hurt the patient in a lasting way. so we started a phase ii where we actually would up the dose in our patient starting with 3 going to 5 going to 9. and what can you see here is again the correlation held. if you had no immune related

adverse event, you had a very small chance of responding. if you had a grade iii, you had an absolutey higher. even if you had a grade 12, you had a better chance. the problem was colitis started to become much more of a problem, 18 and 28%.

so entero colitis, the immune cells started to attack the colon in a few patients and one patient did die from a colon everiation. so then we had to develop an algorythm for dealing with immune responses to get our patients through safely and we

found giving steroids would slow down the adverse events but it wouldn't stop them from having a cancer response. so what we did is we wanted to see how long this would last. was it something durable similar to il-2? we developed algorithms for

managing immown related adverse event. when you get a study to this point and then goes out into the world, we had to develop algorithms for helping clinicians across the country work with this as it went into phase ii and phase iii studies.

what it showed when we looked at the long term. this is 7, 9 years. this is what we called the tail of the curve. most studies of chemotherapies, this line eventually goes down to zero. particularly when you get to 5-7

we were seeing this tail of the curve. there are people getting long term benefit from these drugs. so just to remind you, this is the t-cell. this is the tumor cell. this is that lock and key phenomenon that is the first

thing that has to happen before any other rest of this makes sense. the antigen has to be in the right mhc and presented to the t-cell receptor and that lock and key has to fit and then you want it to have this positive signal so you can use these

antibodies which are anti-pd-1 or another we just talked about a little bit to try to block ctla4. so let's go into a little bit about how these drugs got so this is the one we studied in phase i and phase ii. up limb mab.

it went on to be a national trial run by dana farber and they were able to test it in 540 and what they found was that 38 patients had some sort of response, 3 had their disease go completely away. and again, when you look at however all survival, here are

the data, it is mature to about three years. you can see a tail of the curve. there are people surviving in the 20% range. so it got approved for metastatic melanoma and there were far too few drugs in 2011. it was the first monoclonal

antibody developed for metastatic melanoma they recently updated their survival data and again now that we have got 7, 8, 9, 10 years worth of data, you're still seeing this tail of the curve. you have got patients who at one point had a 16% chance of

survivalling at 5 years and now you have got -- survivalling -- 20% are still alive at 10 years. so tail of the curve is very important when talking about and it is what distinguishes it from most chemotherapies. so it's durable but for a small number of patients.

it doesn't always work. tremendous limb mab is a different form of the anti-ctla4 antibody. and it didn't have a successful trial. when it was tested against a chemotherapy sometimes used for metastatic melanoma, what can

you see is the survival curb is completely overlap. so this drug didn't make it. not every drug does. but because we don't know a lot about exactly how all of this can work in combination with other things, it's now being studied in trials, particularly

we have one here at the nci that the tgib branch is doing where they eradiate a tumor hoping to release new antigens then combine it with this. and that's ongoing. in this vol umab is another drug-- nivolumab, preclinical work was done before leaving the branch to go to johns hopkins

and started with a phase i dose escalations. when you have the resources and expertise to do aifies one in multiple different cohort at johns hopkins, they enrolled close to 250 patients here out of various different diseases. kidney cancer, kas state

resistant prostate cancer and colorectal cancer and others. and the spider plots show you when you measure all the tumors these patients have and you watch it over time, what you want is to see all thighs go down. so what they saw was that in

melanoma, they saw 28% response rate. again in kidney cancer also 27% response rate. which was validating but not all that surprising. what was surprising was non-small cell lung cancer showed up with an 18%.

this is what we call findings the signal. it's phase i. you're not doing it to determine a response rate. you're looking to make sure the drug is safe but you get these trickles, these ideas that it might work.

unfortunately, what it also showed that it didn't show any signal in prostate or colorectal cancer and we talk about prostate cancer being left behind, a lot of this early work is the reason why. but they were still developing grade iii/4 toxicities in 6% of

this is cat scans, a patient with non-small lung cancer. before treatment you could see a smudge here and here. what can happen with niece drugs is when the immune cells go into the cancer, they can make it swell and if you didn't know it this were a regular standard

chemotherapy and you saw this growth of these tumors, yod say the tumors are bigger here at two months. but without any additional treatment, look what happened at four months. now they are gone. so, this is something -- we had

to learn,do immunotherapy as we were doing this because it's different than chemotherapy. because that signal was so strong for melanoma they did a study specifically in melanoma because it had now been approved and all these patients had to be through the therapy and now

you're looking at this versus chemotherapy of choice. the kind of graph you're looking at here takes the best response the patient has. it's a waterfall plot. and for this to be successful, you want to see more below the line than you do above the line.

so a patient having a decrease in tumor are the lines you're seeing here. and what we saw was that with na vol mab, 32% had objective 4 had cancer go away completely. because of this, it was approved for up limb mab refractary melanoma in december of 2014.

so that meant that any patient that wanted to get this had to have already been up limb mab. it's great but it has toxicity. so can we test it in patients who haven't been through this? so this study tested patients with untreated metastatic disease because there were drugs

that had come out at the time to target patients who had b-raf mutations, the fda insisted they had to be wildtype b-raf and not eligible for other drugs. and the test they gave was nevol umab versus cacarbazine. this is very rare. this is a research dream to see

something like this. you know have you got something that is really going to work. now what i will caution you on is the length of time here. this is only 18 months. this isn't very mature data but striking. so, 18 months 70% of the

patients who were treated with na vol you mab were still alive. 40% of them had objective 16 of them had their disease go away. they recently updated this just this last year in louisiana the aacr, and now you're looking at 5, 6, 7 years and again it's not

as impressive as that 70% but look, 5 year overall survival we now doubled from what it historically was up to 34%. all patients. again tail of the curve. perm bro liz mab is another form of anti-pd-1 and it went through the same trials that na vol umab

first had to show the ability to affect response in patients that had already been through up lumab. they treated 157 patients. you can see the response rate there with a low rate of grade iii 4 adverse events. again you'll note the time

course is very short. despite that however, it did get approval in september of 2014. they went on again just to look at two different doses and it showed that it didn't matter which dose of perm bro liz mab you used, the affect was the same.

so the dose now is two milligrams per kilogram rather than 10. when you start talking about the cost of these drugs, that's a huge change for the better for the patients. but then they wanted to see should we do this as first line?

if you remember when i showed you up limb mab it was testing against chemo of choice. perm bro liz mab went head-to-head with up limb mab so they did two different dosing rental mince in a 1-1-1 fashion and treated 834 patients. and you can see here the

response rates despite the dosing schedule didn't matter. you you could get about the a 33-34% response rate with perm bro liz mab with substantial number of complete responses. up limb mab stayed where we thought it was, 12-13% response rate with some crs.

and the response rate clearly split. the difference being the grade iii adverse event were lower for perm bro liz mab and lower in the colitis range. the colitis turned out to be for up limb mab the most devastating of the toxicities.

so they ouch dated this most recently -- updated in jama in 20 scene. these are -- 2016. these are all perm bro liz mab. they have taken out the other arm. woo are hera two years, 60% so in checkpoint modulation, the

two approved antibodies interfere with different receptor ligand complexes. could we combine them perhaps to get better responses or survival? and that's exactly what happened next. so they looked at the

combination therapy for melanoma and what they tested it was again in a 1-1-1 fashion, single agent na vol umab plus up limb mab and single agent. 945 patients. they defined pdl1 positivity as greater than 5%, which is just a detail that is important for

people that look at this but we'll talk about that in a little bit more later. what they found was that the combination could respond 58% of patients could respond to combination therapy versus 44% of patients to single amount na vol umab therapy and only 19% in

up limb mab but lock at the when you combine the two, the side effects skyrocket. so while it can have a phenomenal response rate, and we think those are going to be durable although the data is not yet mature, you pay the price with a lot of toxicities.

so it's still being debated in medical oncology circles as to whether patients should be treated with single agent pd-1 or combination. the relationship for the struggle is we don't always know the pdl1 status of our patients and if you're already pdl1

positive, you get a pretty good response rate to just na vol umab alone without buying the extra toxicities of the combination therapy. whereas if you're pdl1 unknown or negative, you have a very lower rate of responding to single agent na vol umab but

that gets rescued by the addiction of up lummab that's why there is still equipoise in the melanoma community. they have updated their results. this is now not overall survival but progression-free survival with the orange line being the combination therapy, the blue

line being single agent did the green line being up lummab. 18 months 46% of the patients have not yet progressed on they have not updated their overall survival because they claim it is still too immature and i agree. we'll see updated information

from them at asco 2017, next june. but the combination has been approved for the use in patients with metastatic melanoma as of january 20 sixty nine. so why melanoma? if you look at the paper put out by lawrence et al., they

studied the number of number synonymous mutations within different tumor types. and melanoma has the most. it might be a combination of mutated tumor antigens a lottery ticket, the more mutations you have the more likely you're to have a t-cell to recognize your

cancer and the more likely these drugs are to ig night the t-cells to go after it. but what about other highly mutated tumors? so non-small cell lung cancer by far dwarfs melanoma as far as impact on american society with close to 160,000 deaths per

year. if you develop metastatic disease with non-small cell lung cancer you have a 2% chance for 5 years. and there is a correlation of smoking and the number of mutations. bladder cancer, highly lethal

that they don't even put together 5 year over overallsurvival statist accident for it because the numbers are too small. and tumors with mismatched reparody efficiency, in ability to fix dna problems during daughter cell replication, a syndrome and problems with these

four mismatch repair genes. they all have high numbers of somatic mutations and might be candidates for this kind of so an anti-pd-1 agent was tried in non-small cell lung cancer and you can see the waterfall plot we discussed before. a fair number of patients here

that are still alive and who had their tumors go away. this is specifically for the squamous cell subset of non-small cell lung cancer and tested na vol umab against docetaxel and you're seeing a beautiful split like we evaporate seen in chemotherapy

for a long time. based on this data the fda did approve na vol umab for refractary squamous non-cell lung cancer in 2015. the other variety non-squamous again not quite as dramatic as split as the other. but 19% response and that

approval was expanded to include non-squamous non-small lung prep liz mab, the other drug, the first is known as op devo. you might have seen their commercials on t.v. this is known as k trueda. i don't know if they have as much of a t.v. presence but they

were doing a bigger study called keynote one and they treated 500 patients with non-cell small lung cancer and saw objective response of 20%. when you looked at patients who were smokers, who potentially had a higher degree of mutations because of carcinogens bathing

epithelium, they had higher response rate at 22.5%. however, it also engaged t-cells that attacked normal lung tissue. to an extent it included one fatality. however, based on this, fda granted approval of this for

advanced non-small cell lung cancer in october of last year. bladder cancer also highly mutated because of carcinogens we in gest and come in contact with on a daily basis and end up getting filtered by our kidneys and sit in our bladders. so bladder cancer has a fair

number of mutations. mpdl3280a which luckily got a name recently. i don't know how lucky we are. it's a difficult one to say. it's an anti-pdl1. so it blocks the other side of the receptor ligand complex. they treated all commerce but

they did show that patients that had more than 5% of pdl1 had a 43% response rate. so the colors you see here the green, those in the grown are the ones that had high expression of pdl1 on their surface and the ones in red were the ones that did not and while

you can see there are some green that says did not have a good response and a single red that did have a good response, by far most of the greens are over here and most of the yellow and reds are over here. this was updated recently looking at all patients.

have you here a one-year survival of 40% which is almost unprecedented for metastatic bladder cancer. based on this, this drug, which is the first against this target anti-pdl1, atease liz mab which i think will get a easier name called tech win or something

like that was approved for euro thieleial cancer in may. perm bro liz mab the other pd-1 amount was tested in euro thieleial cancer and you can see the very small numbers here, 29 patients that were evaluated and had a response rate of 30%. na vol umab also tested.

78 patients and only 29 of whom were eevaluated. we try not to say the patients are valuable until we had six months to follow them. so at the time this was presented at asco only 29 patients are valuable but they had a response rate of 24%.

so what about those mismatch reparody efficient cancers? the ones that have many, many thousands of mutations. they did three parallel cohorts so mismatch repair syndrome is most well discussed in patients with colorectal cancer but those patients can also form other

cancers, endometrial among them. so they looked at your standard colorectal cancers, mmr proficient and then deficient and then other cancers that are also deficient. and when you can see those with deficient meaning large numbers of mutations are pictured in

blue or black. and those with the ability to repair their dna correctly are in red. and you can see the reds all have their tumors grow with the exception of these and the blues and blacks almost had their tumors go down.

so this really added to the working hypotheses it is these neoantigens that are driving the ability of these drugs to work. and what they did was looked at this. so this gives you a look at the structure of the tumor. what we are looking at.

t tumor and n is normal. so you're looking at the interface where a cancer and the normal surrounding tissue interact. this is a proficient colorectal cancer one that can repair its dna. this is a deficient colorectal

cancer who cannot repair dna problems not correct dna problems and has a large number of mutations. and you can see here not only is there a lot of pdl1 on the surface these are biopsies taken by the way pretreatment. this is before any checkpoint

blockade has been given. so this is the natural living state of these tumors. they have a lot of pdl1 on the surface between the tumor and normal and all of these brown dots here are cd8 t-cells so an infiltration of them at the interface.

and you can see here very few of those cd8 cells infiltrating particularly here, this is blown up. very few of them and very little pdl1 staining. so checkpoint blockade. we talked about highly mutated tumors and melanoma and

non-small cell lung cancer, bladder cancer and tumors with mismatch reparody efficiency. what about news other tumors? so renal cell can respond to hodgkin's lymphoma, reed sternberg six are one of those that oncogeneically upregulate pdl1 and head and neck squamous

cell cancers in hpv can have a lot of mutations. so na vol umab for kidney cancer they tested it versus every lime us, and they found that if you get an objective response in 25% of patients with na vol umab and increase in median survival. besides this, it did receive fda

approval in november of la of the year. hodgkin's lymphoma. you seen enough of these water fall plots now to kind of understand how rare this is. how many of these lines go down. 66% objective responses with 7 patients who had all of their

lymphoma go away. these aren't your run-of-the-mill patients with they have already undergone stem cell transplant and their disease has come back and they already have undergone treatment with rem tux mab and their disease has come back.

so is thee patients have limited options and you're able to create 7 complete remissions. as you might expect on the basis of this strong data, it was approved for refractary hodgkin's lymphoma in may of this year. in head and neck squamous cell

cancer, this they did not require. a look at the tissue to see how much pdl1 was there and they were able to get a response rate in the 18-24 -- 18% range over all, those who were hpv positive had a slightly higher response you can see the overall survival

here at 18 months about 30% still alive. it has been approved for recurrent or metastatic head and neck squamous cancer as of last month. so blocking the pd-1, pdl1 pathway, we have talked about a lot of different tumor types and

a lot of different drugs that targeted this. as of this weekend, when i finish these, these are all the ones that are fda approved. the others are all being evaluated for possible approval. these are the ones that have been approved as of this moment.

what about other cancers? so in breast cancer, i'll go through these fairly quickly. you can see response rate in about 19%. there is controversy as to how many triple negative breakfasticanciers will have pdl1.

this study claimed 60% and one claims 20%. a lot thos do with the antibodies that are used for immunohistochemistry. when looking at triple negative breast cancers and those who had er positive her 2 tumors they were able to get partial

responses in three patients. very small numbers. gastric cancer, a very lethal disease, 22% objective response just to give you an idea of how active this field is, these are just some of the abstracts that were presented at asco 2016 this so you're locking at tumors

ranging from sarcoma to uterine lie oh, myo sarcoma, small cell lung cancer, salivary, endometrial, thyroid, gastric, ovarian, your thieleio cancer and others that combine these drugs with forms of radiation, that combine weapon vaccines that i haven't put on this

list -- with vaccines. you can see the amount of work going into this. these two studies here are done by investigators here at the nci. there is ongoing work here in particular combining some of these monoclonal antibodies with

vaccines and with radiation you can see across a wide variety of cancers, with the exception of uterine sarcoma, there is a signal everywhere. there is one or two patients that can have cures complete responses. this is all very short follow-up

no one would call this anything but a complete response at this the point. we don't use the word cure until we get out to 10 years. but to get to cure you have to start with complete response. so you can see a signal in all these different cancer types.

so these are all the different targets being investigated. even with all the work that i just showed you and all the work that is being done, we only really talked about blocking this pathway, this pathway, and this pathway. there is quite a number of

receptor ligand complexes out there being explored. and that is the state of immune checkpoint at this point. so any questions? >> so the question is one about cost and what this looks like relative to other therapies for patients with melanoma.

what i will tell you is that there are very few treatments for patients with melanoma. so it's not like you're looking at a long list of other chemotherapies to try. prep bow liz mab runs 5000 dollars a dose, that's the cost that we pay when we treat

patients here at the clinical center. imagine it's probably a little more on the outside world. and you're talking about getting one dose of that every 2-3 weeks for about a year. i think any of these therapies when you put them all together,

the dose strategy and the pricing because if it's a little more expensive you don't get quite as often or if you get it less expensive you're on it for a longer time. it round out to $100,000 a year. as competition increases i hope it comes down but it's at that

range for now. >> sure. so what we don't know -- the question was how long do people need to continue? so the patients with up lummab got 4 doses and stopped and didn't need any other therapy. for prep liz mab the current

thinking is if somebody is responding to give them two years of therapy and then stop and the data is not conclusive on whether they need to continue it or not. it's noted evening clear that they need to continue it two years but that is the stopping

point that they have arrived at. the hope with immunotherapy because you're creating a living therapy within someone's body. you're remodeling their t-cell repertoire to attack their if you do it right and if it sticks, then they don't need any further treatment.

while it may be $100,000 for one year or two years, it's not $100,000 for 15 years. >> almost all -- the question is about the toxicities that come when it attacks the colon or the liver or other things. most of them are reversible. so you can treat the toxicity

with steroids and it does not seem to meliorate the tumor the only side effect that appears to be permanent and it means that patients have to be on lifelong hormone replacement s that there are a few patients where the t-cells actually attack the pituitary gland and

they became hypoadrenal so those patients if they are male have to take testosterone. in addition to mineralocorticoids to replace their adrenal function and glucorticoids to address their adrenal function as well. that is very small number but

that's the only one we seen that appears to be permanent. >> the thought why the colitis doesn't exist at the t-cells are persistent is that it's tricky. because we don't know how the repertoire changes and grows but the thought is that once we use the steroids and clear it, the

patches which are a normal immune monitoring function of the small bowel in the mucosa associated lymphoid tissue know that t-cell is the one to keep the brakes on so it doesn't release the brake again does. that make sense? >> any other questions?

i didn't put my twitter handle up on this but if any of you want to follow, we have both a twitter account for the surgery branch, which highlights the work coming out by our postdocs all the time as well as i have my own personal account which i will tweet from asco and aacr

things related to immunotherapy. sl guav sb or -- and my e-mail is in the directory so you can find me if you need moo. you can find me if you need me. very exciting field. i'm sorry for the lateness of my slides. i was trying to get the asco

stuff in.