Well, thank you everyone for being here today. I'm a walker and a talker. So that's exactly what we're gonna do So the the session after lunch is always a hard one. So I'm gonna do my best job and trying to keep you awake So the learning objectives for today's talk are to understand the association of checkpoint inhibition and endocrine toxicities I'm gonna go through case-based clinical scenarios walk you through presentations Management and treatment of these toxicities and then go over kind of helping you think like a toxicity expert You all know endocrinology really well I'm gonna help you think in the nuanced way in which you want to think about Oncology patients and then wrap up with practice innovation and what we can learn from each other. These are my financial disclosures You're welcome to tweet or X about it without any patient identifiers or unpublished data Now I usually give talks to oncologists and they can teach me a thing or two about how these drugs actually work But I'm going to oversimplify this and I think of immune checkpoint inhibitors when I'm driving my car Think of it as a foot off the brake and another foot slamming the gas pedal or the accelerator. I assume that the the placing of this may be a little different in this part of the world but Think of it as your immunity is ramped up at a hundred miles an hour and riding in a 40 mile zone What happens as a result is that your immune system is really running fast and is able to target and kill cancer cells but in the the result of that is that you also have accidents along the way and Immune mediated adverse events or accidents that occur along the way Now when I started doing this about a decade ago, they were two or three FDA approved indications for these drugs now fast-forward 50 plus FDA approved indications with hundreds in the pipeline right now and needless to say I've been busy. The program has grown and we're seeing a rapid increase in the need of endocrinologists who understand toxicities and know how to manage these nuanced endocrine diseases Now if you put all endocrine toxicities in a bag and mix it up hypothyroidism emerges as the number one toxicity that is noted and This is this data comes from 38 randomized control trials I looked at 7,500 plus patients and what they saw was that immune hypothesitis Which is pituitary was more commonly associated with CTLA-4 agents and the thyroid was commonly affected by PD-1 and PD-L1 But there was another theme that emerged is that when you put the combination treatment CTLA-4 and PD-1 Where you take the foot off the brake and slam the gas It makes sense why your immune system is ramped up and why you can have double the amount of toxicities And that's kind of what we have seen as an emerging pattern and I see this clinically very often Now, let's move on to clinical cases. This is a patient of mine Developed acquired generalized lipodystrophy three months after being treated with monotherapy with nivolumab Some clinical cases are as obvious as this and some may not be as our first case of immune hypothesitis So no points in guessing this Diagnosis, this is a 65 year old female with a diagnosis of metastatic adenocarcinoma of the lung Stage four was started on a trial of combination ipinevo and paclitaxel Referred to endocrinology with complaints of severe fatigue headache and an abnormal pituitary MRI Now as you can imagine when you look at these labs the first set of labs done on January 15th Show that the TSH is low for a low normal free T4. So in with my endocrine hat I'm already thinking that the TSH axis is affected now fast forward 10 days What you're seeing is an emerging pattern You see that the TSH is low with the low free T4 putting this patient in a bucket of secondary hypothyroidism now at the same time We also got the ACTH in the cortisol axis and as you can see the ACTH is low cortisol is low and the patient Did not stimulate above 18, which is part of the assay back in the day when this test was done So I'm sure we all agree that this patient has secondary hypothyroidism and secondary adrenal insufficiency We also got a pituitary MRI that showed change in height of the pituitary gland Stock thickening, supercellular convexity, heterogeneous enhancement of the pituitary gland. Now when I started doing this every single patient We suspected of having immune hypophysitis got a pituitary MRI But we learned very quickly that only a third of patients who actually have immune Hypophysitis have positive MRI findings the rest of it is a waste of money So we stopped doing it unless patients have headaches and vision changes. We don't recommend getting a pituitary MRI Now why did this patient get immune hypophysitis? It turns out that the normal pituitary cells actually express CTLA-4 proteins, so it makes sense that you ramp up the immune system and target CTLA-4 and give it an antibody You're going to activate an immune cascade with that results in Hypofunction of the pituitary gland and what we've seen is that a majority of times two to three axes are down so if you have a patient with Secondary hypothyroidism you should be checking the ACTH axis and the gonadal axis in this patient because most oftentimes There'll be more than one axis that is down and you may be missing a diagnosis an important diagnosis in the patient Now for those of you who have taken care of patients with checkpoint induced immune hypophysitis the flavor of checkpoint induced Toxicities or immune hypophysitis is different depending on what agent you're using now It made sense when I said CTLA-4 proteins are expressed and you can get immune hypophysitis These patients get it fast. They get it quicker So they get in the first nine to twelve weeks after initiating treatment and they are very Symptomatic when it comes to a blown up pituitary gland or an inflamed pituitary gland They have headaches and vision changes now the flip side of this which we don't know why why patients get PD-1 and PD-L1 associated Immune hypophysitis these patients get it later in the course. You can see here the mean time is about six months They're sprinkled all across the course and these patients do not have symptoms very often Only a fourth of the patients 25% of patients will have symptoms of headaches and vision changes, which is a blown up pituitary gland Now let's talk about how you would manage this case right now you have this patient acute presentation labs are abnormal The first question you want to ask yourself is this patient in an adrenal crisis? And I don't need to teach you a thing or two about how this needs to be managed We treat it exactly the same way you would manage any case of Adrenal crisis the difference being that you're gonna start them on high-dose steroids The most important thing in these patients is get labs If you have the opportunity to draw some blood get a course at all a CTH because these patients are always sick We're talking about cancer patients. We're not talking about people who are walking on the street and get adrenal insufficiency. These people are tired They're not eating they're losing weight. So you're dealing with a very different patient population. So those labs are very very helpful Now the patient you have the luxury of time and the patient is not in an adrenal crisis What you want to do is you want to get understand the communication that's happening in your body What's what is the pituitary telling the thyroid? What is the pituitary telling the adrenal glands? What is the pituitary telling the testicles and the ovaries? What does that conversation look like and if the patient has headaches and vision changes you want to get a pituitary MRI? Now treatment for immune hypophysitis now just for the show of hands. I want to I want to see over here There's no right or wrong answers. Just raise your hand. Just give your opinion Would you treat this patient with replacement steroids or would you treat this patient with high-dose steroids? High-dose steroids, I hear a lot of mumbling saying high-dose steroids. Okay, so let's put some science into this, right? Let's understand what we know already. So this is a really neat study done by Dana Farber They took patients with immune hypophysitis put them in two different buckets They gave one bucket high-dose steroids and they gave the other bucket replacement doses of steroids What they found was there was no statistically significant difference in patients who got high versus normal steroids And this is why we've moved away from practice when I started doing this. Everyone got MRIs. Everyone got high-dose steroids We are saving people a lot of money by not doing all of this In fact patients who were giving high-dose steroids had a higher mortality. It was a follow-up study So unless the patient has a blown-up pituitary gland, you do not want to use fire extinguisher dose or anti-inflammatory doses of steroids So now coming to the treatment now you have this patient you have labs your biochemical signature You have imaging findings The patient is not in an adrenal crisis and the patient has all these symptoms of headache and vision changes You all were those of you who said high-dose steroids you were correct You would treat this patient with high-dose steroids because you want to shrink that pituitary gland Alleviate the symptoms and put the patient back on replacement steroids So you would start with one meg per keg and then go down On prednisone down to ten five to ten milligrams of prednisone and then switch them over to hydrocortisone We prefer that as an agent unless there is an absolute indication for the patient to be on prednisone Now on the flip side if you have a patient who just is not does not have adrenal insufficiency Does not have a blown-up pituitary gland no MRI findings You'd replace what the body can't make ACTHs access is down give them hydrocortisone TSH access is down give them levothyroxine gonadal access is down Obviously look at the patient profile They high risk for clots if it's a male look at that profile and then you can replace them with testosterone Now moving on to the prognosis now, this is a very common question I get asked by most of my patients what now doc What's gonna happen? Am I gonna remain on this treatment for the rest of my life? Can I continue on my cancer treatments? This is their worry when they come and the answer I go back to this longitudinal case cohort study where they looked at patients times zero times six months and saw how many patients actually kept the initial diagnosis of ACTH TSH deficiency or gonadal deficiency and ACTH deficiency persists I have never seen a patient and I have tried trust me I have tried originally when we didn't have data about this to get people off of steroids, right? Especially in those where I don't have those baseline labs and I have failed miserably patients are unable to tolerate if they have adrenal insufficiency They will not be able to tolerate doses Under replacement doses or physiologic replacement of steroids when you get them down to five milligrams of hydrocortisone, they're gonna feel awful So that's your answer don't taper them if you have that answer TSH and gonadal access recovers So let's look at what happened with our patient, right? Patient was continued for with their cancer treatments received high-dose steroids tapered down continues on steroids And then we started on a hundred twenty-five a levothyroxine and then the doses came down to zero So the TSH axis actually recovered I'm gonna put a plug here about checkpoint now podcast series as that as was mentioned earlier This is a podcast that I host and produce. It's been online for about four years There are two different kinds of episodes one is for you clinicians I understand 25 minutes does not do justice to understand everything about adrenal insufficiency thyroid and type 1 diabetes So this is an additional source of information for you. You have it on Apple Google Please use this and then there is a second episode episode 25, which is for patients So if you have a patient sitting in front of you in clinic You want to educate them about stress dosing why they got this problem? Just feel free to use this tell them to go on their drive back home They can listen to it and come back to you with questions. So it's meant to save you time in clinic So moving on to our next case, which is a case of autoimmune thyroiditis 66 year old Caucasian male with a history of metastatic small cell lung cancer with metastatic disease to the liver and Lymph nodes presents with fatigue 18 pound weight loss over two months altered mental status and ongoing diarrhea the patient was admitted because of another toxicity, which is autoimmune colitis and Also received TFTs at the same time So if you look at the first lab set, which is the TSH of zero point two zero When I put my endocrinology had I cannot make any sense of this, right? It could be TSH deficiency because this patient received combination therapy or it could be primarily hyperthyroidism Where there's too much TSH coming out or being poured out and it is shutting down the TSH So I don't I can't make sense of an isolated lab value, which is what I often tell oncologists I need to see the communication between the pituitary and the end organs. I cannot may tell you a Diagnosis without that. So fast forward in a few days We saw the patient and now the patient has primary hyperthyroid T4 is high Suppressing the TSH fast forward a few more days labs are normal and then fast forward a few more days TSH is high appropriately and T4 is low. So putting this patient in a bucket of primary Hypothyroidism, which is different from our previous patient, which is secondary Hypothyroidism now what is important here? You all know how this plays out with general thyroiditis But what is important here is to understand the time frame It moves very quickly and it makes more sense when I talk about the typical course of painless thyroiditis Which kind of plays out over months and when you look at these patients, they play out over days and weeks So if you do not get labs on these patients quickly, you may miss the hyperthyroid phase or they may go into deep hypothyroid state Which you're trying to treat at that point so get labs frequently And this is why FDA mandates that every patient who's receiving checkpoint inhibitors Whether it's every three weeks or six weeks needs to get thyroid function tests at every infusion. This is a reason why it is mandated Now moving on to why did this patient get thyroiditis now? I'm going to oversimplify this I know there's lots of experts in this field here, but HLA class two molecules are expressed in thyroid follicular cells. You have polymorphisms. It makes you more susceptible to autoimmune attack and makes sense. You give an immune enhancer, like checkpoint inhibitors, it triggers thyroiditis and Graves' disease. Graves' disease, less common. I'm telling you, I can count on the number of fingers I have how many patients over the last decade that I've seen with Graves' disease. So don't overdiagnosis unless you are absolutely sure that the patient has Graves' disease. Thyroiditis, thousands of patients so far, I can't even keep up with the numbers. So you're looking at the zebras when it comes to Graves' disease in these particular patients. Not that it can occur, but it can absolutely occur, but keep a low threshold. Think about thyroiditis first. So what is our diagnostic approach for this patient? So you all know how patients with hyperthyroid and hypothyroid present. So I'm not gonna go over clinical findings, but it's important to note that these patients are most oftentimes asymptomatic. They actually walk in with TSHs of 140 with undetectable free T4s and ask me, I don't know why I'm here, my oncologist just told me. And I think because they develop it so quickly in weeks and days that they may not express all the features of the clinical manifestation. That's my speculation that over the years that I've seen these patients. And cancer patients are very forgiving. They write off a lot of symptoms, thinking that is because of chemotherapy, because of this side effect, because of that, oh, I have cancer. I should be going through these symptoms. So they write off a lot of these symptoms. So you really need to parse it out. You really need to talk to them, sit down and understand what's going on, especially with regards to timeline. When did what start? When did it get worse? What is percentage difference between three weeks ago and now? Because you have very objective lab findings on these patients. So you'll put them in these two different buckets. And then the way we would manage this patient really depends on when you catch the patient. And I'm gonna say this again. It really depends on when you catch the patient. There is a hypothyroid phase and then a hypothyroid state. And we're actually gonna move into the nomenclature. By next year, we should be putting out a consensus statement to actually suggest that hyperthyroid phase and state, because state stays, phase is something that is transient. So I want you to think about it in that way. So if you have a patient sitting in front of you whose labs tell you that they're hyperthyroid and they're asymptomatic. Hey, I don't know why I'm here. You wait and watch. They will move very quickly from hyper to normal to hypo, or they may not move into normal. They go deep, straight deep into hypothyroidism. If the person sitting in front of you is symptomatic, they're shaking, they're tremulous, they're sweaty, they're pacing in the room, just like your typical hyperthyroid patient, you would treat them for their symptoms. Give them beta blockers. They got a painful thyroid. Give them NSAIDs, give them steroids. I've never had to do a thyroidectomy because remember, it is a phase. It goes away. It comes and it goes. Now with a hypothyroid state, you're going to treat them with replacement levothyroxine. And as you know already, it's one to 1.6 micrograms per kilogram, depending on the patient sitting in front of you. If this is a patient who's elderly, has arrhythmias, you really want to downplay that dose and start low and go conservative. We tend to be more aggressive because we know that the patient who has a TSH of 20 today is going to have a TSH of 40 in two weeks. So we actually give heavy-handed doses of levothyroxine, especially because patients get monitored very closely in the oncology world. So it's not like they're going away for three months. They're getting their labs done in two more weeks. So you have the opportunity to adjust. So you will do this based on the patient sitting in front of you. Now, what happened with this patient? Patient is in remission. So I'm showing you excellent cases. These people would have died if this was 15 years ago. It is a better time to have cancer. People are living and they're living without cancer, but with chronic long-term toxicities. And this is the reality of cancer world. And as an endocrinologist, if you have not seen this, trust me, as these drugs become more and more approved in your region, you're going to see more and more of this like we're seeing it in the United States. The patient continues on levothyroxine. And in old tradition, checkpoint now, there's two different podcast episodes. You have episode two, which is directed towards clinicians, and episode 21 that you can share with your patients. And then there's an ATA thyroid stimulating podcast that I did a few months ago that talks about managing thyroid toxicities. Now, moving on to our last case, immune-mediated type 1 diabetes. Has anyone seen this yet? Wow, that's, all right, so that's great. So you guys can chime in as well. So 54-year-old patient with regionally advanced melanoma presented to the oncology clinic for his third immunotherapy treatment and noted to have nausea, fatigue, polyuria, increased thirst, son has a history of type 1 diabetes. Blood glucose was 424, no known history of prior diabetes. Now, these are the patient's labs. As you can see, glucose is high. Sodium corrected to the glucose is normal. Anion gap is high. You have a positive beta-hydroxybutyrate. C-peptide's low, that means endogenous insulin production is low. One out of the four antibodies that were tested were positive and I can tell you from studies that we have regarding type 1 diabetes from checkpoint-induced type 1 diabetes, 50 to 60% cases do not have positive antibodies. I'm gonna repeat that. 50 to 60% patients do not have positive antibodies. It is helpful if it's positive. If it's negative, you will be heavily relying on your C-peptide. So that is why always, always, always get a C-peptide. It helps you put the patient in the right bucket because remember, some of these patients also have immune-mediated pancreatitis and that can have an initial shock effect on the pancreas and they can have transient insulin deficiency, which improves with time. So getting that C-peptide can be very valuable in putting the patient in the right bucket and talking, having that conversation with the patient. How long do I need to be on insulin? You have it in front of you, the C-peptide's undetectable, that's that patient you're gonna say, you're gonna be on this for the rest of your life. I've taken care of about three dozen type 1 patients over the years. 50% of them have passed away, unfortunately, because of their cancer progressing. 50% are alive and thriving and doing well off of cancer treatments. So it's a very mixed bag of patients that I see. I don't see such a high mortality with immune hypophysitis or with thyroiditis. In fact, the prognosis, when you get an accident, immune hypophysitis, melanoma patients tend to live twice as long as those who did not get immune hypophysitis. That is amazing. So when I tell patients that you're probably gonna live twice more than people who did not get the side effect, it's a silver lining to a dark crowd, but it helps that conversation. Now moving on how and why this patient got type 1 diabetes. Now I'm gonna talk about a model, a mouse model or a translational, I'm not a translational scientist. I have a lot of respect for people who do that, but not my cup of tea, but I'm gonna break this down for all the clinicians in the room. So the model that they used, this study was done 10 years before these drugs were approved. So no real connection, but I thought it was a great study. 10 week old, female, non-obese, diabetic mice, and they did immune checkpoint blockade in these mice. And that mouse model spontaneously develops insulinitis. You do nothing to those mice, they're gonna get insulinitis and develop type 1 diabetes by the time it's week 16. So it's a beautiful model, right? So you give this mouse model, you put them in three or four different buckets, do nothing with one bucket. One bucket you give CTLA-4, the other two buckets PD-1 and PD-L1 inhibitors. And what they saw was that the mice that were exposed to PD-1 and PD-L1 developed type 1 diabetes within days of exposure. And it turns out that human pancreatic beta cells lack CTLA-4, but they express PD-L1. So it makes sense, a similar format to immune hypophysitis, pituitary expresses CTLA-4, pancreas expresses PD-L1. I am yet to see a case of CTLA-4 monotherapy induced type 1 diabetes. Either it's monotherapy with PD-1 or PD-L1 or a combination with the two. So it goes to say that the science still prevails and you can draw a lot of conclusion as to why. The pancreas is more susceptible when patients are treated with PD-1 and PD-L1. Now going beyond the guidelines, right? And there's a ton of guidelines. There's ASCO guidelines, there's CISTI, there's NCCN. And when I give this talk to oncology groups, I talk about helping them think beyond the guidelines. Like how do you process that minimal information taken to the next level, right? Now you all are absolutely fantastic in taking care of type 1 diabetes and decay. I do not need to go over the management of that. But what I wanna go over today is a nuanced approach. If you have a patient sitting in front of you with type 1 diabetes from checkpoint inhibitors, give them a hug, hold their hand, tell them it's gonna be okay. Because these patients go through a lot of emotional struggle. They're going through cancer. Some of them are going through intermittent steroids, which is going to be the next talk. Their blood sugars are all over the place and they can't eat because they're so nauseous. And they have to watch what they're eating and give themselves five to six injections a day. Just think about it. How awful can that life be and how life churning that diagnosis of type 1 diabetes can be? So a little bit of reassurance to these patients goes a long way. And we give a lot of emotional support to these patients. We're actually doing a diabetes distress study in patients who are diagnosed with type 1 diabetes from checkpoint inhibitors because there is such a palpable level of anxiety or health issue related anxiety in these patients. So remember to do that in these patients. And their approach is very different. You're not telling these patients to eat less. You're telling them, please eat. We will match your insulin to your requirements because that's another problem we see in cancer patients. They start restricting. They go through restrictive calorie intake because they're concerned about their blood sugars going up. So they stop eating and that's not good for their cancer. So you have to tell them, eat. We will fix their blood sugar. It's a very nuanced approach to how we manage the general population. Now, case conclusion. The patient received infusion of pembrolizumab. On the day the patient was diagnosed with DKA. So the patient was diagnosed with DKA on the labs in the oncology clinic. They called me. I said, go ahead and give them the infusion. Patient came to our clinic. We gave him IV fluids, started him on insulin. Remember this patient's son had type one diabetes. Very different patient, right? He already knew how to do it. He knew all the shots. He knew how to check ketones, everything. So very different patient. Typically, this kind of patient would go to the hospital and get educated, stay there for two or three days, learn everything about diabetes, get all the regimens sorted out before they get home. Now, the patient was discharged and then continues on insulin and now developed hypothyroidism, primary hypothyroidism, a month or two later. I've had patients who've developed adrenal insufficiency and type one on the same day. And I've had, he unfortunately passed away, but you see this come about so aggressively and so abruptly that you have patients you're watching and have tested ACTA, have tested antibodies. Two weeks later, they have positive antibodies. They come in with DKA. So it's really interesting. You have to keep a really low threshold with these patients. Now, knowing this patient's familial risk, this is a question I often ask my oncology colleagues. When you knew that this patient had a strong family history of type one in the son, would that change your decision to give this patient treatment? I can tell you he's absolutely thriving. He received only four treatments, this treatment which caused DKA and the next treatment, and he has been cancer-free for the last five years. So he's doing well. And he has accepted his diagnosis and he's fine with it. But some patients are absolutely not fine with it. They still blame the treatments for their new life with type one diabetes. So you have to really meet the patient where they are. Now, overall conclusions. Endocrinopathies are common. Course of illness, chance of recovery is different. Timely labs, as I mentioned earlier, is critical. Pause and pause before giving steroids. Have you checked relevant labs? Now, we have a few more seconds, so I'm gonna end up with telling you a little bit of what we're doing in this world. We have several initiatives, which I can absolutely share with folks if you wanna come meet me after the meeting about how you can be engaged in the world of toxicity management. There is an entire new world within endocrinology, rheumatology, neurology, cardio-oncology, nephrology that is emerging. And it's very timely, as you can see. But you should expect international consensus-based guidelines. I've been leading this effort for about two years. We have international colleagues, oncology, dermatology, endocrinology, all engaged in this. And we have developed principles of how you would manage these toxicities, which ultimately will go, hopefully, into guidelines of how you would manage this. It puts patients in buckets of probable diagnosis, possible and definite diagnosis of endocrinopathies. And with that, I'll leave you with some options of how you can get engaged. As I was mentioning, there are multiple ways to get engaged. I started the Oncoendocrinology Special Interest Group at Endocrine Society, which is one of the way, ACE is a wonderful way to be engaged because we do publish in ACE journals to keep up with what's going on. We're actually submitting a case report, the patient that you saw acquired generalized lipodystrophy. It's under review with one of the ACE journals. And you can follow me on LinkedIn, learn things on the podcast as well. So I appreciate your time, and I'll take questions, I guess, at the end of the session. Thank you very much.

checkpoint inhibitors

endocrine toxicities

hypothyroidism

immune-related side effects

oncoendocrinology

patient care