Sloan Kettering Cancer Center in New York City. I would like to welcome you to today's master class on managing toxicities with TKIs in combination with checkpoint inhibitors and endometrial cancer, which is supported in part by ESI. I am so pleased to be here today and I thank the leadership of the IGCS Education Committee and Workgroup on Advances and Updates for the kind invitation to present today. IGCS is committed to providing meaningful educational opportunities through a unique year-round educational engagement program. This platform provides the level of strategic engagement and exposure that is needed to educate and inform gynecologic oncology professionals on current and future treatments to optimize patient care. While I will focus my presentation on the combination of lenvatinib and pembrolizumab, the recent approval of this combination in advanced recurrent endometrial cancer, I want to stress that these approaches to toxicity management really are applicable to other agents in the VEGF TKI and checkpoint inhibitor classes. I also want to preface today's presentation by adding that this is a relatively high-level overview on AE or adverse reaction management and that you should always consult the prescriber information or PI for both oral TKIs like lenvatinib and checkpoint inhibitors such as pembrolizumab when assessing toxicity and deciding on management because there are definite nuances to AE management that are beyond the scope of today's presentation. Before we get started, I just wanted to mention a few housekeeping items. Firstly, please know that the recording of today's webinar will be available on the IGCS education portal within a week. Next, we encourage you to submit questions via the Q&A feature at the bottom of your screen and we will do our level best to address as many of these questions as possible. With that, let's go ahead and get started. Here are my disclosures. Just by way of background, we know that the worldwide incidence of endometrial cancer and disease-associated mortality are sharply rising. Mortality rates are rising by almost 2% per year and in 2020, there were an estimated greater than 97,000 deaths worldwide attributed to endometrial cancer. Globally, racial disparities and socioeconomic as well as geographical differences are also very important determinants of endometrial cancer incidence and mortality. And while cancer survival has improved since the mid-1970s for the most common malignancies, endometrial cancer is a notable exception and I think this largely reflects a lack of major treatment advances in this disease. And in endometrial cancer, we are clearly losing vital ground. In the U.S., for example, the two-fold higher risk of death from ovarian cancer compared with endometrial cancer in the early 1990s has been virtually eliminated. Endometrial cancer mortality rates have caught up to ovarian cancer and will soon surpass ovarian cancer mortality rates if these alarming trends continue. As a malignancy, regardless of molecular subtype, platinum-taxane combination chemotherapy for advanced recurrent endometrial cancer is the current standard of care. However, this regimen is associated with finite efficacy and patients with recurrent endometrial cancer often become chemotherapy-resistant. Further challenging the equation is the fact that response to second-line cytotoxic agents is at best modest. As we know, lenbatinib at the MTD, a recommended phase two dose of 20 milligrams orally daily in combination with pembrolizumab, 200 milligrams IV every three weeks, received accelerated approval in 2019 for advanced microsatellite-stable or mismatch-repair-proficient endometrial cancer based on the results of the Phase 1b2 Keynote 146 study. This was followed up by the confirmatory Phase 3 trial known as Study 309 Keynote 775, which enrolled advanced endometrial cancer patients regardless of MMR status who had one but were allowed two prior lines of platinum therapy as long as one line was administered in the neoadjuvant or adjuvant setting. Eligible patients were randomized one-to-one to lenbatinib 20 milligrams orally once daily plus pembrolizumab 200 milligrams IV every three weeks versus treatment of physician's choice where the options were doxorubicin versus weekly paclitaxel. Primary endpoints were progression-free survival, unblinded review, and overall survival. And as we have seen, the median PFS and OS were improved in both the PMMR and all-comer populations. And the all-comer population, remember, also included the DMMR patients. And with a median follow-up of just over 11 months, the overall survival for the PMMR cohort was 17.4 versus 12 months in favor of Lenpembro with a hazard ratio of 0.68. And OS for all comers was 18.3 versus 11.4 months in favor of Lenpembro with a hazard ratio of 0.62. At ASCO 2022, PFS2 data were presented from study 309, keynote 775, and median PFS2 was notably longer in the lenbatinib plus pembrolizumab arm versus the TPC arm in the PMMR group and in the all-comer group as we can see here. And again, the P values were highly statistically significantly positive. And PFS2 favored lenbatinib plus pembrolizumab over TPC across key subgroups, including mismatch repair status and histology. And so lenbatinib plus pembrolizumab versus chemotherapy of physician's choice also demonstrated clinically meaningful improvements in progression-free survival on next line of therapy in patients with previously treated advanced endometrial cancer. The most common any grade treatment emergent adverse events for lenbatinib plus pembrolizumab were expected were consistent with class effect and included hypertension, hypothyroidism, diarrhea, nausea, and decreased appetite. The most common grade three or greater events on Lenpembro were hypertension in 38% of patients followed by weight decrease, decreased appetite, and diarrhea, each occurring in 10% of patients or less. Median times to onset of key adverse reactions is shown here for all patients. And as we can see, the most common key adverse events really occur within the first three months of therapy. Therefore, frequent proactive monitoring of patients during the first few cycles will allow for early detection and more prompt management of our patients. Adverse reactions with the shortest median time to onset included hypertension at 2.1 weeks, fatigue at 2.3 weeks, and musculoskeletal disorders at 3.1 weeks. Adverse reactions with a relatively longer time to onset included hypothyroidism at 8.7 weeks, hand foot syndrome at approximately 10 weeks, and weight decrease at 11 weeks. In the safety analysis population of Keynote 775, the median duration of treatment was 231 days with Lenvatinib plus Pembrolizumab and 105 days with chemotherapy. Among patients receiving Lenvatinib plus Pembrolizumab, the median dose intensity of the Lenvatinib was 13.8 milligrams per day, and the median number of cycles for Pembrolizumab was 10. Among patients receiving chemotherapy, the median number of cycles was five for doxorubicin and six for paclitaxel. The median time to first dose reduction for Lenvatinib was 1.9 months, and approximately 46% of patients in the Lenvatinib Pembrolizumab group had two or more dose reductions of the Lenvatinib. Median percent change in some of target lesion diameters, as assessed by independent review, is shown here, and as we can see, despite Lenvatinib dose reductions, median tumor size decreased over time. So, based on data from differentiated thyroid cancer and renal cell carcinoma, it appears that initiating Lenvatinib at the recommended starting dose is important, starting at lower doses may be inferior and not necessarily associated with less toxicity. Hence, I think the goal here should be to prepare patients for therapy, and then to medically maximally support them before dose reduction, and really to every extent possible throughout their therapy, and to always prioritize patient safety. And as you know, based on study 309, Keynote 775, in 2021, Lenvatinib plus Pembrolizumab was FDA approved as a combination therapy for advanced endometrial cancer that is not MSI high or mismatch repair deficient, following progression on prior therapy in any setting. And the European Commission approved the combination for advanced recurrent endometrial cancer, regardless of MMR, MSI status, when patients experience progression following prior platinum therapy in any setting. With this, let's shift and discuss AE management approaches. So, I want to just stress again that the scope of this presentation does not allow for detailed treatment of each adverse reaction, and that all clinicians really should refer to their prescriber information for both Lenvatinib and Pembrolizumab regularly as patients are treated on this combination. Additionally, while our approach to adverse reaction management is consistent with the prescribing information for both agents, for hypertension, we do advise much tighter control of blood pressure prior to initiation of therapy, and certainly during therapy than is noted in the Lenvatinib PI. It's important to remember that this regimen is highly efficacious and beneficial to a broad cohort of endometrial cancer patients, and that the adverse reactions of Lenvatinib and Pembrolizumab are consistent with other agents in these classes and are predictable and manageable. Remember also that adverse reactions may occur early in the course of therapy, hence frequent patient assessments, judicious use of supportive care measures, and engagement with a multidisciplinary team are highly effective strategies for the management of ARs, and I'll sort of touch on this repeatedly through the remainder of my presentation. But, you know, it really does take a team to manage our patients with endometrial cancer regardless of what therapy they're on. They often have other medical comorbidities, metabolic syndrome, etc., and so I think a comprehensive multidisciplinary approach to patient care is advisable for all patients with endometrial cancer. And while the learning curve can be steep with this regimen, this regimen is here, and we all need to learn how to safely manage our patients on this therapy. And so, pre-treatment, what is the clinician's role? So, I think the main things are you want to educate yourself regarding the most common adverse reactions. You want to educate your patients and really encourage them to be proactive and prompt in reporting symptoms early, when they're low-grade, before something becomes a high-grade toxicity. Train our physician assistants, nurse practitioners, and nurses since they're frontline health providers and really need to understand mechanism of action of these drugs, common adverse events, and how to manage our patients when they're on these therapies. Very importantly, review the concomitant medications that our patients are on regularly, certainly at every visit, and check for drug-drug interactions. What is the patient role? So, patients need to ensure that they have a thorough understanding of the common adverse reactions and really what warrants a call to the clinic. They need to understand which agents are available for supportive care and which drug to use for which adverse reaction. And patients, again, need to adopt this attitude of proactivity. I need to call early. I need to call often. I need to be aggressive about using the supportive care measures that my clinician has advised. Regarding specific adverse reactions before treatment begins, so I think the clinicians, you know, should ensure for blood pressure that the BP is well-controlled and, you know, less than 140 over 90. And to be honest, I think ideally as close to the normotensive range as possible for at least a week before initiating therapy. For patients that are on antihypertensives, they should be stable on their regimen for a week or more before you initiate treatment. Ensure that baseline ejection fraction is normal on an ECHO or a MUGA scan. For nonhypertensive patients, consider prescribing an antihypertensive so that it's available should the patient need it. I recommend angiotensin receptor blockers such as Losartan or ACE inhibitors such as lisinopril or calcium channel blockers such as amylodipine. In general, I recommend avoiding pure beta blockers and of course diuretics if possible because they can lead to dehydration and or electrolyte imbalances. All patients should have and should know how to use a home blood pressure monitor to assess their blood pressures daily. Patients should be advised to call, in my opinion, if the blood pressure is greater than or equal to 140 over 90, even one time because generally if the blood pressure has started to rise or is showing some resistance to the therapy that they're on, likely they're going to need to escalate their blood pressure therapy soon. So it's just good to go ahead and do that when you first see signs that the blood pressure is rising. Proteinuria, so you want to obtain a baseline urinalysis to assess for baseline protein level and ideally within three days of treatment initiation. Diarrhea, so patients should maintain adequate hydration. They should be educated to call at first soft or loose bowel movement and again strongly consider prescribing a prophylactic antidiarrheal agent such as loperamide for example. Hypothyroidism, so obtain baseline thyroid function tests. If a patient has a history of thyroid dysfunction, you know this really should be optimally controlled and managed before treatment initiation. For nausea vomiting, ensure that these issues are well controlled on a stable anti-emetic regimen. Ensure that patients have no obstructive symptoms, that their weight and nutritional status are overall stable and all patients should be prescribed prophylactic anti-emetics in my opinion. For weight loss, ensure no signs of malnourishment or cachexia. Consider involvement of a nutritionist and if possible, spend some time at the initial visit talking about high calorie foods that the patient could utilize if they see weight loss. For stomatitis, mucositis and skin issues, consider baseline dental and or dermatology eval as needed. Ensure ongoing oral skin toxicity issues from prior chemo for example are stable and just on the dental piece, I will say that poor dentition is not that uncommon in our patients, so if there's any concern about dental issues, best to get those things evaluated before you initiate lenbatinib because then invariably, you know, the regimen has to be held for dental interventions and that I don't think is ideal. So if you can, you know, address these issues a priori, I think it's better. For pain, very important to ensure that our patients are on a stable regimen for pain control prior to therapy initiation. So remember that the recommended starting dose of lenbatinib is 20 milligrams orally once daily. This comes in two 10 milligram capsules. It can be taken with or without food at approximately the same time every day. Pembrolizumab is administered 200 milligrams IV flat dose every three weeks and one cycle is 21 days. Here, dose modifications to manage any potential AEs related to lenbatinib and our pembrolizumab are shown here. So lenbatinib again starts at 20 milligrams, that's two 10 milligram capsules. First dose reduction would be to 14 milligrams. So that's one 10 milligram capsule and one four milligram capsule. Remember that lenbatinib comes in 10 and four milligram capsule sizes and doses. Second dose reduction would be 10 milligrams of lenbatinib. So that's one 10 milligram capsule. Third dose reduction would be eight milligrams of lenbatinib. So that's four milligram capsules and they would take two of those. There is a fourth dose reduction of lenbatinib that is possible to four milligrams of lenbatinib daily. Approximately six percent of patients on keynote 775 did dose reduce to four milligrams of lenbatinib. And then pembrolizumab, just want to point out that there is no dose reduction of pembrolizumab. It is flat dose. Great. All right. So here we show the general approach to lenbatinib modification based on severity of adverse reactions. Please note that there are exceptions to the grade three, grade four severity advice. Some grade three adverse reactions require treatment discontinuation, whereas some grade four adverse reactions do not. So please refer to the lenbatinib prescriber information for specific adverse reactions just to ensure that you are managing these patients optimally. This is just a general guide for the most common adverse reactions that are related to lenbatinib. For asymptomatic laboratory abnormalities such as grade three or greater elevations in amylase and lipase that are not considered clinically relevant by the clinician, treatment should continue without interruption. Excluding grade four laboratory abnormalities judged to be non-life threatening, in which case you manage them as grade three. For grade four adverse reactions that are deemed associated with lenbatinib, generally we discontinue lenbatinib therapy. And importantly, for overlapping toxicities, so GI toxicity, skin, endocrine, liver, et cetera, remember that the lenbatinib half-life is approximately 28 hours. So an AR that is lenbatinib associated will improve quickly. And if it does not improve within a few days of holding lenbatinib, then you should be thinking that this might be immune mediated and hence pembrolizumab related. So just to go over this table in general for lenbatinib, adverse reactions that are grade one or tolerable grade two, we continue treatment with no change. Adverse reactions that are intolerable grade two or grade three, at first occurrence, you interrupt treatment until it improves to grade zero one or tolerable grade two, and then dose reduce the lenbatinib to 14 milligrams daily. Second occurrence, same thing. You interrupt therapy until grade zero one or tolerable grade two and dose reduced to 10 milligrams. Third occurrence to eight milligrams, fourth occurrence to four milligrams. I will say that this might be the same adverse reaction, or it could be a different adverse reaction, but this is the algorithm that is generally followed. And again, for grade four adverse reactions in general, we discontinue lenbatinib therapy. So for pembrolizumab, for an AR that is grade one, we continue therapy. For AR that is intolerable or persistent grade two, we hold pembrolizumab therapy. And at this time for many adverse reactions deemed pembrolizumab related, you would initiate steroids. For grade three adverse reactions, we hold or discontinue the treatment based on the specific adverse reaction. And for adverse reactions that are recurrent grade three or grade four, the general guidance is to permanently discontinue therapy. Adverse reactions that require discontinuation of pembrolizumab include, but are not limited to Guillain-Barre syndrome, encephalitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and grade three reactions to include pneumonitis, AST, ALT, bilirubin increase, nephritis, renal failure, and myocarditis. And again, please always consult the Pembro PI for detailed guidance regarding specific AEs. Remember that dose modifications, including interruptions of lenbatinib plus pembrolizumab and dose reductions for lenbatinib are important management strategies for adverse reactions. Optimal medical management should be utilized first, followed by lenbatinib and or pembrolizumab dose interruptions or lenbatinib dose reductions according to the respective prescriber information. For the most common sort of key adverse reactions, the recommendation from the lenbatinib PI is to withhold lenbatinib treatment for persistent or intolerable grade two or grade three adverse reactions. Then patients may resume lenbatinib therapy upon improvement of the adverse reaction to a tolerable grade two or a reaction that is grade one or less in severity. Hypothyroidism is a common adverse reaction with this regimen, and it may be treated with thyroid replacement therapy and may not require discontinuation, interruption, or reduction. Grade four laboratory abnormalities can be managed as grade two or grade three ARs per the lenbatinib prescriber information. So again, for specific abnormalities, please refer to the PI. Now, although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system, cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. The wide range of potential immune-related adverse events requires, in my opinion, a multidisciplinary collaborative management plan by providers across the clinical spectrum. So regarding immune-mediated adverse reactions, it's important to remember that severe life-threatening immune-mediated ARs you treat with IV corticosteroids followed by oral steroids, and generally, the recommended initial dose is one to two milligrams per kilogram of prednisone or the equivalent. Corticosteroid taper should only begin once the immune-mediated AR is less than or equal to grade one and should continue. You should continue to taper over at least four weeks. Other immunosuppressive therapy, if initiated for immune-mediated ARs that are not improved with corticosteroids, really ideally should be done in consultation with a subspecialist. Discontinue pembrolizumab permanently if immune-mediated adverse reaction does not resolve or corticosteroid taper is not less than or equal to 10 milligrams per day of prednisone or the equivalent within 12 weeks of the last dose of pembrolizumab. Once held, pembrolizumab may be resumed once the immune-mediated AR has decreased to less than or equal to grade one on corticosteroid taper. So again, just general principles on how we manage immune-mediated ARs. I will now discuss our management approach for select lenbatinib and pembrolizumab adverse reactions. In general, if you're not sure what the offending agent is, is it the lenbatinib, is it the pembrolizumab, I generally recommend to start withholding the lenbatinib if you're not sure. Obviously, closely follow the patient, see them back, you know, in a day or two. And if it is lenbatinib related, generally things will improve quickly. If it does not improve within a few days, consider that pembrolizumab is the responsible agent. So for hypertension, what do we tell the patient? So again, we want patients to check their blood pressure daily, in my opinion, for the first six to nine weeks. This can then be done less frequently. Of course, if the patient's blood pressures are stable, patients should be advised to keep a log of their blood pressure readings and should bring that log to every appointment so that the clinician can review what their values have been. We recommend that patients contact the physician if the blood pressure reading is above 140, is 140 over 90 or above. Again, even one time is our general approach. And again, really the goal here should be to medically maximally optimize blood pressure control before lenbatinib is dose reduced. On the clinician side, you want to ensure that blood pressure is well controlled on stable antihypertensives and ideally less than 140 over 90 for one week prior to beginning therapy. Monitor blood pressure in clinic weekly, ideally for the first six to nine weeks of therapy. Provide patients with a blood pressure cuff prescription and ensure that the patient knows how to use it. Start antihypertensive medications if the blood pressure increases to 140 over 90 or above. Again, even once is my, you know, recommendation. Additional antihypertensive medications should be expeditiously added as required. And again, generally we recommend starting with an ARB or an ACE inhibitor or a calcium channel blocker and then try to maximize one drug. And then once you've done that, then you add a second drug. Hold lenbatinib for grade three hypertension that persists despite optimization of hypertension regimen. Resume lenbatinib at a one level dose reduction with hypertension when it's better grade two or less. And consider early renal referral for recalcitrant hypertension. And again, for grade four hypertension, you would permanently discontinue lenbatinib. For proteinuria, you want to monitor UA ideally weekly for the first three or four weeks and then every two or three weeks after that. And again, it should be one plus or negative for protein. If protein is greater than or equal to two plus, we interrupt therapy and obtain a 24 hour urine protein collection. General guidance is that if there is two grams of protein or greater in that 24 hour collection, you hold lenbatinib until it's a grade zero or one, and then can resume at a reduced dose. Once the results are back to one plus or negative, you again resume lenbatinib at that level one dose reduction. And again, consider referral to nephrology for patients that have persistent severe proteinuria because occasionally renal biopsies are required to really understand what the etiology is. And so general points, consider more frequent assessments. If a patient has proteinuria that is two plus or greater until the results are one plus or negative. And generally we tend to monitor more frequently for the subsequent two cycles or so. Consider ARBs or ACE inhibitors for patients who have hypertension and proteinuria. And remember that for nephrotic syndrome, arterial thromboembolic events, you discontinue for any grade. Remember that in nephrotic syndrome, the protein excretion is greater than 3.5 grams for 24 hours. And patients have hypoalbuminemia and peripheral edema. If a patient has renal failure and it's grade three or four, we hold lenbatinib. Once it's improved to grade zero or one or at the patient's baseline, you can initiate at a reduced dose or discontinue the lenbatinib depending on the severity or persistence of the renal failure. For diarrhea, patients should monitor number of stools, volume frequency, should monitor for blood, mucus, excessive flatulence, tinnitus. There should be generally patients benefit from having a stool diary so that they can identify potential triggers. Attention to timing of diarrhea is helpful. Patients should have an antidiarrheal at home for use as needed. Diets that bind the patient may help control diarrhea. Patients should immediately notify the physician at first. Loose bowel movement should consume liberal quantities of clear liquids. And if they're not able to do so, should notify the clinician because they may need IV fluids and or electrolyte replacement and assessment. Clinicians should obtain baseline bowel movement information, ensure that patients know to call at first sign of diarrhea. Patients should initiate antidiarrheal at first onset of loose bowel movements, monitor and manage electrolytes and fluid status in dehydrated patients, consider early admission and GI evaluation for suspicion of colitis. Subjects with grade two or greater diarrhea, especially suspecting colitis, you should obtain a GI consult and they would perform appropriate endoscopy to rule out colitis. Importantly, for grade two or three immune mediated colitis, hold PEMBRO and initiate steroids. For recurrent grade three or four immune mediated colitis, PEMBRO should be permanently discontinued. General point, diarrhea is an overlapping toxicity. So remember that lumbatinib-induced diarrhea will improve quickly when you hold lumbatinib. If symptoms of diarrhea persist despite medical management and lumbatinib is still suspected to be the cause, then follow the guideline on the table. I think it was slide 20. Again, monitor for signs and symptoms of enterocolitis, diarrhea, abdominal pain, blood or mucus in the stool with or without fever, and also be mindful about possible peritoneal signs, ileus, et cetera. For grade three or four fistula or GI perforation, we DC treatment. For arthralgia and myalgia, so again, balance of rest activity, light exercise, yoga, analgesics are helpful. Acupuncture is helpful in some patients. And our job really as clinicians is to monitor their analgesic regimen, consider referral to our pain palliative care, rehab medicine specialists, and really maximize supportive care. Stomatitis, so diligent mouth care, very helpful. Salt water, baking soda rinses two or three times a day. Avoid hot, spicy, acidic foods. Stay well hydrated. Keep your lips moist. Patients should avoid mint flavored or whitening toothpaste or alcohol containing mouthwash. They should brush teeth after every meal, ideally with a softer pediatric toothbrush and fluoride toothpaste. And as clinicians, there are a number of oral rinses that we can prescribe. Some of those are listed here. Ensure that concomitant problems, such as herpes, thrush dental issues are also not present. And consider referral to our subspecialists as needed. And again, maximize supportive care. Anorexia, weight loss, nausea. So patients should consume small, frequent meals, high calorie diet, again, full fat milks, yogurt, cheeses, as long as you don't have diarrhea. The various butters that are available, avocados, et cetera, nutritional supplements. They should keep a food log. What are they eating? How much are they eating? When are they eating? Certain teas can be helpful for nausea. So ginger tea, chamomile tea, peppermint tea. And again, consider referral to nutritionists for our patients. On the clinician side, you know, document the weight at baseline and follow it each visit. Ensure that nausea is well controlled and prescribe antiemetics. Generally, metoclopramide, ondansetron, are the most commonly used medications. Appetite stimulants can be prescribed if needed. For example, magase, and you can use it for a sign of anorexia. And again, referral to the nutritionist is very helpful. For hand foot syndrome, educate patients about skin care on their hands, feet, and skin. And to look for any changes such as peeling or blisters. Frequently moisturize skin on hands and feet specially. Avoid hot showers, baths, saunas, hot tubs. Don't soak your skin in hot water for too long. Pedicures are generally an issue, so be careful. Comfortable shoe wear, footwear is important. And obviously, to notify the MD at first sign of skin irritation, scaling, pain, or ulceration. And the clinicians really need to examine the skin carefully, including the hands and feet. Take off the socks, take off the shoes, really examine the skin, get between the fingers and toes, and look at it carefully. Various ointments are helpful and can be used prophylactically. Very, very helpful. For grade one or tolerable skin toxicity, topical clobetazole and silvadene can be helpful. For intolerable grade two, grade three, or greater toxicity, really best to have dermatology evaluate the patient. AST, ALT, bilirubin, elevation, electrolyte abnormalities. So for the patient, avoid hepatotoxic medications, avoid alcohol, inform the clinician immediately if there are any new medications that you're taking. Inform regarding any new skin rash or scleral icterus. Avoid herbals, high-dose vitamins, and any alternative therapies. The clinician should check these values prior to each cycle of therapy. And really, every two weeks, I think, in the first six to nine weeks, more frequently, of course, is needed, and then can be done every cycle. Consider checking hepatitis serologies and referral to GI or renal for persistent grade two or greater toxicity. Begin with holding lenvatinib, and if no improvement, then likely immune-mediated. For grade two immune-mediated issues with these various parameters, we would generally hold Pembro and initiate steroids. Remember that for grade three, grade four, AST, ALT, or bilirubin rise, we DC Pembrolizumab, and consider early admission for patients with such abnormalities so they can have appropriate imaging steroids, biopsy, consultation with subspecialists, etc. Additional point is that this is an overlapping toxicity that certainly can arise. So again, begin by holding lenvatinib if you're not sure which agent it is, and if there's no improvement, very, very quickly, then it's likely immune-mediated. And I think that's really important to remember. And the other point that I wanted to make was that routine assessments of amylase or lipase, we don't do them unless it's clinically warranted. Hypothyroidism. So review common signs and symptoms of hyper and hypothyroidism, fatigue, weight change, insomnia, etc. Clinicians should monitor TFTs before beginning treatment, and every three to six weeks thereafter. Again, follow the prescriber information regarding this, and initiate thyroid replacement therapy for grade two or greater hypothyroidism, and monitor closely for any symptoms related to a thyroid disorder, and refer to endocrinology as needed. Just a slide on overlapping toxicities. Again, things that can helpful and points to keep in mind are time of onset of the adverse reaction, what point in the cycle did it come on, associated symptoms. Some of these I've touched on. Imaging, subspecialty consultation, direct inspection, and if needed, biopsy can be informative. And I think that generally, you know, it's wise to begin with holding Linvatinib, recheck labs, and see the patient back very quickly in a couple of days, and if not improved, then consider immune-mediated toxicity. Here we show concomitant medications that patients received to treat adverse reactions of interest on study 309, Keynote 775, and the point I want to make here is that these are the usual suspects of drugs that we commonly use and all have familiarity and experience with. So I hope this table will be helpful to you, but, you know, there are really a lot of great supportive care therapies for the common adverse reactions, and we should use them liberally. So here's just a slide on lessons that we've learned across the way. Again, early, thorough patient education regarding common toxicities, very important. Think about developing basic patient education materials to disseminate to your patients. Proactively train your team, very important. Develop a consistent management strategy and discuss the management openly with your patients. Ensure that blood pressure, weight, nausea, etc. are well controlled prior to initiating therapy. Prescribe medications for the common toxicities and have your patients adopt a culture of calling early and often, and this whole idea of shared responsibility really is important for the patients to be actively engaged in their care. Review concomitant medications regularly. Judicious dose holds and reductions are helpful, and I really think weekly visits during those first two to three cycles are very helpful. Be aware of overlapping toxicities. Consider early consultant involvement, and remember that attention to patient care should not wane over time. And in conclusion, in general, adverse reactions reported with lenbatinib plus pembrolizumab therapy were as expected and often occurred within those first three months of treatment initiation. Patients continue to benefit from lenbatinib plus pembrolizumab treatment despite lenbatinib dose reductions, and therefore, clinicians should not avoid dose reductions when they are warranted. Clinicians should attempt to maintain patients on this regimen with dose interruptions reductions as necessary to manage adverse reactions, and it's important to remember that we play a critical role in prompt adverse reaction identification and management in our patients. Such management may potentially reduce treatment interruptions and or lenbatinib dose reduction and certainly will improve patient quality of life. I want to mention that there are additional resources that are available. There is a support pack that is coming through AZI very soon that I think will be very helpful to you in managing the common adverse reactions that you're likely to anticipate, and the second point here is a link to a publication that directly discusses common adverse reactions with lenbatinib and pembrolizumab that I think will be informative and potentially helpful for you. And so that's all the time we have for today. I would like to thank the leadership of the IGCS Education Committee Workgroup on Advances and Updates and ECI for sponsoring this seminar. The recording of today's session will be available on the IGCS Education Portal by the end of the week. Upcoming IGCS sessions may be found on the IGCS website. And finally, as you all may know, the IGCS annual global meeting will be September 29 through October 1 in New York City. Come visit me and all our colleagues who get to call NYC home. IGCS welcomes all members and friends to New York City. We're really looking forward to seeing you all. Visit igcs2022.com for more information, and we wish you all continued health and safety. Please stay well, and thank you so much for your kind attention.

toxicities

endometrial cancer

lenvatinib

pembrolizumab

toxicity management

Phase 3 clinical trials

adverse events