a GYN Medical Oncologist at Memorial Sloan Kettering Cancer Center and also the Section Head for Endometrial Cancers. I'm so pleased to be here today and thank the leadership of the IGCS Education Committee and Workgroup on Advances and Updates for the very 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 needed to educate and inform the gynecologic oncology community on current and future treatments to optimize patient care. Before we get started, I wanted to mention a few housekeeping items. Please know that a recording of this webinar will be available on the IGCS education portal within a week. Additionally, 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. Now, on to my talk entitled Study 309, Keynote 775, A Randomized Phase III Study to Compare the Efficacy and Safety of Linvatinib and Pembrolizumab versus Treatment of Physician's Choice in Advanced Endometrial Cancer. Next slide, please. Here are my disclosures. Next slide. So as we know, there remains a high unmet need for effective therapies to treat advanced recurrent endometrial cancer, and no globally accepted standard second-line treatment has really been identified following prior platinum-based chemotherapy. Checkpoint inhibitors have previously shown benefit in MSI-high and mismatch repair deficient tumors to include endometrial cancers. Linvatinib is a multikinase inhibitor of VEGF receptors 1 through 3, FGFR receptors 1 through 4, PDGFR alpha, and oncogenes KIT and RET, which are implicated in tumor angiogenesis as well as cancer progression. Now, Linvatinib and anti-PD-1 monoclonal antibody combinations have displayed significant and superior antitumor effects compared to either compound alone in multiple syngeneic models. And in Keynote 146 or Study 111, which was a Phase 1b2 basket study, Linvatinib and anti-PD-1 monoclonal antibody Pembrolizumab showed compelling efficacy and manageable safety profiles in previously treated advanced recurrent endometrial carcinoma. And this Phase 3 confirmatory study compared the efficacy and safety of LEN plus Pembro versus treatment of physician's choice or TPC with the options of doxorubicin or paclitaxel following platinum-based therapy in advanced recurrent endometrial cancer. Next slide. With regards to study design, key eligibility criteria included advanced metastatic or recurrent endometrial cancer with measurable disease via resist 1.1 per blinded independent central review. In this study, patients had to have one but were allowed two prior lines of platinum-based therapy if one was administered in the neoadjuvant or adjuvant setting, and there was no restriction on prior hormone therapy. Patients were stratified by MMR status and then were further stratified within the MMR-proficient cohort by region, ECOG status, and prior history of pelvic radiation. Eligible patients were randomized one-to-one to LEN-Vatnib 20 milligrams orally once daily plus Pembrolizumab 200 milligrams IV every three weeks versus TPC of doxorubicin 60 milligrams per meter squared IV every three weeks or paclitaxel 80 milligrams per meter squared weekly, three weeks on, one week off. Pembrolizumab on study could be administered for a maximum of 35 doses, and LEN-Vatnib could continue beyond that point if a patient was clinically benefiting, and the maximum cumulative dose of doxorubicin allowed was 500 milligrams per meter squared. Primary endpoints were progression-free survival by blinded review and overall survival, and secondary endpoints included objective response rate and quality life analysis. Next, please. Next slide. Thank you. 827 patients were randomized between the two treatment arms. The arms were balanced with regards to age, prior radiation therapy, ECOG status, as well as race distribution. 84% of patients in both arms were MMR-proficient. The full histologic spectrum was balanced between treatment arms. Endometrioid adenocarcinomas were the most common histology, representing approximately 60% of cases in both arms, and the distribution of low-grade and high-grade endometrioid carcinomas were comparable between the arms. Serious histology was the most common non-endometrioid subtype, followed by clear cell and mixed histologic subtypes, and their proportions were relatively balanced between the arms. 79% in the LEN-Pembro and 76% of patients in the TPC arm had one prior platinum-based therapy, and 55% in the LEN-Pembro versus 60% of patients in the TPC arm received neoadjuvant and or adjuvant platinum-based chemotherapy. Next slide, please. In both the P-MMR and all-comers cohorts, the objective response rate was doubled with LEN-Pembro compared to TPC. In the P-MMR cohort, the objective response rate was 30% versus 15%, and in all-comers cohort, which included the D-MMR patients, the objective response rate was 32% versus 15% in favor of LEN- Pembro. Complete response partial response rates were also approximately double for LEN-Pembro versus TPC. The median duration of response in the P-MMR cohort was 9.2 versus 5.7 months for LEN- Pembro versus TPC, and in all-comers, the median duration of response was 14.4 versus 5.7 months in favor of LEN-Pembro. Next slide, please. The median PFS for the P-MMR cohort was 6.6 versus 3.8 months for LEN-Pembro versus TPC with a hazard ratio of 0.6. In all-comers, the median PFS was 7.2 versus 3.8 months for LEN-Pembro versus TPC with a hazard ratio of 0.56, and as we can see, these curves separate early in the course of therapy and at approximately the first radiologic assessment. Next, please. So despite informal crossover, when LEN-Pembro became approved in many countries based on Keynote 146 results in September 2019, with a median follow-up of 11.4 months, the overall survival for the P-MMR cohort was 17.4 versus 12 months for LEN-Pembro versus TPC, hazard ratio 0.68. OS for all-comers was 18.3 versus 11.4 months in favor of LEN-Pembro, hazard ratio of 0.62. The OS curves again separate early and at approximately the three-month mark. And though not shown here, PFS and OS analysis in all assessed subgroups, including MMR status, histology, and prior lines of therapy favored LEN-Pembro. Next, please. Now, in the D-MMR cohort, the objective response rate was 40 versus 12 percent for LEN-Pembro versus TPC. CR PR rates were approximately tripled for LEN-Pembro versus TPC, so complete response rate was 14 versus 3 percent, partial response rate 26 versus 9 percent. Twice as many patients experienced progressive disease on TPC versus LEN-Pembro. Median duration of response in the D-MMR cohort was not reached versus 4.1 months for LEN-Pembro versus TPC. Next slide. Within the D-MMR population, statistically significant improvements in PFS and OS were seen with LEN-Pembro compared to TPC. The median PFS for the D-MMR cohort was 10.7 versus 3.7 months for LEN-Pembro versus TPC. The hazard ratio was 0.36. Next, please. And with a median follow-up of 12 months, OS for the D-MMR cohort was not reached versus 8.6 months for LEN-Pembro versus TPC with a hazard ratio of 0.37. Next, please. And meaningful efficacy improvements in patients with previously treated advanced endometrial cancers were seen across all major histologies in both the P-MMR and all comer populations. Here we show PFS by histology in the P-MMR population. LEN-Pembro here is represented in the teal blue color. Median PFS was significantly higher in endometrioids, serous, and clear cell cancers with hazard ratios ranging from 0.49 to 0.59. Next slide. Here we have PFS by histology for all comers. Again, clear benefit is seen across all histologies for LEN-Pembro with hazard ratios ranging 0.47 to 0.53. Next slide, please. And overall survival is shown here by histology for the P-MMR patients. Again, the same trend is seen with hazard ratios in the 0.34 to 0.78 range and benefit to LEN-Pembro seen across histologies. Next, please. And OS by histology for all comers is shown here. And the benefit for LEN-Pembro, again, is seen for all histologies with hazard ratio from 0.33 to 0.68. Next slide, please. The median duration of treatment in all comers was more than double for LEN-Pembro at 231 days versus 105 days for TPC. This could have accounted for the differences in grade three or greater treatment emergent adverse events that were seen between the arms. But grade three or greater TEAEs occurred in 89% versus 73% of patients on LEN-Pembro versus TPC. LEN-Vatnib dose reduction occurred in 67% versus 13% of patients on TPC. The median time to first dose reduction of LEN-Vatnib was 1.9 months and the median dose intensity of LEN-Vatnib was 13.8 milligrams per day. Study drug interruption occurred in 69% of patients on LEN-Pembro versus 27% of patients on TPC. LEN-Vatnib was interrupted in 59%, Pembro in 50, and both were interrupted in 31% of patients. Study drug discontinuation occurred in 33% of patients on LEN-Pembro versus 8% of patients on TPC. LEN-Vatnib was discontinued in 31%, Pembro in 19%, and both were discontinued in 14% of patients. Next slide. The most common NE grade adverse events for LEN-Pembro were expected and included hypertension, hypothyroidism, diarrhea, nausea, and decreased appetite, whereas with TPC, anemia, nausea, and neutropenia were most common. The most common grade three or greater events on LEN-Pembro were hypertension in 38% followed by weight decrease, decreased appetite, and diarrhea, each occurring in 10% of patients or less, whereas with TPC, the cytopenias were most common. Next please. So here we show a summary of health-related quality of life data at baseline and from baseline to week 12. Instruments that were included included the EORTC QLQC30, QLQEN24, and the EQ5D5L visual analog scale, and quality of life scores were similar with no substantial differences observed from baseline to week 12 between the two treatment groups. Next slide please. Again, overall scores were generally maintained over time, and importantly, no significant differences were observed in quality of life scores between treatment groups. Next please. And so LEN-Pembro's map showed statistically significant and clinically meaningful improvements in objective response rate, progression-free survival, and overall survival versus treatment of physician's choice regardless of MMR status in endometrial cancer following platinum-based chemotherapy. Benefits of PFS and OS were observed across all analyzed subgroups, including histology, a number of prior therapies, and this was in both the PMMR and DMMR cohorts, and LEN-BATNA plus Pembro's map had a manageable safety profile that is generally consistent with the established safety profiles of the individual monotherapies. And this regimen now has full FDA approval for treatment of MMR-proficient microsatellite-stable endometrial cancer following one prior line of platinum therapy in any setting, and in Europe, this regimen is approved for both MMR-deficient and proficient endometrial cancers following one prior platinum therapy. Next please. So the median time to first onset of key adverse reactions on keynote 775 occurred within approximately three months of treatment initiation in both the all-comer and PMMR populations. And here we show the data for the all-comer population. Adverse reactions with the shortest median time to onset included hypertension at 2.1 weeks, fatigue at 2.3 weeks, and musculoskeletal disorders or arthralgias at 3.1 weeks. Nausea, stomatitis, decreased appetite and proteinuria arose in weeks four to five. And adverse reactions with a relatively longer time to onset included hypothyroidism at 8.7 weeks, hand-foot syndrome at 9.7 weeks, and then weight decrease at 10.7 weeks. So the bulk of the adverse reactions come on early in the course of therapy, and extra vigilance during this time is of paramount importance and goes a long way in improving patient tolerance and quality of life. Next, please. Shown here are data from Keynote 146, which again was the phase 1B2 study that informed Keynote 775 that shows Lenvatinib doses over time among responders, and also shows change in median tumor size over time. Importantly, responses occurred early, and in most instances at or before week eight, and this is shown by the open circles in the swimmer's plot. And continued reductions in tumor size over time were observed among responding patients despite Lenvatinib dose reductions, and this is shown in the different colors in the swimmer's plot. It is notable that 64% of responses were seen at the 20 milligram dose of Lenvatinib. Also, the steepest decline in tumor burden appeared to be earlier during the course of therapy. This suggests that clinicians should start treatment at the recommended dose of Lenvatinib, 20 milligrams orally once daily, plus pembrolizumab, 200 milligrams IV every three weeks, and reduce Lenvatinib dosage as necessary to prioritize safety and tolerability along with maximization of supportive care efforts. The data suggests that antitumor activity can continue to occur with reduced dosages of Lenvatinib. However, lower starting doses could lead to inferior efficacy and not necessarily less toxicity. And this is supported by a recent study of Lenvatinib in patients with differentiated thyroid cancer, and a second study of Everolimus and Lenvatinib in renal cell carcinoma. Both studies found that the objective response rate was not non-inferior in patients who started treatment at a lower starting dose compared to the recommended higher dose of Lenvatinib, suggesting that optimal Lenvatinib therapy may be achieved by starting at the recommended higher starting dose and reducing as medically necessary following maximization of supportive care. Next slide. Median percent change in sums of target lesion diameters as assessed by independent review are shown here from keynote 775. The blue line represents the MMR proficient population, magenta are the all comers, and continued reductions in tumor size over time were observed among patients despite Lenvatinib dose reductions occurring in 66% of patients. It is notable that most of the responses were seen at the 20 milligram Lenvatinib dose. Hence, patients can continue to benefit from Lenvatinib plus pembrolizumab treatment despite Lenpembro interruptions, Lenvatinib dose reductions, and Lenpembro discontinuation. Next please. So here I show our approach to patient preparation for this regimen. So firstly, we inform our patients regarding IO and TKI mechanism of action. So again, this can be basic. You don't have to get into terrible details here, but they really need to understand how these drugs work. We then talk about the common adverse events that can be expected. And we talk about how we as a team are going to approach those specific common adverse events. So these include, of course, hypertension. So firstly, we ensure that all of our patients have a blood pressure that is as close to the normotensive range as possible, but certainly less than 140 over 90. We ensure that for our hypertensive patients that we're not making any changes to their antihypertensive regimen at least a week before we start this regimen. So they really need to have stable blood pressure and you don't wanna be making changes to their medicines right before you start this regimen. For patients that do not have a history of hypertension, we do prescribe a prophylactic antihypertensive and we like to use the angiotensin receptor blockers, but calcium channel blockers and others are also acceptable just based on your institution practice. We ensure that our patients all have a blood pressure cuff or some sort of recording device at home. We ensure they know how to use those machines and that they're checking their blood pressure at home once daily in the morning. And again, that they are calling us when their blood pressure goes above 140 over 90, even one time. And once that happens, they are instructed to begin their prophylactic antihypertensive that again, they already have at home. For our patients that already have a history of high blood pressure, we then very quickly will up titrate their regimen. And if patients are maxed out on two antihypertensives, generally that's the time that will involve our nephrology colleagues. So again, very important to ensure that blood pressure is well controlled before beginning. When you begin for patients that are not hypertensive, that they have a prophylactic drug at home ready to go and that they're instructed to begin that therapy when the blood pressure goes up above 140 over 90 again. And our practice is if it goes up above that level, even once it's gonna continue to go up generally. So we will ask them to go ahead and begin the antihypertensive. But again, the key is they have to call us when that happens so that we know that we now need to initiate more frequent follow-up with that patient. Diarrhea, so again, we prescribe prophylactic anti-motility agent. We use loperamide and patients are instructed to use if necessary at the first onset of diarrhea. But the second thing they have to do is they have to call us again so we can understand the nature of the diarrhea, the frequency, the volume. Are there other associated symptoms that may point to a immune-mediated colitis versus a lenbatinib-induced toxicity or both? So very, very important that they begin the supportive care, but the second thing they need to do is notify the clinician that a toxicity has arisen. And the idea is to catch it early before things really become more severe and more difficult and challenging to manage. Nausea, loss of appetite. So again, we offer dietary recommendations. We refer to nutritionists early in the course of therapy. We prescribe adequate prophylactic anti-medics and instruct patients on how to take them so that they don't wait, but really start the therapy at the first onset of nausea. For skin toxicity, hand-foot syndrome, again, the first thing is please notify us the second the skin starts to get even dry before it gets cracked or has ulcers or other issues. We want to catch things early. We provide skincare recommendations, emollients, topical treatments, and lifestyle modifications and recommendations are also made. As far as mucositis is concerned, so prophylactic mouth care guidance, salt water, baking soda rinses, brushing teeth after every meal with a soft or pediatric toothbrush, using a fluoride toothpaste, and avoiding whitening toothpaste or treatments, and certainly no alcohol-based mouthwashes. For pain, also we ensure that they're really having good pain control before we begin this regimen. Next slide. And as far as laboratory assessments are concerned, so we check thyroid function tests, CBC, comprehensive metabolic panel, electrolytes, urinalysis, at least every cycle, and certainly at baseline. But we often will check these more frequently just depending on the patient and what's going on. So these are sort of the general lab parameters that I think really do need to be followed closely on this regimen. And again, with regards to the blood pressure, hypertension is a common toxicity. So we ensure that the blood pressure is stable before we begin the regimen. And again, ideally in the normotensive range, but certainly below 140 over 90. We ensure that our hypertensive patients are on stable antihypertensive therapy for at least a week, ideally greater than before you begin this treatment. And patients must have a reliable blood pressure monitor at home. And again, they need to check their blood pressure once daily in the morning and call if the blood pressure goes up above 140 over 90 at any point. Very, very helpful. Next. So here are just some lessons that we've learned along the way. First, again, is early thorough patient education regarding the common toxicities. So helpful. Patients know what's coming. They know what they're gonna do. It really prepares them. They feel so much more confident. Develop patient education materials in your practices, keep them simple, and have a space at the bottom or on the side where you can write out the supportive care regimen that you're prescribing for each of the common toxicities so that patients really are pretty clear on what they need to take and also what they need to call you for. And disseminate this to your patients. Proactively train your teams, your whole team. So this includes our PAs, NPs, our nurses, who of course are at the front lines and really provide so much of the management and supportive care necessary on this regimen. They need to know about the common toxicities and they need to know about how your practice will manage those adverse events and what are the strategies gonna be. And again, develop a consistent management strategy. So everyone's sort of thinking about these toxicities in a similar manner. I think that's really helpful. Discuss, again, the management plan thoroughly with your patients for the most common toxicities. Really so helpful. They're engaged, they're proactive, they know what's happening. It really does make a big difference. Again, ensure the blood pressure, weight, nausea, pain, any skin issues are well-controlled prior to initiating therapy. So this whole concept of trying to prehab your patients a little bit before you begin this regimen, again, very helpful in my opinion. Prescribe supportive care medications for common toxicities, as I mentioned. And then I think adopting a culture of call early and often. Patients need to know they're not bothering us. We really wanna hear about symptoms early so we can nip them in the bud and address a toxicity when it's mild before it becomes really serious. And also this concept of shared responsibility. So here's what we as your team are going to offer you. We're gonna offer you this novel therapy. We're gonna give you these supportive medicines, but we need you to call us if your blood pressure is above 140 over 90. We need you to check your blood pressure every day. We need you to be prompt in taking your supportive care medicines and then to call us so we know what the degree of side effects is at home so we can escalate care if needed. Review concomitant medications regularly. There are drug-drug interactions, so important to do so. And then judicious dose holds and reductions, of course, are helpful. I think our patients need to know that we're really gonna try to start at the recommended starting dose and we're gonna try to maintain dose density, but that at some point we're gonna need to hold the Lenvatinib and or dose reduce and that that's really par for the course with these VEGF-TKIs and that they need to expect that. Consider weekly visits for those first two or three cycles. Again, in our practices here, we find that that really is so helpful. So I do recommend that. Beware of overlapping toxicity. So certainly as it pertains to diarrhea, hypothyroidism and liver function abnormalities, consider early consultant involvement. I think, again, profoundly helpful. That's what our subspecialist colleagues are there for. We all need to help each other. So do consider involving your consultants early. And then the last point I'll make is that I think attention to patient care in this regimen really should not wane over time. There are immune-mediated toxicities that can come on later. So it is important to always be vigilant. Next slide, please. And I think it's important to remember that optimal patient care on this therapy really benefits from a multidisciplinary team approach that is coordinated and proactively working to ensure patient safety. Endometrial cancer patients are often medically complex. They have metabolic syndrome and other comorbidities that can make any therapy administration challenging. So I think a multidisciplinary approach for endometrial cancer patients really should be the norm and is important, certainly, on this regimen. Next slide, please. And that's all the time we have for today. I would like to, again, thank the leadership of the IGCS Education Committee and Workgroup on Advances and Updates for having me today. Reminder that the recording of today's session will be available on the IGCS Education Portal by the end of the week. Additionally, upcoming IGCS education events may be found on the IGCS website. Next, please. And finally, as you may know, the IGCS Annual Global Meeting will be held September 29 to October 1 in New York City. Come visit me and our colleagues who have the privilege of calling NYC home. IGCS welcomes all members and friends to NYC, and please visit igcs2020.com for more information. We wish you all continued health and safety. Stay well, and thank you very much for your kind attention today. So, I see there's one question here. It asks about symptoms and signs that point to immune-mediated colitis rather than lumbatinib. Sure. So, I think this is a very common issue and comes up a lot. I think things that can be very helpful, again, can include, you know, things like volume of stool, frequency of stool. Is there any bleeding? Are there any associated abdominal symptoms, cramping, pain, et cetera? Also, timing of the diarrhea can be helpful. Did it come on at the beginning of the cycle? Is it coming on in the middle of a cycle? Generally, lumbatinib-induced diarrhea tends to be lower in volume and responds very quickly to holding the lumbatinib. So, the first step, you know, generally is that we recommend holding the lumbatinib to see if there's improvement. You'll know pretty readily if there is. And then if not, then I think your, you know, focus on this being potentially immune-mediated will be higher. Sometimes it's really difficult, to be honest. And so, I think, you know, again, low bar for patients where you're really worried to consider an urgent care ER evaluation and subspecialty referral. But always a good idea to try to hold the lumbatinib first and see if there's improvement in the diarrhea. Yeah. Great point here about the mucositis. And I think, yes, a steroid mouthwash is extraordinarily helpful, aside from the recommendations that I had discussed. And we do also prescribe steroid mouth rinses for our patients. I'll tell you, dermatologists also have a number of sophisticated methods in which they can manage mucositis. So, if after a steroid mouth rinse, a patient still has persistent mucositis but is maintaining their weight and hydration, and you want to try to maintain the dose density of the lumbatinib, I would consider a referral to dermatology. They have been very helpful in multiple instances. I see a question here about, do we see a lot of patients who suffer from tumor enlargement in the initial two cycles and then shrink after cycle three or four? We have seen this. And so, you know, my general recommendation to you is that if you have a patient that is, you know, otherwise clinically benefiting and is not having significant side effects or symptoms related to the treatment or their disease, you know, you can carefully try to continue therapy until that next planned scan. We have seen patients, you know, with responses that do deepen over time. Just trying to make sure I address all these comments. Thank you so much for the questions and comments. I see a question here. If a patient has comorbidities, do you still start at the 20 milligram dose? You know, I think what I would tell you all is that we have to be really good clinicians at the end of the day. You know your patients very, very well, and obviously patient safety is the most important thing. I think that the goal should be whenever possible to try to prehab and optimize management of comorbidities that may be ongoing and try to initiate at the starting dose of lendatinib, but of course there are instances in which, you know, considering a lower starting dose may be more appropriate, and I think at the end of the day, you know, we just need to keep our patients in mind and do our best to try to manage their comorbidities. Okay, I think we're at the nine o'clock mark. I'm happy to take any final questions. All right, well, I thank you all very much for having me today. It really was a privilege. I'm available should you have any questions, please feel free to email me at any point or to reach out and I wish you all a wonderful day. Thank you so much.

Linvatinib

Pembrolizumab

endometrial cancer

objective response rate

progression-free survival

adverse events

multidisciplinary team approach