Melanie Cole, MS (Host): Welcome to Better Edge , a Northwestern Medicine podcast for physicians. I'm your host, Melanie Cole. And joining me today is Dr. Emma Barber. She's an assistant professor of Gynecologic Oncology in the Department of Obstetrics and Gynecology at Northwestern Medicine. She's here to share key insights from the phase 3 KEYNOTE-775 study: “Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer,” shedding light on how this study has revolutionized the identification of patient populations benefiting from second-line immunotherapy in endometrial cancers.

Melanie Cole, MS: Dr. Barber, it's a pleasure to have you join us today. Can you please start by explaining the goals and design of the study 309 KEYNOTE-775, and how lenvatinib and pembrolizumab were compared to the treatment of choice for advanced endometrial cancers?

Dr Emma Barber: Thank you so much for having me. I'm really excited to talk about this study. We've seen huge advancements in endometrial cancer over the last five years, and this study really represents one of those key discoveries. So, as everyone knows, primary treatment for endometrial cancer traditionally has been chemotherapy, a platinum and taxane-based combination. And our second-line therapies were pretty substandard, response rates around 20% to a variety of different chemotherapies or anti-angiogenic that could be used in the second-line setting. We had seen the effects of pembrolizumab in patients that were mismatch-repair deficient and showing really high response rates as a single agent. But unfortunately, for the majority of endometrial cancer patients that are mismatch-repair proficient, around 70% to 80%,  we didn't really see that efficacy with the single agent pembrolizumab, sort of response rates in the 10% to 15 % range.

And so, what this study did was try to look at the combination of lenvatinib with pembrolizumab. So, lenvatinib, an oral tyrosine kinase inhibitor, working along the VEGF pathway, combined with pembrolizumab to try to improve the efficacy and improve on those single agent response rates of pembrolizumab. So, this study was a phase 3 randomized study, enrolled over 800 patients and, again, the majority of them with mismatch repair proficient disease, around 700 with mismatch repair proficient disease. And it randomized them to lenvatinib with pembrolizumab compared to second-line chemotherapy, which was our standard at that time.

Melanie Cole, MS: This is so interesting and such advancements in medicine. What were the key findings regarding progression-free survival and overall survival in the study?

Dr Emma Barber: Yeah. So, really exciting that even in this cohort that was mismatch repair proficient dominant, we saw dramatic benefits in both progression-free as well as overall survival. So, hazard ratios on the order of 0.5, 0.6 for these outcomes. So, dramatic benefit delaying the risk of progression and improving survival for these patients.

Melanie Cole, MS: Well then, how did lenvatinib and pembrolizumab perform compared to the treatment of physician choice?

Dr Emma Barber: In this study, it showed improvement in both progression-free and overall survival. Again, around a doubling of the PFS benefit as well as OS benefit, and not really driven by the mismatch repair deficient patients, really seeing that benefit even for those that are mismatch repair proficient.

Melanie Cole, MS: Well then, how did they demonstrate benefits? And tell us about across the different patient subgroups, such as you mentioned a little bit earlier, mismatch repair status, histology, prior lines of therapy. Tell us a little bit about those benefits.

Dr Emma Barber: So, this study really showed that those benefits were sustained across these subpopulations. So, even patients that were mismatch repair proficient, again had a hazard ratio that maybe was a little bit higher than the overall study, overall study around just a little bit over 0.6 and hazard ratio just in mismatch repair proficient around maybe 0.65, 0.7. But really, that benefit persisted across all of these subgroups, which is really exciting as it being a universal option that we can give to all patients in the second-line.

Melanie Cole, MS: Were there notable differences, Dr. Barber, in the objective response rates between the two treatment arms?

Dr Emma Barber: This study was powered on progression-free survival and overall survival versus just response rate. But again, dramatic benefits seen for these patients, so improved response, improved duration of response in the patients that received that combination compared to physician's choice chemotherapy.

Melanie Cole, MS: Were there any safety concerns or adverse events observed?

Dr Emma Barber: So, this is an issue with this combination and one that I know we all run into in practice when prescribing this, and I can share a little bit about some of the national response to this study incorporating it into real world practice.

So, the overall rate of adverse events that were grade 3 or higher was higher in the patients that received the lenvatinib and pembrolizumab compared to those that received physician's choice chemotherapy. This is largely driven by the lenvatinib, as we all see in real world experience, really the hypertension issues with repeated diarrhea, fatigue, loss of appetite, we can see this with lenvatinib. And I think important to note that, in this study, they started everybody at 20 milligrams orally a day, and a lot of patients required dose reductions. And so, there is sort of active debate right now in the field about whether people just go right with that 20 milligram starting dose, knowing that they're going to have to dose-reduce a substantial portion of patients or whether people start a lower dose. A common thing you see done nationally is around 14 milligrams, instead of starting at the 20. I think both are very reasonable options. My own personal practice is I tend to start folks at 14 just because, once patients and providers and nursing staff, et cetera, experience some of these really high rates of toxicity, I can see some reticence to prescribe the drug or to continue to take the drug. And I think this is a drug that really benefits patients. A lot of patients receive dose reduction in this study, and still have the great outcomes that we see in this study.

So, I think it's something to consider, an individualized starting dose. Is this going to be a patient that's going to tolerate 20 milligrams? Should I be thinking about 14? And I think that's individualized, center to center. But I think if the toxicity from this combination is preventing you from providing it to patients, this is a recommendation I would really strongly consider about trying a lower starting dose, because ultimately this combination can't help patients if they're not taking it or we're not giving it to them. And I think the adverse events are a component of that.

Melanie Cole, MS: You make such great points with your expertise in this area, Dr. Barber. And based on the results of this study, what are the potential implications for treating advanced endometrial cancers? How are these results being incorporated? As you've just spoken to providers about reluctance or reticence to prescribe this, what do you see happening as far as incorporating these into clinical practice?

Dr Emma Barber: In the G1 oncology community, I think we are consistently giving this second-line. We have gotten very good at giving this combination. We've been really lucky in GYN cancers over the last five years that we've gotten a lot of new therapies. And so, I think we've been good at incorporating them. And I think hopefully a lot of that reticence is fading. But I just mentioned that to folks, if that's something that really worries you about the published toxicity rates, that's a potential way to help ameliorate that.

In terms of how does this set into the landscape, I think this is a huge area of debate right now with the presentation and publication in the New England Journal of GY018,  which was phase 3 study of carboplatin plus paclitaxel plus pembrolizumab compared to carboplatin plus paclitaxel plus placebo in the upfront setting, so patients with newly diagnosed measurable disease stage III or IV endometrial cancer.

And in this study, we saw a dramatic benefit for patients that were mismatch repair deficient, not as much with patients that are mismatch repair proficient. There is now FDA indication that we can give pembrolizumab plus carboplatin and paclitaxel in the upfront setting for those who that are DMMR. And there's a question about patients that are PMMR, should we be giving them pembrolizumab in the upfront setting given that the hazard ratios from that study were not as compelling?

And I think we have to put those findings into context of the combination of lenvatinib and pembrolizumab. If we think that the benefit upfront for patients that are PMMR, mismatch repair proficient, is modest in GY018 and we are now introducing that pembrolizumab earlier for maybe a modest benefit, we're taking away the ability to give that combination with lenvatinib in the second-line. I think for patients that are mismatch repair deficient, it makes a lot of sense to use pembrolizumab upfront. But I think ongoing debate and sort of more data needed about whether or not that combination with chemotherapy in the upfront setting makes sense for patients that are mismatch repair proficient, specifically because of the compelling results of the combination of lenvatinib plus pembrolizumab compared to pembrolizumab alone in patients that are mismatch repair proficient.

Melanie Cole, MS: Well, it certainly is compelling. As we wrap up, Dr. Barber, what would you like the key takeaways from this podcast to be for other providers, what would you like them to know about what's going on in the world of treatment of advanced endometrial cancers?

Dr Emma Barber: I think what we've learned is that endometrial cancer is a malignancy that responds well to immunotherapy. Definitely for patients that are mismatched repair deficient, which is 20% to 30% of patients, they respond very well to pembrolizumab either as a single agent or given in combination with chemotherapy. However, it's not just limited to patients that are mismatch repair deficient. I think what KEYNOTE-775 tells us is that even patients that are mismatch repair proficient can benefit from immunotherapy from checkpoint, inhibitors from pembrolizumab with the combination of a TKI, with the combination of lenvatinib. And so, I think that's something that all endometrial cancer patients should receive at some point if they have metastatic disease, stage III or IV patients. And I think that the toxicity is a real issue, but the toxicities are very manageable and should be something that you can consider a different starting dose or dose reductions to allow patients to stay on therapy, but this is a therapy that benefits many patients with endometrial cancer.

Melanie Cole, MS: Thank you so much, Dr. Barber, for joining us today and sharing the results of this very important study with us. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org to get con connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podc ast for physicians. I'm Melanie Cole. Thanks so much for joining us today.