Adverse Events Associated With Immunotherapy in the Treatment of Endometrial Cancer

Christian Marth, MD, PhD, reviews the adverse effects of pembrolizumab and lenvatinib in the treatment of endometrial cancer, as well as the patient experience with these treatments.


Bradley J. Monk, MD, FACS, FACOG: Let’s end by talking about adverse events. I think you would agree with the following statement, that the immune-related adverse events in endometrial cancer are similar to other tumor types. Would that be fair?

Christian Marth, MD, PhD: Yes.

Bradley J. Monk, MD, FACS, FACOG: However, we have pembrolizumab and lenvatinib, which is now approved. And lenvatinib starts at different doses depending on the tumor type. We use 20 mg of lenvatinib with pembrolizumab. What’s your experience with the adverse event profile with this [pembrolizumab]/lenvatinib combination,] which now you’re using in the second-line pMMR [mismatch repair–proficient] subset?

Christian Marth, MD, PhD: It’s a very efficient combination, which showed us that we could again also prolong survival in endometrial carcinoma. Second line, [I’ve] never seen before. That’s also really game-changing. But there is remarkable toxicity for sure. Nevertheless, it’s important to start with the full dose, because if we reduce the 20 mg and go back and try to lower the dose to avoid toxicity, I think that’s dangerous. We should apply what has been shown in the trial, start with the full dose, get a response, and reduce the dose according to guidelines. We saw initially a very high percentage of dose reductions, 67%. We saw from the KEYNOTE-775 study [NCT03517449] a lot of interruptions, almost 60%. This is changing because we are aware of the adverse effects, and our experience now is much better.…

Bradley J. Monk, MD, FACS, FACOG: [We’ve learned] So much…

Christian Marth, MD, PhD: We have learned to use this combination. We know that there’s hypertension that we have to carefully monitor. All our patients get the blood pressure measurement instrument at home. They have a prescription for an antihypertensive drug. And if Saturday into Sunday, the blood pressure’s going up, then they immediately start treatment and they’re going back to the physician’s later, not waiting until they have a hypertensive crisis. I think that is really important. Diarrhea is also an important adverse effect that almost 8% of patients had grades 3 and 4 as described in KEYNOTE-775 [results]. Diarrhea is important to understand because we have 2 different possibilities. We can have lenvatinib-induced diarrhea, TKI [tyrosine kinase inhibitor] diarrhea, and on the other side, we can have, which is a rare event but still important, colitis induced by pembrolizumab. Both result in diarrhea, and it is important to distinguish them because the treatment is completely different. For colitis, you have to stop [pembrolizumab] or you have to give corticosteroids. There is actually a very good ASCO [the American Society of Clinical Oncology] guideline on how to follow those patients with all the grading. On the other side, if you have TKI-induced diarrhea, then you can use simple measurements. Patients can change their diet and use the BRAT diet. It’s banana, rice, apples, and toast. You should give a lot of fluids and loperamide very early.

Bradley J. Monk, MD, FACS, FACOG: And interrupt and dose-reduce too.

Christian Marth, MD, PhD: And dose-reducing. I think with this, we saw recently much better tolerance of treatment.

Bradley J. Monk, MD, FACS, FACOG: 100%.

Christian Marth, MD, PhD: It is so important that we can continue then with this treatment. This is really a game-changing result.

Bradley J. Monk, MD, FACS, FACOG: …Again, [this is the] same between Europe and the US. At my local institution, we break it down into 4 categories. We say, look, pembrolizumab is part of pembrolizumab/lenvatinib, and there are immune-related adverse events and you know how to manage them, which is what I’d say to my advanced practice provider. And then we say that lenvatinib is an anti-VEGF and you know how to manage that, proteinuria, hypertension, and so on. And then they’re chronic. And when it’s chronic, fatigue can happen. And then it’s oral, so you can have GI [gastrointestinal issues]. So the immune-related adverse events, the VEGF, the chronic fatigue, and ultimately GIs…. Also, if the blood pressure is too high, the first thing you do is stop the medication. So we give those guidelines. We have patient handouts and that sort of thing, so that’s an exciting regimen. I’m excited to see LEAP-001 [phase 3 trial results; NCT03884101] vs chemotherapy in the pMMR subset frontline. That hopefully will be available soon.

Christian Marth, MD, PhD: May I add something about the toxicity? Because that’s very important.

Bradley J. Monk, MD, FACS, FACOG: Yes, of course.

Christian Marth, MD, PhD: The hypertension is coming very, very early.

Bradley J. Monk, MD, FACS, FACOG: Very, and fast.

Christian Marth, MD, PhD: And fast. We learned with bevacizumab it’s something that is slowly increasing and increasing. This is different in lenva [lenvatinib]. It’s coming very fast and very early. And then you have a delayed effect. The patients might also lose weight, and that’s becoming very…

Bradley J. Monk, MD, FACS, FACOG: Chronic.

Christian Marth, MD, PhD: …Chronic. And this is very important that you follow your patients and not send them out and see them in 3 months. You have to follow them and react to the weight loss, also the fatigue, you have to take action on those adverse effects so that the treatment is better tolerated.

Bradley J. Monk, MD, FACS, FACOG: Finally, I said we were going to talk about adverse events. But really that is the patient experience. And the patient experience is not perfect through patient-reported outcomes. At ASCO 2023 [Annual Meeting], there was a report of the patient-reported outcomes from the RUBY trial [phase 3 NCT03981796]. Briefly summarize what that has shown for the tolerability of RUBY long-term.

Christian Marth, MD, PhD: RUBY, long-term was an improvement of the quality of life and many, many factors that have been analyzed. In the long term there was no difference, so certainly no detrimental effect. In the beginning, it was really statistically significantly better than the chemo [chemotherapy], I think.

Bradley J. Monk, MD, FACS, FACOG: So thinking about that, we’re helping patients maintain tumor control longer. Early preliminary overall survival benefit, and they’re living better.

Christian Marth, MD, PhD: I never saw this, that if you [add] another drug, the quality of life is becoming better.

Bradley J. Monk, MD, FACS, FACOG: Yes, generally. Why don’t you give us your final words, and then we’ll close it out? Go ahead. What are your final words to our audience about endometrial cancer, advanced and metastatic?

Christian Marth, MD, PhD: It’s really a bright future, and I dream of really personalized medicine where we do exact molecular characterization and define what is the best treatment. And there are tumor types out there, NSMP [no specific molecular profile], where we need more work to understand what the factors driving this disease are and how can we interfere with this.

Bradley J. Monk, MD, FACS, FACOG: I want to thank you as a leader. You’ve been an impactful leader in the European Network of Gyneacological Oncological Trial groups [ENGOT], and I want to thank you. We have a great collaboration between ENGOT and GOG [Gynecologic Oncology Group], so thank you. You’re also a good enroller. If you look at some of the top enrollers, in almost every trial we see Christian Marth. Look at that…. I want to thank our audience for joining us today. This has been very informative. Thank you for viewing this. We hope you found thisprogram both useful and informative, and also fair and balanced to inform your clinical treatment of endometrial cancer. Thank you, and so long for now.

Transcript edited for clarity.

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