Matthew A. Powell, MD, reviews key takeaways from the Study-309/KEYNOTE-775 trial investigating lenvatinib plus pembrolizumab for the treatment for endometrial cancer.
Matthew A. Powell, MD: So [let’s focus] more on lenvatinib and pembrolizumab for patients with recurrent endometrial cancer in the second- and third-line space: [findings from] the KEYNOTE-775 trial initially presented by Vicky Makker, [MD,] and subsequently published in the Journal of Clinical Oncology in 2023. Key takeaways in this trial [were] a doubling of the progression-free survival, doubling of the overall survival at 3 years, and the response rate also doubling. And [that’s] unprecedented when we look at what our options are in the second and third line for patients with advanced endometrial cancer. Again, this is for the proficient mismatch repair population. It’s where this is currently approved. It certainly has activity in the deficient mismatch repair population, but it doesn’t seem to improve over the activity of just single-agent checkpoint.
It’s important to point out [that the article in] The Oncologist by Dr Makker [et al], [“Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Carcinoma Treated With Lenvatinib Plus Pembrolizumab”], [looked] at managing the adverse effects of this combination. When we look at anticipating hypertension, managing diarrhea, managing suspected colitis, these are important considerations in how you manage 2 drugs at the same time that can have overlapping toxicities. In the real world, these combination strategies are showing great activity. Dosing with dose holds and dose delays is very important [for] keeping patients on therapy, keeping their ability to tolerate these medications long term as these patients are having these long-term benefits. Making it a livable combination is important. The quality of life is quite impressive. You look across all strata, and you see improvements in their health-related quality of life for the patients on lenvatinib/pembrolizumab vs chemotherapy. And that’s surprising to a lot of people. But once we get these patients on the right dose for the right patient, they do quite well. And it’s borne out in their quality-of-life assessments.
What are some of the considerations I think about when using lenvatinib and pembrolizumab? Again, this combination can work quite fast. So it is nice for the patients who may have ascites. I’m going to think about starting with that FDA-approved, or study dose, 20 mg daily of lenvatinib and 200 mg IV [intravenous] of pembrolizumab. There may be patients, though, who have ongoing illness or [for whom] I don’t have their blood pressure [level] controlled yet. I may be starting at slightly lower doses, but in general, starting at the FDA-approved dose is recommended. There are some studies out there starting at 14 [mg] and escalating back up to 20 or 18 [mg]. These could be strategies that people have done. It seems to maintain efficacy, but there are no head-to-head trials comparing that. So [we should be] starting with the study doses [and] doing appropriate dose reductions based on adverse effects but also preparing the patient up front so [we get] that hypertension under control, talking to them about diarrhea strategies and managing that, [and] talking about their fatigue. Dose holds and dose delays are important to manage fatigue, and it may be that they need a few days off periodically to help maintain them. However, most patients do end up on an appropriate dose for them, 10 to 14 mg, what a lot of patients end up on over time. Once their disease starts to get under control, that’s when I feel a little more comfortable with those lower doses and balancing some of these adverse effects with that.
Diarrhea is a special concern. We’re always concerned, could this be immune-related colitis vs TKI [tyrosine kinase inhibitor]-induced diarrhea? Typically, what we’ll do is hold the TKI, hold their lenvatinib, see whether it resolves quickly. If it does not, then we have to think more about immune-related colitis and think about further investigations and the use of steroids to counteract that colitis. I point you to Dr Makker’s The Oncologist publication. That [has] very good details about how to get patients ready for this regimen and how to manage patients on this regimen.
Transcript is AI generated for clarity and readability.