Exploring Immunotherapy Combinations in Endometrial Cancer - Episode 3
Vicky Makker, MD, reviews the safety profile of lenvatinib-pembrolizumab in advanced endometrial cancer from the phase 3 KEYNOTE-775/Study 309 trial and the management of common adverse events.
Vicky Makker, MD: In terms of the safety profile, managing common adverse events [AEs], as well as a brief comment or two about dose reductions, I would share the following. Firstly, the median duration on treatment was more than double for lenvatinib-pembrolizumab at 231 days vs 105 days for TPC [treatment of physician’s choice]. This could account for the difference in the rate of treatment-emergent adverse events [TEAEs] that were seen between the 2 treatment arms. As expected, the safety profiles for lenvatinib-pembrolizumab vs TPC are different. Overall, the safety profile of lenvatinib-pembrolizumab was generally consistent with those of the individual agents. The most common any-grade TEAEs for lenvatinib-pembrolizumab were hypertension; hypothyroidism, which was predominantly grade 1 or grade 2; diarrhea; nausea; and decreased appetite. The most common with TPC were anemia, nausea, neutropenia, and alopecia. Lenvatinib-pembrolizumab had more grade 3 to 5 TEAEs compared to TPC. Grade 3 or greater events occurred in 89% of patients on lenvatinib-pembrolizumab. The most common was hypertension in 38% of patients, followed by weight decrease, decreased appetite, and diarrhea. Each occurred in 10% of patients or less. Grade 3 or greater events occurred in 73% of patients on TPC, and the most common were cytopenias. Regardless of causality, grade 5 events occurred in 5.7% of patients on lenvatinib-pembrolizumab vs 4.9% of patients on TPC.
Lenvatinib dose reduction occurred in 67% of patients vs 13% of patients on TPC. Study drug interruption occurred in 69% of patients on lenvatinib-pembrolizumab vs 27% of patients on TPC. Lenvatinib was interrupted in 59% of patients, while pembrolizumab was interrupted in 50% of patients. Both were interrupted in 31% of patients. Study drug discontinuation occurred in 33% of patients on lenvatinib-pembrolizumab vs 8% of patients on TPC. Lenvatinib was discontinued in 31% of patients, pembrolizumab in 19% of patients, and both were discontinued in 14% of patients.
I have a few points regarding the lenvatinib starting dose. Available data at this time support initiating lenvatinib at a starting dose of 20 mg orally once daily and then dose reducing as medically necessary following maximization of supportive care. The AEs with this agent are consistent with what we see with other VEGF TKIs [tyrosine kinase inhibitors]. Dose interruptions and reductions as needed following maximization of supportive care are par for the course. Data available in endometrial cancers and other cancers, such as thyroid cancer, suggest that optimal therapy may be achieved by starting at the higher, or in this case, recommended 20-mg dose, and reducing as medically necessary following maximization of supportive care. This is my general approach as I take care of patients as well. I try to initiate at the 20-mg dose of lenvatinib, maximize supportive care, enlist the help of subspecialist colleagues, and dose reduce as necessary based on symptomatology.
A key point I’ve learned along the way is that clinical team and patient education, comprehensive patient assessments, maximization of supportive care measures, and timely subspecialist involvement can significantly improve the patient experience, tolerance, and quality of life. Additionally, I can share some lessons I’ve learned along the way. Certainly, our team has learned as we’ve taken care of many patients on this combination. Those would include early and thorough education for not only the patient, but family members as well regarding the most common adverse events that can occur with this regimen. That is key. Developing patient education materials, keeping them simple but ensuring that they cover the most common adverse events, is also important. Having those available to disseminate to patients is very helpful.
Develop a management plan proactively with patients regarding the most common adverse events. This should include their knowledge so that they know what the common adverse events are, but also what supportive care measures will be taken. “Here is what we will use to manage high blood pressure, here is what we will use to manage diarrhea should it occur, here is the antinausea regimen that we would recommend,” and so on. It should be written down so it’s clear to the patients and they know what to take and when to take it. Ensuring that blood pressure, weight, nausea, etc, are well controlled prior to initiating therapy is very important. This concept of prehabilitation for the patient and ensuring that their status is optimized to every extent possible before you initiate this therapy can be profoundly helpful. Adopting a culture of calling early and often, along with the idea of shared responsibility, is very helpful. Have patients call early in the course of developing an adverse event before it becomes very severe.
Be clear about our responsibility and what we need to do as clinicians, while also expressing the things patients need to be aware of. “You need to check your blood pressure every day. You need to call if it’s above a certain parameter. You need to take your medications regularly.” Being proactive is very helpful. Proactively training the team is really important. This includes our PAs [physician assistants], nurse practitioners, research nurses, and RNs [registered nurses] regarding the most common adverse events and what the management strategy is going to be. It’s important to understand when dose holds are appropriate, when dose reductions are appropriate, and when they’re not as helpful. It’s very important for us to consider weekly visits for patients, especially during those first 2 to 3 cycles, so that you can be certain they have a good start and are managing their toxicities well. It’s important to have early consultant involvement, involve your subspecialists, and remember that attention to patient care cannot wane over time.
Transcript Edited for Clarity