Pembrolizumab/Lenvatinib Extends Survival in Advanced/Recurrent Endometrial Cancer Subgroups

Christian Marth, MD, PhD

Although first-line treatment with the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) did not meet the prespecified statistical criteria for progression-free survival (PFS) and overall survival (OS) vs physician’s choice of chemotherapy in patients with mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer, other subgroups of patients experienced a survival benefit when treated with the combination, according to Christian Marth, MD, PhD.

Findings from the phase 3 ENGOT-en9/LEAP-001 study (NCT03884101) presented during the 2024 SGO Annual Meeting on Women's Cancer showed that in patients with mismatch repair–deficient (dMMR) disease, pembrolizumab plus lenvatinib elicited improvements in PFS (HR, 0.61; 95% CI, 0.40-0.92) and OS (HR, 0.57; 95% CI, 0.36-0.91) compared with chemotherapy.

Additionally, patients who received prior neoadjuvant or adjuvant chemotherapy experienced PFS and OS improvements with pembrolizumab/lenvatinib vs chemotherapy. These benefits were observed in the pMMR population (PFS HR, 0.60; 95% CI, 0.37-0.97; OS HR, 0.67; 95% CI, 0.41-1.11).

“The great impact is for those patients who underwent the prior chemotherapy, even if it was only neoadjuvant or adjuvant,” Marth said in an interview with OncLive^®. "This is a group of patients who experienced a major benefit with pembrolizumab/lenvatinib.”

In the interview, Marth expanded on the findings from LEAP-001 presented at the 2024 SGO Annual Meeting on Women’s Cancer and provided additional rationale for exploring pembrolizumab plus lenvatinib in this patient population. Marth is a professor and head of the Department of Obstetrics and Gynecology at Innsbruck Medical University in Austria.

OncLive: What was the rationale for exploring the combination of pembrolizumab and lenvatinib as a first-line treatment for patients with advanced or recurrent endometrial cancer?

Marth: In the phase 3 KEYNOTE-775 trial (NCT03517449), patients with advanced/recurrent endometrial cancer treated with lenvatinib plus pembrolizumab had better outcomes compared with physician’s choice of chemotherapy in the second-line setting. Therefore, the aim was now to move [pembrolizumab plus lenvatinib] forward into the first-line setting, and we designed this phase 3, randomized trial to treat patients with advanced or recurrent endometrial cancer in the primary setting compared with the standard of care carboplatin plus paclitaxel.

Based on their respective mechanisms of action, what is the synergistic effect when combining pembrolizumab and lenvatinib?

We know there is anti-angiogenesis, and lenvatinib is able to affect the cancer to make it more susceptible to immunotherapy. Many factors, like regulatory T cells and key immune cells, are regulated by angiogenesis, and blocking angiogenesis with a TKI like lenvatinib increases the potential activity of checkpoint inhibition. This has been shown in several types of tumors, [including] in the second line of endometrial cancer.

Are there any other details to know about the patient population enrolled in LEAP-001?

We enrolled 842 patients with endometrial cancer who were either in advanced or recurrent setting. They had to be naive for any [systemic] treatment [in the advanced setting]; neoadjuvant or adjuvant chemotherapy [was permitted]. This was a special environment because the majority of other trials thus far applied [pembrolizumab plus lenvatinib] in the second-line setting.

What were some of the principal efficacy findings observed in this trial?

Unfortunately, the trial didn't meet the primary end points of PFS and OS in the pMMR population. However, in the dMMR [population], a prolongation of PFS and OS was achieved [in the pembrolizumab/lenvatinib arm], and [the dMMR population accounted for] approximately 25% of the population [in each arm].

On the other hand, we observed that patients [in the dMMR and overall populations] who underwent the prior neoadjuvant or adjuvant chemotherapy [experienced] a greater [PFS and OS] benefit [in the pembrolizumab/lenvatinib arm], maybe because this prior chemotherapy might induce chemotherapy resistance. Thus, checkpoint inhibition plus angiogenesis inhibition with pembrolizumab and lenvatinib [could have] great potential for those patients.

Considering the established safety profiles of lenvatinib and pembrolizumab, were there any new safety concerns identified when they were combined in this trial?

We didn't find any new signals. The median duration of treatment was 10 months in the pembrolizumab/lenvatinib arm, whereas it was only 4 months in the chemotherapy arm. Therefore, this means that the probability to detect any adverse effects [for the combination] is greater, and [the safety profile] was as we expected. We saw [higher rates of] hypertension, hypothyroidism, and diarrhea in the group with pembrolizumab and lenvatinib. On the other hand, chemotherapy induced more hematotoxicity, neuropathy, and alopecia.

Reference

Marth C, Moore RG, Bidzinski M, et al. Lenvatinib Plus pembrolizumab versus chemotherapy as first-line therapy for advanced or recurrent endometrial cancer: primary results of the phase 3 ENGOT-En9/LEAP-001 study. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting for Women’s Cancer; March 16-18, 2024; San Diego, CA.