Lenvatinib/Pembrolizumab Misses OS End Points, But Still Shows Activity, in Advanced Endometrial Cancer

Key Takeaways

  • Lenvatinib/pembrolizumab showed numerical increases in overall survival and progression-free survival, especially in patients with prior chemotherapy.
  • The combination therapy demonstrated notable antitumor activity across different histologic subtypes of endometrial cancer.
Sandro Pignata, MD, PhD

Sandro Pignata, MD, PhD

Although the first-line administration of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) did not demonstrate statistically superior survival outcomes compared with chemotherapy in patients with mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer, numerical increases in overall survival (OS) and progression-free survival (PFS), as well as notable antitumor activity across histologic subtypes, were observed among patients with prior neoadjuvant/adjuvant chemotherapy, according to data from an exploratory analysis of the phase 3 ENGOT-en9/LEAP-001 study (NCT03884101).1

Findings from the randomized, open-label trial were presented at the 2024 ESMO Gynecological Cancers Congress, where an analysis of PFS and OS according to histology showed trends in favor of the lenvatinib/pembrolizumab combination vs chemotherapy in patients with endometroid histology vs non-endometroid histology. In the all-comers and pMMR populations who presented with endometroid histology, hazard ratios (HRs) for PFS were 0.78 (95% CI, 0.62-0.97) and 0.96 (95% CI, 0.75-1.24), respectively; corresponding HRs for OS were 0.80 (95% CI, 0.63-1.01) and 0.93 (95% CI, 0.71-1.22). Conversely, all-comers with non–endometroid histology had a PFS HR of 1.12 (95% CI 0.83-1.50) and OS HR of 1.14 (95% CI, 0.84-1.54). In those with pMMR disease and non–endometroid histology, the PFS HR was 1.06 (95% CI, 0.77-1.44) and the OS HR was 1.16 (95% CI, 0.85-1.58).

A numeric trend toward PFS and OS benefit was also observed among patients with prior exposure to neoadjuvant or adjuvant chemotherapy. In the all-comer population, the HR for PFS was 0.52 (95% CI, 0.33-0.82) and the HR for OS was 0.64 (95% CI, 0.40-1.03). In the pMMR population, HRs were 0.60 (95% CI, 0.37-0.97) and 0.67 (95% CI, 0.41-1.11) for PFS and OS, respectively.

The objective response rate (ORR) was 55.7% (95% CI, 50.8%-60.5%) with lenvatinib/pembrolizumab and 55.5% (95% CI, 50.6%-60.35) with chemotherapy in the all-comer population. Among the pMMR population, ORRs were 50.6% (95% CI, 45.0%-56.2%) and 54.7% (95% CI, 49.0%-60.2%), respectively. The median duration of response (DOR) was 23.2 months (range, 1.0+ to 49.0+) with the doublet and 10.9 months (range, 1.1+ to 46.9+) with chemotherapy in all comers; corresponding DORs were 16.1 months (range, 1.0+ to 48.7+) and 10.6 months (range, 1.1+ to 43.8+) in the pMMR population.

“Based on all these data, we can conclude that lenvatinib/pembrolizumab can be considered an option for patients who have received previous therapy, reinforcing the data from the [phase 3] KEYNOTE-775 study [NCT03517449],” presenting author Sandro Pignata, MD, PhD, the IRCCS National Cancer Institute “Fondazione G. Pascale” in Naples, Italy, stated in an oral presentation.

In July 2021, treatment with lenvatinib plus pembrolizumab was granted regular approval by the FDA for patients with advanced endometrial cancer that is not microsatellite instability-high or mismatch repair deficient (dMMR), have disease progression following prior systemic therapy in any setting, and are not candidates for curative surgery or radiation. This approval was based on data from KEYNOTE-775, in which the regimen demonstrated a significant OS and PFS benefit vs investigator's choice of doxorubicin or paclitaxel.2 Subsequent analyses of this trial showed that treatment benefit was observed regardless of disease histology.1

LEAP-001 accordingly compared the efficacy and safety of this chemotherapy-free doublet with paclitaxel and carboplatin in the first-line treatment of patients with stage III, IV or recurrent advanced endometrial cancer. Patients were required to have measurable or nonmeasurable radiographically apparent disease, no previous exposure to chemotherapy outside of the neoadjuvant or adjuvant setting, an ECOG performance status of 0 or 1, and available tumor tissue for mismatch repair testing. Patients were stratified according to whether they had pMMR or dMMR disease. Those with pMMR endometrial cancer were further stratified by their ECOG performance status, whether they had measurable disease, and if they received prior chemotherapy and/or chemoradiation.

A total of 842 patients were enrolled onto the study and randomly assigned 1:1 to receive 20 mg of oral lenvatinib once daily plus 200 mg of intravenous (IV) pembrolizumab every 3 weeks (n = 420) for up to 35 cycles vs 175 mg/m2 of IV paclitaxel plus carboplatin at an area under the curve of 6 every 3 weeks (n = 422) for up to 7 cycles.

The trial’s dual primary end points were PFS per RECIST criteria by blinded independent central review (BICR) and OS. Secondary end points included ORR, safety, and health-related quality of life (HRQOL). DOR was an exploratory end point. In the current exploratory analysis, PFS per RECIST criteria by BICR and OS were analyzed by tumor histology.

A total of 842 patients were enrolled onto the study, 420 of whom received lenvatinib/pembrolizumab and 422 who received chemotherapy. In these respective arms, 320 and 322 patients had pMMR disease; 100 patients with dMMR endometrial cancer were included in each arm.

Within the all-comer population, the median age in the combination arm was 63 years (range 22-93) vs 64 years (range, 32-88) in the chemotherapy arm. In these respective arms, 17.6% vs 16.1% of patients received prior chemotherapy and/or chemoradiotherapy; the majority of patients in both arms had an ECOG PS of 0 (59.5% with doublet; 56.9% with chemotherapy); and had measurable disease (99.5%; 98.6%).

The most common histology was non–high-grade endometroid cancer (combination arm, 33.6%; chemotherapy arm, 37.0%) followed by high-grade endometrioid cancer (33.1%; 30.1%). Patients also had serous carcinoma (18.3%; 19.0%), mixed histology (6.9%; 5.5%), clear cell carcinoma (2.9%; 4.5%), and other histologies (5.2%; 4.0%).

In the all-comer population, the median PFS was 12.5 months (95% CI, 10.3-15.1) with the combination vs 10.2 months (95% CI, 8.4-10.4) with chemotherapy (HR, 0.91; 95% CI, 0.76-1.09). The median OS was 37.7 months (95% CI, 32.2-43.6) vs 32.1 months (95% CI, 27.2-35.7) in each respective arm (HR, 0.93; 95% CI, 0.77-1.12).

For the pMMR population, the median PFS was 9.6 months (95% CI, 8.2-11.9) vs 10.2 months (95% CI, 8.4-10.5) in these respective arms (HR, 0.99; 95% CI, 0.82-1.21). The median OS was 30.9 months (95% CI, 25.4-37.7) in the lenvatinib/pembrolizumab arm vs 29.4 months (95% CI, 26.2-35.4) in the chemotherapy arm (HR, 1.02; 95% CI, 0.83-1.26; noninferiority P = .246).

Further breakdown of efficacy by histology in the pMMR population showed a numerical trend towards superior PFS with the combination over chemotherapy in patients with high-grade endometrioid carcinoma (HR, 0.84; 95% CI, 0.59-1.21), clear cell carcinoma (HR, 0.70; 95% CI, 0.25-1.96), and mixed histology (HR 0.86; 95% CI 0.36-2.07). This was not evident in patients with non–high-grade endometroid carcinoma (HR, 1.05; 95% CI, 0.74-1.51) or serous carcinoma (HR, 1.18; 95% CI, 0.81-1.74).

A similar trend was observed in the all-comer population, with a numerical trend in favor of the doublet for patients with high-grade endometrioid carcinoma (HR, 0.72; 95% CI, 0.52-0.98), non–high-grade endometroid carcinoma (HR, 0.82; 95% CI 0.60-1.12), clear cell carcinoma (HR, 0.60; 95% CI, 0.21-1.70), and mixed histology (HR 0.83; 95% CI 0.41-1.70). The HR for those with serous carcinoma was 1.29 (95% CI, 0.88-1.89).

In the assessment of OS by histology in the pMMR population, patients with high-grade endometroid cancer (HR, 0.72; 95% CI, 0.49-1.06) and mixed histology (HR, 0.55; 95% CI, 0.23-1.33) appeared to experience benefit with lenvatinib and pembrolizumab vs chemotherapy; HRs did not favor the doublet numerically in those with non–high-grade endometroid carcinoma (HR, 1.16; 95% CI, 0.76-1.73), clear cell carcinoma (HR, 1.87; 95% CI, 0.67-5.17), and serous carcinoma (HR, 1.15; 95% CI, 0.79-1.67).

Among all comers, HRs slightly favored the combination in high-grade endometroid carcinoma (HR, 0.64; 95% CI, 0.46-0.89), non–high-grade endometroid carcinoma (HR, 0.97; 95 % CI 0.69-1.37), and mixed histology (HR, 0.59; 95% CI, 0.26-1.32) numerically. HRs were 1.81 (95% CI, 0.58-4.46) and 1.18 (95% CI, 0.81-1.71) in patients with clear cell and serous carcinoma, respectively.

Assessment of response rates by histology showed that lenvatinib plus pembrolizumab was active and produced responses across all histologies in both the pMMR and all-comer populations. Signs of higher activity with the doublet were seen in the high-grade endometroid and clear cell carcinoma populations.

In the pMMR population, 51.0% (95% CI, 40.7%-61.3%) and 45.5% (95% CI, 16.7%-76.6%) of patients with high-grade endometrioid carcinoma and clear cell carcinoma, respectively, achieved an ORR with the doublet. Conversely, 56.7% (95% CI, 45.8%-67.1%) and 31.6% (95% CI, 12.6%- 56.6%) achieved an ORR with chemotherapy. The median DOR was 16.4 months (range, 2.1+ to 46.3+) and not reached (NR; 6.1+- 30.2+) with the combination in those with high-grade endometroid and clear cell carcinoma, respectively. The median DOR with chemotherapy was 10.9 months (range, 2.1+ to 38.3+) and 11.1 months (range, 4.2+ to 30.6+) for patients with these respective histologies. Similar results were observed in the all-comer populations.

Notable limitations for the ad-hoc exploratory analysis include a small sample size for certain histologic subtypes. Additionally, the study was not designed or powered to demonstrate improvement in survival within these subgroups.

Disclosures: Dr Pignata discloses financial and personal interests, as well as service on an advisory board for Roche, AstraZeneca, MSD, Clovis, GSK, and PharmaMar; he also discloses financial interests and receiving institutional funding from Roche, MSD, Pfizer, and AstraZeneca.


  1. Pignata S, Marth C, Moore RG, et al. Phase III ENGOT-En9/LEAP-001 study: Lenvatinib + pembrolizumab (LEN/PEMBRO) vs chemotherapy (chemo) as first-line (1L) therapy for advanced or recurrent endometrial cancer. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract 39MO.
  2. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed June 21, 2024.
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