Lenvatinib Plus Pembrolizumab Displays Survival Benefit in Subgroups of Patients With Endometrial Cancer

Frontline treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) did not meet the prespecified statistical criteria for overall survival (OS) or progression-free survival (PFS) vs chemotherapy in patients with mismatch repair–proficient (pMMR) advanced or recurrent endometrial cancer, however the combination did prolong survival in key subgroups, according to data from the phase 3 ENGOT-en9/LEAP-001 study (NCT03884101) presented during the 2024 SGO Annual Meeting on Women's Cancer.

Across the prespecified analysis population, the median PFS was 9.6 months (95% CI, 8.2-11.9) with lenvatinib plus pembrolizumab vs 10.2 months (95% CI, 8.4-10.5) with chemotherapy among those with pMMR disease (HR, 0.99; 95% CI, 0.82-1.21), and the median OS was 30.9 months (95% CI, 25.4-37.7) vs 29.4 months (95% CI, 26.2-35.4) in each arm (HR, 1.02; 95% CI, 0.83-1.26). Among the all-comer population, the median PFS in each respective arm was 12.5 months (95% CI, 10.3-15.1) vs 10.2 months (95% CI, 8.4-10.4; HR, 0.91; 95% CI, 0.76-1.09), and the median OS was 37.7 months (95% CI, 32.2-43.6) vs 32.1 months (95% CI, 27.2-35.7; HR, 0.93; 95% CI, 0.77-1.12).

Among patients with pMMR disease who received prior neoadjuvant or adjuvant chemotherapy, the median PFS was 12.5 months (95% CI, 6.5-20.3) with lenvatinib plus pembrolizumab vs 8.3 months (95% CI, 6.1-10.2) with chemotherapy (HR, 0.60; 95% CI, 0.37-0.97). The PFS rate in each respective arm was 51.0% vs 25.4% at 12 months and 26.6% vs 8.5% at 24 months. The median PFS was 15.0 months (95% CI, 8.3-21.0) vs 8.3 months (95% CI, 6.2-10.2) in each respective arm across the all-comer population (HR, 0.52; 95% CI, 0.33-0.82). Additionally, the 12-month PFS rate in this population was 56.1% vs 25.1%, and the 24-month rate was 31.8% vs 8.6%.

Among those with pMMR disease and prior receipt of neoadjuvant or adjuvant chemotherapy, the median OS was 34.2 months (95% CI, 22.0-not reached [NR]) in the lenvatinib/pembrolizumab arm vs 21.1 months (95% CI, 15.1-28.1) in the chemotherapy arm (HR, 0.67; 95% CI, 0.41-1.11). The OS rate in each arm was 81.1% vs 80.4% at 12 months and 62.3% vs 45.1% at 24 months. Among all-comers who received prior neoadjuvant or adjuvant chemotherapy, the median OS was 34.2 months (95% CI, 26.6-NR) vs 22.1 months (95% CI, 16.4-35.7) with lenvatinib/pembrolizumab vs chemotherapy, respectively (HR, 0.64; 95% CI, 0.40-1.03). The 12-month and 24-month OS rates in each arm were 84.1% vs 82.8% and 66.7% vs 46.6%, respectively.

In the pMMR population previously treated with adjuvant or neoadjuvant chemotherapy, the objective response rate (ORR) was 60.4% (95% CI, 46.0%-73.5%) with lenvatinib plus pembrolizumab and 43.1% (95% CI, 29.3%-57.8%) with chemotherapy. The median duration of response (DOR) in this population was 16.6 months (range, 2.1+ to 35.2+) vs 8.3 months (range, 2.2+ to 30.6%) across each respective arm. Among all-comers, the ORR was 63.5% (95% CI, 50.4%-75.3%) vs 43.1% (95% CI, 30.2%-56.8%) in each respective arm, and the median DOR was 19.9 months (range, 2.1+ to 35.4+) vs 8.3 months (range, 2.2+ to 30.6+).

“These data confirm that [lenvatinib/pembrolizumab] is an active combination for endometrial cancer and should be regarded as an important treatment option for advanced endometrial cancer that is pMMR with disease progression [following] prior systemic therapy in any setting,” lead study author Christian Marth, MD, PhD, head and professor of the Department of Obstetrics and Gynaecology at Innsbruck Medical University in Austria, said in a presentation of these findings.

In the LEAP-001 study, 842 patients were randomly assigned 1:1 to receive lenvatinib at 20 mg orally once a day plus pembrolizumab at 200 mg intravenously every 3 weeks (n = 420) for up to 35 cycles or paclitaxel at 175 mg/m2 intravenously plus carboplatin area under the curve 6 intravenously every 3 weeks (n = 422) for up to 7 cycles.

The trial’s dual primary end points were PFS based on blinded independent central review using RECIST v1.1 criteria and OS. Secondary end points included ORR, safety, and health-related quality of life (HRQOL). DOR was an exploratory end point.

Patients with stage III, stage IV, or recurrent endometrial carcinoma with radiographically apparent disease were able to enroll on the study. Additional eligibility criteria included having an ECOG performance status of 0 or 1 and available tumor tissue for mismatch repair testing. Patients who received no prior chemotherapy apart from 1 previous line of neoadjuvant or adjuvant platinum-containing chemotherapy if recurrence took place at 6 or more months following the last dose were also eligible for enrollment.

The pMMR population included 320 patients in the lenvatinib/pembrolizumab arm and 322 in the chemotherapy arm. Additionally, among those with mismatch repair deficient (dMMR) disease, 100 patients each made up the lenvatinib/pembrolizumab and chemotherapy arms.

Among the all-comer population, the median age was 63 years in the combination arm (range 22-93) and 64 years (range, 32-88) in the chemotherapy arm, and 17.6% vs 16.1% received prior chemotherapy and/or chemoradiotherapy. Additionally, most patients had endometrioid histology (66.7% vs 67.1%), which included those with high-grade endometrioid (33.1% vs 30.1%) and non–high-grade endometrioid carcinoma (33.6% vs 37.0%).

Among patients with dMMR disease, the median PFS was 31.8 months (95% CI, 22.5-NR) with lenvatinib plus pembrolizumab vs 9.0 months (95% CI, 8.2-17.1) with chemotherapy (HR, 0.61; 95% CI, 0.40-0.92). The median OS was NR (95% CI, 47.0-NR) in the lenvatinib/pembrolizumab arm and NR (95% CI, 27.2-NR) in the chemotherapy arm (HR, 0.57; 95% CI, 0.36-0.91). Of note, a higher proportion of patients in the chemotherapy arm received any subsequent therapy.

The ORR was 72.0% (95% CI, 62.1%-80.5%) among patients with dMMR disease who received lenvatinib plus pembrolizumab vs 58.0% (95% CI, 47.7%-67.8%) in those who were treated with chemotherapy. Across each respective arm, the median DOR was NR (range, 2.8 to 49.0+) vs 11.7 months (range, 2.1+ to 46.9+).

According to Marth, HRQOL findings were generally comparable between the lenvatinib/pembrolizumab and chemotherapy arms, although the experimental combination elicited improvements in neuropathy and alopecia.

The median duration of treatment was 316.5 days (range, 1.0-1568.0) with lenvatinib plus pembrolizumab compared with 126.0 days (range, 1.0-554.0) in the chemotherapy arm. Additionally, 99.5% and 98.5% of patients from each respective arm experienced any-grade adverse effects (AEs), 97.9% and 96.8% had any treatment-related AE (TRAE), 71.7% and 40.9% experienced AEs leading to treatment interruption, and 47.4% and 19.5% had AEs resulting in treatment discontinuation.

The most common any-grade TRAEs in the lenvatinib plus pembrolizumab arm included hypertension (62.6%), hypothyroidism (59.0%), and diarrhea (42.1%). In the chemotherapy arm, common TRAEs of any grade included alopecia (52.6%), anemia (48.2%), and nausea (40.1%). Any-grade AEs of special interest in the lenvatinib/pembrolizumab arm appeared to be comparable with prior reports of pembrolizumab monotherapy apart from increases in hypothyroidism (62.6%), hyperthyroidism (16.4%), and colitis (5.2%).

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.