Evaluating Lenvatinib and Pembrolizumab as a First-Line Chemotherapy-Free Option for Advanced Endometrial Cancer

According to an article published in the Journal of Clinical Oncology, endometrial cancer (EC) is the 6th most common cancer in women on a global level. Researchers explored the effectiveness of combination levatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, an anti-PD-1 monoclonal antibody, as a first-line treatment for advanced or recurrent EC. The combination of lenvatinib + pembrolizumab is an established treatment for advanced or recurrent endometrial cancer (aEC) in patients regardless of mismatch repair (MMR) status.

This approval stems from studies such as the phase I/II Study 111/KEYNOTE-146 and the confirmatory phase III Study 309/KEYNOTE-775, which demonstrated improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared with physician’s choice chemotherapy. These studies also confirmed a manageable safety profile for this combination therapy, further supporting its use in previously treated advanced or metastatic EC.

Standard first-line therapy for inoperable stage III-IV or recurrent EC often involves chemotherapy-based regimens, including combinations with immunotherapy. Trials such as NRG-GY018 and RUBY have validated the addition of anti-PD-1 therapies like pembrolizumab or dostarlimab to paclitaxel-carboplatin. At the start of the ENGOT-en9/LEAP-001 study, paclitaxel-carboplatin was the standard of care for first-line treatment. ENGOT-en9/LEAP-001, a phase III global trial, aimed to evaluate the novel lenvatinib-pembrolizumab combination against standard chemotherapy, marking the first registrational intent trial comparing a chemotherapy-free regimen with the established standard for aEC.

ENGOT-en9/LEAP-001 was conducted at 171 global centers and adhered to strict ethical guidelines. Female patients aged 18 or older with stage III-IV or recurrent, histologically confirmed EC were eligible to participate. Participants were randomized to receive either lenvatinib-pembrolizumab or paclitaxel-carboplatin, with stratification by MMR status and other clinical factors. Treatment continued until disease progression, unacceptable toxicity, or withdrawal, with pembrolizumab limited to 35 cycles and lenvatinib extended as necessary. Tumor imaging, adverse event assessment, and patient-reported outcomes were integral to the study protocol.

The study's dual primary endpoints were PFS and OS, with secondary endpoints including ORR, changes in quality-of-life scores, and safety. Efficacy analyses were performed for both the intention-to-treat and MMR-defined populations. The trial enrolled 842 patients, of whom 642 were in the MMR-proficient group. Baseline characteristics were similar across treatment groups, and follow-up extended to a median of 38.4 months. This robust design allowed for comprehensive evaluation of the comparative benefits and risks of the 2 treatment regimens.

Preliminary results demonstrated the efficacy of lenvatinib-pembrolizumab in improving outcomes for patients with aEC, particularly in the MMR-proficient group. Safety findings were consistent with prior studies, confirming the manageable toxicity of the regimen. The trial highlights the potential of chemotherapy-free combinations in transforming the treatment paradigm for EC, paving the way for innovative approaches in this challenging disease setting.

“In conclusion, lenvatinib + pembrolizumab did not meet the prespecified statistical criteria for PFS or OS versus paclitaxel-carboplatin in patients with aEC in the first-line setting,” said study authors.

Reference

Marth C, Moore RG, Bidziński M, et al. First-line levatinib plus pembrolizumab versus chemotherapy for advanced endometrial cancer: a randomized, open-label, phase III trial. JCO. Published online November 26, 2024. doi:10.1200/jco-24-01326