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Progression-Free Survival and Overall Survival Significantly Longer with Lenvatinib Plus Pembrolizumab Than with Chemotherapy in Advanced Endometrial Cancer

Findings from the Study 309–KEYNOTE-775 among patients who had disease progression after the receipt of previous systemic platinum-based therapy
26 Jan 2022
Anticancer agents & Biologic therapy;  Cancer Immunology and Immunotherapy;  Gynaecologic malignancies

In a phase III Study 309–KEYNOTE-775 treatment with lenvatinib plus pembrolizumab led to significantly longer progression-free survival (PFS) and overall survival (OS) than chemotherapy of the treating physician’s choice, both in the population with mismatch repair–proficient (pMMR) disease and in the overall study population of patients with advanced endometrial cancer who had disease progression after the receipt of previous systemic platinum-based therapy. Benefits were seen across all evaluated subgroups. The findings are published by Dr. Vicky Makker of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 19 January 2022 in The New England Journal of Medicine.

Previously in a phase II Study 111–KEYNOTE-146, treatment with a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT, lenvatinib in combination with PD-1 inhibitor pembrolizumab had compelling efficacy in patients with previously treated advanced endometrial carcinoma. High-grade adverse events were managed with supportive therapy and dose modifications, with a relatively low incidence of discontinuation due to adverse events.

The Study 309–KEYNOTE-775 was conducted to confirm the results of that earlier study by comparing the efficacy and safety of lenvatinib plus pembrolizumab with the physician’s choice of doxorubicin or paclitaxel chemotherapy in patients with advanced endometrial cancer who had disease progression after the receipt of at least one platinum-based therapy.

Two primary endpoints were PFS as assessed on blinded independent central review according to the RECIST v1.1, and OS. The endpoints were evaluated in patients with pMMR disease and in all patients. Safety was also assessed. Patients were randomly assigned in a 1:1 ratio. In total, 827 patients of whom 697 with pMMR disease and 130 with mismatch repair–deficient disease were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients).

The median PFS was longer with lenvatinib plus pembrolizumab than with chemotherapy in pMMR population, 6.6 versus 3.8 months (hazard ratio [HR] for progression or death 0.60, 95% confidence interval [CI] 0.50 to 0.72; p < 0.001) and also in overall population, 7.2 versus 3.8 months (HR 0.56, 95% CI 0.47 to 0.66; p < 0.001).

The median OS was longer with lenvatinib plus pembrolizumab than with chemotherapy in pMMR population, 17.4 versus 12.0 months (HR for death 0.68, 95% CI 0.56 to 0.84; p < 0.001) and in overall population, 18.3 versus 11.4 months (HR 0.62, 95% CI 0.51 to 0.75; p < 0.001).

The efficacy curves separated early and remained consistently separated throughout the evaluation period. The benefits in PFS and OS were seen across all evaluated subgroups, including subgroups defined according to less-common yet aggressive histologic features, history of pelvic irradiation, and previous lines of therapy.

Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy. The most frequent adverse events with incidence of ≥30% in the respective treatment groups were hypertension, hypothyroidism, diarrhoea, nausea, decreased appetite, vomiting, decreased body weight, fatigue, and arthralgia among patients receiving lenvatinib plus pembrolizumab and anaemia, nausea, neutropenia, and alopecia among those receiving chemotherapy.

The QLQ-C30 was completed for more than 95% of the patients in the two treatment groups at baseline; scores at 12 weeks after randomisation were available for 80% of the patients in the lenvatinib–pembrolizumab group and for 62% of those in the chemotherapy group. No substantial differences between the groups were observed in the QLQ-C30 global health status quality-of-life scores over time. 

The study limitation is relatively short duration of follow-up, which may mean that responses are evolving. Although the protocol-specified criteria were met for the efficacy analyses, safety and efficacy monitoring is ongoing.

The authors concluded that lenvatinib plus pembrolizumab led to significantly longer PFS and OS than chemotherapy among patients with advanced endometrial cancer who had disease progression after the receipt of previous systemic platinum-based therapy.

The study was supported by Eisai and Merck Sharp and Dohme, a subsidiary of Merck.

Reference

Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. NEJM; Published online 19 January 2022. DOI: 10.1056/NEJMoa2108330

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