NICE Recommends Pembrolizumab Plus Lenvatinib for Previously Treated Advanced or Recurrent Endometrial Cancer

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has recommended the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for use in previously treated patients with advanced or recurrent endometrial cancer whose cancer has progressed on or after platinum-based chemotherapy and who cannot have curative surgery or radiotherapy.¹

The recommendation was supported by data from the phase 3 KEYNOTE-775 trial (NCT03517449), which showed that at a median follow-up of 14.7 months, patients treated with the combination experienced a median progression-free survival (PFS) of 7.3 months compared with 3.8 months for those given paclitaxel or doxorubicin monotherapy (HR, 0.56; 95% CI, 0.48-0.66).

Additionally, the median overall survival (OS) was 18.7 months in the pembrolizumab/lenvatinib arm vs 11.9 months for the paclitaxel or doxorubicin monotherapy arm (HR, 0.65; 95% CI, 0.55-0.77).

In July 2021, the FDA granted a regular approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation.2 That regulatory decision was also based on data from KEYNOTE-775.

The multicenter, open-label, randomized trial enrolled patients with histologically confirmed endometrial carcinoma with documented evidence of advanced, recurrent, or metastatic disease.3 Patients needed to have radiographic evidence of disease progression after 1 prior line of systemic, platinum-based chemotherapy. Notably, up to 1 additional line of platinum-based chemotherapy in the neoadjuvant or adjuvant setting was permitted. Other key inclusion criteria included at least 1 measurable lesion per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

Patients were excluded from the trial if they had carcinosarcoma, endometrial leiomyosarcoma, or endometrial stromal sarcomas; unstable central nervous system metastases; gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib; preexisting grade 3 or higher gastrointestinal or non-gastrointestinal fistula; radiographic evidence of major blood vessel invasion/infiltration; or clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment.

Patients were randomly assigned 1:1 to receive 200 mg of intravenous (IV) pembrolizumab once every 3 weeks plus 20 mg of oral lenvatinib per day during each 21-day cycle, or physician’s choice of paclitaxel or doxorubicin. IV paclitaxel was given at 80 mg/m2 once per week on a 3-weeks-on/1-week-off schedule. IV doxorubicin was administered at 60 mg/m2 on day 1 of each 21-day cycle.

PFS and OS served as the trial’s co-primary end points. Secondary end points included objective response rate, health-related quality of life, and safety.

Additional data published in the New England Journal of Medicine showed that at a median follow-up of 12.2 months in the pembrolizumab/lenvatinib group and 10.7 months in the chemotherapy group, the median PFS for the overall population was 7.2 months for the combination arm (n = 411) vs 3.8 months for the chemotherapy arm (n = 416; HR, 0.56; 95% CI, 0.47-0.66; P < .001).4 Among patients with mismatch repair–proficient (pMMR) disease, pembrolizumab/lenvatinib (n = 346) elicited a median PFS of 6.6 months vs 3.8 months for chemotherapy (n = 351; HR, 0.60; 95% CI, 0.50-0.72; P < .001).

Additionally, pembrolizumab/lenvatinib produced a median OS of 18.3 months compared with 11.4 months for chemotherapy in the overall population (HR, 0.62; 95% CI, 0.51-0.75; P < .001). In the pMMR population, the median OS was 17.4 months for pembrolizumab/lenvatinib vs 12.0 months for chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; P < .001.

More than 99% of patients experienced any-grade adverse effects (AEs) in both treatment groups. Hypertension (64.0%) was the most common any-grade AE in the pembrolizumab/lenvatinib arm, and anemia (48.7%) was the most common in the chemotherapy arm.

Additionally, 88.9% of the patients in the experimental arm experienced grade 3 or higher AEs, compared with 72.7% of patients in the chemotherapy arm. The most common serious AEs consisted of hypertension (4.2%) in the pembrolizumab/lenvatinib group and febrile neutropenia (4.1%) in the chemotherapy group.

Grade 5 AEs were reported in 5.7% of the patients in the combination arm and 4.9% of patients in the chemotherapy arm.

References

1. Final appraisal document: pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer. National Institute for Health and Care Excellence. May 2023. Accessed May 22, 2023. https://www.nice.org.uk/guidance/gid-ta10692/documents/final-appraisal-determination-document
2. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed May 23, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib
3. Lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in participants with advanced endometrial cancer (MK-3475-775/E7080-G000-309 Per Merck Standard Convention [KEYNOTE-775]). ClinicalTrials.gov. Updated November 28, 2022. Accessed May 22, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03517449
4. Makker V, Colombo N, Herráez AC, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330