At the primary analysis, the confirmatory phase III Study 309/KEYNOTE-775 demonstrated statistically significant, clinically meaningful improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus chemotherapy with doxorubicin or paclitaxel in patients with previously treated advanced endometrial cancer, both in patients with mismatch repair proficient (pMMR) tumours and in all-comer patients, and no new safety signals.
On 14 April 2023, Dr. Vicky Makker of the Medical Oncology, Memorial Sloan-Kettering Cancer Center in New York, NY, US and colleagues reported in the JCO the results from the final prespecified OS analysis. Updated PFS and ORR, efficacy by subgroups (histology, prior therapy, and MMR status), and updated safety are also reported. The results further support lenvatinib plus pembrolizumab as standard therapy in patients with previously treated advanced endometrial cancer.
The authors wrote in the background that approximately 10-15% of patients with endometrial cancer have advanced disease at diagnosis, and the 5-year relative survival rate among patients with distant metastases is approximately 20%. The single-arm phase Ib/II Study 111/KEYNOTE-146 that evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced endometrial cancer showed notable efficacy and manageable safety, irrespective of MMR status.
In the latest article published in the JCO, the authors report final prespecified OS and updated PFS and ORR according to blinded independent central review per RECIST v1.1 in pMMR and all-comer patients and safety in all-comers included in the open-label, phase III Study 309/KEYNOTE-775. Additionally, they report PFS, OS, and ORR by prespecified subgroups: histology (endometrioid or non-endometrioid), prior therapy (1, 2, ≥ 3 lines), and MMR status. Efficacy and safety were assessed in all randomly assigned patients and all patients who received ≥1 dose of study treatment.
In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician’s choice, doxorubicin 60 mg/m2 intravenously once every 3 weeks or paclitaxel 80 mg/m2 intravenously once weekly, 3 weeks on, 1 week off (n = 416).
Lenvatinib plus pembrolizumab showed benefits in OS with HR 0.70 in population with pMMR tumours (95% confidence interval [CI] 0.58 to 0.83) and HR 0.65 in all-comers population (95% CI 0.55 to 0.77), in PFS with HR 0.60 in population with pMMR tumours (95% CI 0.50 to 0.72) and HR 0.56 in all-comers (95% CI 0.48 to 0.66), 32.4% versus 15.1% ORR in pMMR, and 33.8% versus 14.7% in all-comers. Furthermore, OS, PFS, and ORR favoured lenvatinib plus pembrolizumab in all subgroups of interest.
No new safety signals were observed, and safety results were comparable with those reported at the primary analysis. Safety results were also comparable with those reported for lenvatinib plus pembrolizumab in the earlier Study 111/KEYNOTE-146 and to established side effects profiles of each agent in endometrial cancer. Similarly, safety results were also comparable to each agent and the combination in other tumour types.
The authors concluded that the results are consistent with the primary analysis, highlighting the durable and robust treatment benefit of lenvatinib plus pembrolizumab. OS benefit was maintained despite 10% of the pMMR population and 8.7% of all-comers in the chemotherapy arm receiving subsequent lenvatinib plus pembrolizumab. Efficacy results in the chemotherapy arm were comparable with findings from other phase III studies investigating second-line or later treatments.
The findings were previously presented in part at the ESMO 2022 Congress (Paris, France, 9-13 September 2022), the Annual Global Meeting of the International Gynecologic Cancer Society (New York, NY, 29 September-1 October 2022), and the European Congress on Gynecologic Oncology (Berlin, Germany, 27-30 October 2022).
The study was sponsored by Eisai Inc, Nutley, NJ, US and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, US.
Reference
Makker V, Colombo N, Casado Herráez, et al. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. JCO; Published online 14 April 2023. DOI: 10.1200/JCO.22.02152
