The combination of lenvatinib and pembrolizumab continued to show benefits in efficacy vs chemotherapy among patients with endometrial cancer treated in Study 309/KEYNOTE-775.
In the mismatch repair proficient (pMMR) and all-comer populations of patients with endometrial cancer, progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) favored treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) vs chemotherapy, according to the final prespecified OS analysis for Study 309/KEYNOTE-775 (NCT03517449).1
The majority of patients who were treated with lenvatinib plus pembrolizumab experienced tumor shrinkage regardless of histology, and there were no new safety signals observed with the combination.
Additionally, safety results were comparable with those reported at the primary analysis, as well as those previously reported for lenvatinib plus pembrolizumab in the earlier Study 111/KEYNOTE-146 (NCT02501096) and to established AE profiles of each agent in endometrial cancer.
"We are becoming more comfortable with this lenvatinib/pembrolizumab which which was brought to us through a series of trials," Robert L. Coleman, MD, FACOG, FACS, of Texas Oncology, told Targeted OncologyTM. "This was first of all, confirmatory, and to have this expectation for chemotherapy and to see how well it was done was, for many of us, very exciting."
A total of 827 patients with advanced, recurrent, or metastatic endometrial cancer were randomly assigned to receive treatment with lenvatinib plus pembrolizumab (n = 411) or chemotherapy (n = 416) arms. In the first arm, patients were administered lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks. In the second arm, patients were treated with chemotherapy of the treating physician's choice, which consisted of either doxorubicin 60 mg/m2 intravenously once every 3 weeks or paclitaxel 80 mg/m2 intravenously once weekly for 3 weeks on and 1 week off.
Among these patients, 697 had pMMR tumors and 130 had mismatch repair deficient (dMMR) tumors. The median follow-up was 18.7 months in the lenvatinib plus pembrolizumab group and 12.2 months in the chemotherapy group (14.7 months overall).
Between treatment groups, baseline characteristics were balanced and characteristics of dMMR patients were generally consistent with those of the pMMR and all-comer populations. A total of 84.2% of patients in the lenvatinib plus pembrolizumab arm and 84.4% in the chemotherapy arm had confirmed pMMR tumors. In the lenvatinib plus pembrolizumab arm vs chemotherapy arm, the median age of patients was 64 years (range, 30-82), and 65 years (range, 35-86), and most patients were white (63.5% v 59.4%) in the all-comer population.
Included in the study were patients with advanced endometrial cancer who received at least 1 previous platinum-based chemotherapy regimen, had measurable disease by blinded independent central review, an ECOG performance status of 0 or 1, and tissue available for MMR testing. Patients were stratified based on region, ECOG performance status, and history of pelvic radiation.2
Once enrolled, patients were randomly assigned in a 1:1 ratio to receive 20 mg of oral lenvatinib daily plus 200 mg of pembrolizumab intravenously once every 3 weeks or 60 mg/m2 of doxorubicin once every 3 weeks or 80 mg/m2 of paclitaxel weekly for 3 weeks o and 1 week off.
The primary end points of the study included OS and PFS, and key secondary end points were ORR, health-related quality of life, pharmacokinetics, and safety. The trial also assessed DOR as an exploratory end point.
Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v14.7%) versus chemotherapy1. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.
In the pMMR population, OS was longer among patients treated with lenvatinib plus pembrolizumab at a median of 18.0 months (95% CI, 14.9-20.5) compared with a median of 12.2 months in the chemotherapy arm (95% CI, 11.0-14.1; HR, 0.70; 95% CI, 0.58-0.83). Similar results were also seen in the all-comer population with those given lenvatinib plus pembrolizumab having a median of 18.7 months (95% CI, 15.6-21.3) and those given chemotherapy having a median of 11.9 months (95% CI, 10.7-13.3; HR, 0.65; 95% CI, 0.55-0.77).
PFS in the pMMR population was longer in the lenvatinib plus pembrolizumab arm at a median of 6.7 months (95% CI, 5.6-7.4) vs in the chemotherapy arm with a median of 3.8 months (95% CI, 3.6-5.0; HR, 0.60; 95% CI, 0.50-0.72). There were also similar results seen in all-comer patients. Those treated with lenvatinib plus pembrolizumab had a median PFS of 7.3 months (95% CI, 5.7-7.6) vs 3.8 months in the chemotherapy arm (95% CI, 3.6-4.2; HR, 0.56; 95% CI, 0.48-0.66).
There was a higher percentage of patients with pMMR tumors with a confirmed objective response when treated with lenvatinib plus pembrolizumab (32.4%) compared with those treated with chemotherapy (15.1%). In these groups, 5.8% and 2.6% of patients, respectively, achieved complete responses (CRs). The median duration of response (DOR) was 9.3 months (range, 1.6+ to 39.5+) with lenvatinib plus pembrolizumab vs 5.7 months (range, 0.0+ to 37.1+) with chemotherapy. In the all-comer population, the ORR was 33.8% among patients treated with the combinations vs 14.7% for those treated with chemotherapy. Additionally, 7.5% and 2.6% of patients in the combination and chemotherapy arm had CRs, respectively.
With lenvatinib plus pembrolizumab, the median DOR was 12.9 months (range, 1.6 + to 39.5+) vs 5.7 months (range, 0.0+ to 37.1+) with chemotherapy. There were more patients who experienced tumor shrinkage in the lenvatinib plus pembrolizumab arm vs in the chemotherapy arm, and clinically meaningful improvements across efficacy end points were seen in the dMMR population among patients treated with lenvatinib plus pembrolizumab.
“The results further support lenvatinib plus pembrolizumab as standard therapy in patients with previously treated advanced [endometrial cancer],” concluded the study authors.