Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) 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]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.

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% v 14.7%) versus chemotherapy. 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.

INTRODUCTION

Approximately 10%–15% of patients with endometrial cancer (EC) have advanced disease at diagnosis,¹ and the 5-year relative survival rate among patients with distant metastases is approximately 20%.² The single-arm phase Ib/II Study 111/KEYNOTE-146 that evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced endometrial carcinoma showed notable efficacy and manageable safety, irrespective of mismatch repair (MMR) status.³ At the primary analysis, the confirmatory phase III Study 309/KEYNOTE-775 (ClinicalTrials.gov identifier: NCT03517449) demonstrated statistically significant, clinically meaningful improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus chemotherapy (doxorubicin or paclitaxel) in previously treated advanced EC (both in patients with mismatch repair proficient [pMMR] tumors and in all-comer patients) and no new safety signals.⁴

We report the final prespecified OS analysis for Study 309/KEYNOTE-775. Updated PFS and ORR, efficacy by subgroups (histology, prior therapy, and MMR status), and updated safety are also reported.

METHODS

Inclusion/exclusion criteria and procedures for this open-label, phase III trial were previously published⁴ (Data Supplement [online only] for summary).

We report final prespecified OS and updated PFS and ORR (blinded independent central review per RECIST v1.1) in pMMR and all-comer patients and safety in all-comers. Additionally, we report PFS, OS, and ORR by prespecified subgroups (histology [endometrioid or nonendometrioid], 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, respectively.

The nonparametric Kaplan-Meier method was used to estimate survival curves for PFS and OS, and a stratified Cox proportional hazards model with Efron's method of handling ties was used to assess hazard ratios (HRs). The stratified Miettinen and Nurminen's method was used to assess differences in ORR. Differences in percentages of patients with an objective response and the 95% CIs (not adjusted for multiplicity) with strata weighting according to sample size were reported. For OS, PFS, and ORR analyses, the stratification factors used for random assignment were applied. PFS and OS subgroup analyses were conducted using an unstratified Cox model, and ORR subgroup analyses were conducted using the unstratified Miettinen and Nurminen's method (except pMMR analyses, which used the same stratified methods used for primary analyses). All analyses are descriptive.

This study was approved by each research site's institutional review board or independent ethics committee. All patients provided written, informed consent.

RESULTS

Patients and Treatments

Eight hundred twenty-seven patients were randomly assigned to the lenvatinib plus pembrolizumab (n = 411) or chemotherapy (n = 416) arms; 697 patients had pMMR tumors and 130 had mismatch repair deficient (dMMR) tumors. Data cutoff occurred on March 1, 2022 (>16 months of additional follow-up from the primary analysis). The median follow-up was 18.7 months in the lenvatinib plus pembrolizumab arm and 12.2 months in the chemotherapy arm (14.7 months overall). Patient disposition is summarized in Data Supplement.

Baseline characteristics were balanced between the treatment groups (Table 1), and characteristics of dMMR patients were generally consistent with those of the pMMR and all-comer populations (Data Supplement). Of all randomly assigned patients, 84.2% in the lenvatinib plus pembrolizumab arm and 84.4% in the chemotherapy arm had confirmed pMMR tumors. Treatment history is summarized in the Data Supplement.

TABLE 1.

Baseline Demographic and Clinical Characteristics: pMMR and All-Comer Populations

Efficacy

OS in the pMMR population was longer in the lenvatinib plus pembrolizumab arm (median, 18.0 months; 95% CI, 14.9 to 20.5) versus the chemotherapy arm (median, 12.2 months; 95% CI, 11.0 to 14.1; HR, 0.70; 95% CI, 0.58 to 0.83; Fig 1A), with similar results observed in all comers (lenvatinib plus pembrolizumab median, 18.7 months; 95% CI, 15.6 to 21.3; chemotherapy median, 11.9 months; 95% CI, 10.7 to 13.3; HR, 0.65; 95% CI, 0.55 to 0.77; Fig 1B). Similar results were observed when excluding patients in the chemotherapy arm who received subsequent lenvatinib plus pembrolizumab or those who received any subsequent PD-1/PD-L1 checkpoint inhibitor therapy (Data Supplement). PFS in the pMMR population was longer in the lenvatinib plus pembrolizumab arm (median, 6.7 months; 95% CI, 5.6 to 7.4) versus the chemotherapy arm (median, 3.8 months; 95% CI, 3.6 to 5.0; HR, 0.60; 95% CI, 0.50 to 0.72; Fig 1C). Similar results were seen in all-comer patients (lenvatinib plus pembrolizumab median, 7.3 months; 95% CI, 5.7 to 7.6; chemotherapy median, 3.8 months; 95% CI, 3.6 to 4.2; HR, 0.56; 95% CI, 0.48 to 0.66; Fig 1D).

FIG 1.

OS: (A) pMMR population and (B) all-comer population. PFS^a: (C) pMMR population and (D) all-comer population. ^aAssessed by blinded independent central review; per RECIST v1.1. HR, hazard ratio; OS, overall survival; PFS, progression-free survival; pMMR, mismatch repair proficient.

The percentage of patients with pMMR tumors with a confirmed objective response was higher with lenvatinib plus pembrolizumab (32.4%) than with chemotherapy (15.1%), with 5.8% and 2.6% of patients, respectively, achieving complete responses (CRs); the median duration of response (DOR) was 9.3 months (range, 1.6+ to 39.5+) with lenvatinib plus pembrolizumab versus 5.7 months (range, 0.0+ to 37.1+) with chemotherapy (Data Supplement). Similar results were observed in the all-comer population (confirmed ORR, 33.8% v 14.7%); 7.5% and 2.6% of patients had CRs, respectively; the median DOR was 12.9 months (range, 1.6 + to 39.5+) with lenvatinib plus pembrolizumab and 5.7 months (range, 0.0+ to 37.1+) with chemotherapy (Data Supplement). More patients experienced tumor shrinkage in the lenvatinib plus pembrolizumab arm versus the chemotherapy arm (Data Supplement). Additionally, clinically meaningful improvements across efficacy end points were observed with lenvatinib plus pembrolizumab in the dMMR population (Data Supplement).

Overall, PFS, OS, and ORR in the pMMR and all-comer populations favored lenvatinib plus pembrolizumab in all subgroups of interest (Data Supplement). Of note, the majority of patients who received lenvatinib plus pembrolizumab experienced tumor shrinkage regardless of histology (Data Supplement).

Safety

Seven hundred ninety-four patients treated with lenvatinib plus pembrolizumab (n = 406) or chemotherapy (n = 388) were included in the safety analysis population. Drug exposure is summarized in the Data Supplement; dose modifications and discontinuations are summarized in the Data Supplement.

Any-grade treatment-emergent adverse events (TEAEs) occurred in 99.8% of patients who received lenvatinib plus pembrolizumab and 99.5% of patients who received chemotherapy. The most common TEAE in the lenvatinib plus pembrolizumab arm was hypertension (65.0%); the most common TEAE in the chemotherapy arm was anemia (48.7%) (Table 2). Grade ≥ 3 TEAEs occurred in 90.1% of patients receiving lenvatinib plus pembrolizumab and 73.7% of patients receiving chemotherapy (grade 5 TEAEs occurred in 6.4% and 5.2% of patients, respectively; Table 2). Concomitant medications for adverse events (AEs) in patients who received lenvatinib plus pembrolizumab are summarized in the Data Supplement. Serious AEs are summarized in the Data Supplement. Treatment-related AEs are summarized in the Data Supplement. AEs of special interest and clinically significant AEs are summarized in the Data Supplement.

TABLE 2.

TEAEs in Patients Who Received Study Treatment

Subsequent Therapy

Subsequent therapies are summarized in the Data Supplement. PFS on next-line therapy in pMMR and all-comer populations favored lenvatinib plus pembrolizumab (Data Supplement).

DISCUSSION

With extended follow-up, lenvatinib plus pembrolizumab continued to show considerable efficacy benefit versus chemotherapy. The results were consistent with the primary analysis (Data Supplement), highlighting the durable and robust treatment benefit of lenvatinib plus pembrolizumab. OS benefit was maintained despite 10.0% 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 trials investigating second-line or later treatments.^5,6

No new safety signals were observed, and safety results were comparable with those reported at the primary analysis.⁴ Safety results were also comparable with those reported for lenvatinib plus pembrolizumab in the earlier Study 111/KEYNOTE-146³ and to established AE profiles of each agent in EC.^7-10 Similarly, safety results were also comparable to each agent and the combination in other tumor types.^7,11-15

The results further support lenvatinib plus pembrolizumab as standard therapy in patients with previously treated advanced EC.

DATA SHARING STATEMENT

The data will not be available for sharing at this time because the data are commercially confidential. However, Eisai Inc will consider written requests to share the data on a case-by-case basis.

AUTHOR CONTRIBUTIONS

Conception and design: Antonio Casado Herráez, Kan Yonemori, Eva M. Guerra Alia, Robert Orlowski, Gianmaria Barresi

Financial support: Kan Yonemori

Administrative support: Kan Yonemori

Provision of study materials or patients: Nicoletta Colombo, Antonio Casado Herráez, Bradley J. Monk, Helen Mackay, Alessandro D. Santin, David S. Miller, Sally Baron-Hay, Isabelle Ray-Coquard, Kan Yonemori, Yong Man Kim, Eva M. Guerra Alia, Ulus A. Sanli

Collection and assembly of data: Vicky Makker, Antonio Casado Herráez, Bradley J. Monk, Helen Mackay, David S. Miller, Richard G. Moore, Sally Baron-Hay, Isabelle Ray-Coquard, Kimio Ushijima, Yong Man Kim, Eva M. Guerra Alia, Ulus A. Sanli, Robert Orlowski, Jodi McKenzie, Gianmaria Barresi, Domenica Lorusso

Data analysis and interpretation: Nicoletta Colombo, Antonio Casado Herráez, Bradley J. Monk, Helen Mackay, Alessandro D. Santin, David S. Miller, Richard G. Moore, Isabelle Ray-Coquard, Kan Yonemori, Eva M. Guerra Alia, Steven Bird, Robert Orlowski, Jodi McKenzie, Chinyere Okpara, Gianmaria Barresi

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775

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