Abstract
Objective
In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis.
Methods
Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis.
Results
Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively.
Conclusion
Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.
Trial Registration
ClinicalTrials.gov Identifier: NCT03517449
Keywords: Asian; Chemotherapy; Endometrial Cancer; Immunotherapy; Drug Therapy, Combination; Survival
Synopsis
We evaluated outcomes in East Asian patients with advanced/recurrent endometrial cancer from Study 309/KEYNOTE-775. Lenvatinib+pembrolizumab improved progression-free survival, overall survival, and objective responses. The safety profile was manageable with dose modification and supportive care. Results were consistent with the overall population.
Graphical Abstract
INTRODUCTION
Endometrial cancer (EC) is the sixth most common cancer among women worldwide [1]. In East Asia, the incidence of EC has increased across all age groups [2,3,4], and 5-year survival rates in patients who are diagnosed with advanced disease or who experience disease recurrence have remained low (26%–32%) with standard-of-care treatments [2,5,6]. In the Global Burden of Disease Study, the age-standardized incidence of EC increased between 1990 and 2019 at a higher rate among patients from East Asia (26.8%) compared with the global study population (15.3%) [7]. Although the age-standardized death rate due to EC decreased over the same time period in Republic of Korea (2.68% to 0.77%), it remained relatively stable in Japan (1.78% to 1.7%) and increased in Taiwan (0.96% to 1.64%) [7]. Therefore, the burden of EC has remained substantial in the East Asian population. Additionally, evidence has shown differences in the genomic profile between Asian and non-Asian patients with EC [8], which could influence response to treatment.
Treatment options for patients in East Asia may include surgical resection (if possible), radiotherapy, hormonal therapy, chemotherapy, or a combination of these treatments [9,10]. More recently, the combination of the multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) lenvatinib plus the immune checkpoint inhibitor pembrolizumab has been approved as a treatment option for patients with advanced EC in Japan, Republic of Korea, and Taiwan as well as in Europe and the United States.
Approval of lenvatinib plus pembrolizumab was based on results of the phase 3 Study 309/KEYNOTE-775, in which lenvatinib plus pembrolizumab significantly prolonged progression-free survival (PFS) and overall survival (OS) and significantly improved objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC; doxorubicin or paclitaxel) in patients with advanced EC whose disease recurred or progressed after 1 or 2 previous platinum-based chemotherapy regimens [11]. In the final prespecified analysis for OS [12], the hazard ratio (HR) was 0.70 (95% confidence interval [CI], 0.58–0.83) in the mismatch repair proficient (pMMR) population and 0.65 (95% CI=0.55–0.77) in the all-comer population. The HRs for PFS were 0.60 (95% CI=0.50–0.72) and 0.56 (95% CI=0.48–0.66), respectively. The ORR was 32.4% with lenvatinib plus pembrolizumab and 15.1% with TPC in the pMMR population and 33.8% and 14.7%, respectively, in the all-comer population. The most common grade ≥3 adverse events (AEs) in the combination therapy arm were hypertension (39.2%), decreased weight (10.8%), diarrhea (8.1%), and decreased appetite (7.6%) [12]. The safety profile of lenvatinib plus pembrolizumab was consistent with that reported in the phase 2 Study 111/KEYNOTE-146 [13,14] and those of the individual agents [15].
This exploratory analysis of Study 309/KEYNOTE-775 was conducted to evaluate outcomes at the time of the final prespecified analysis for OS in patients enrolled in East Asia (Japan, Republic of Korea, and Taiwan).
MATERIALS AND METHODS
1. Study design and patients
Study 309/KEYNOTE-775 (ClinicalTrials.gov, NCT03517449) was a phase 3, multicenter, randomized, open-label trial. Methods were previously published in detail [11]. Briefly, adult women with histologically confirmed advanced, recurrent, or metastatic EC; ≥1 measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and radiographic evidence of disease progression after 1 previous platinum-based chemotherapy regimen were eligible. Patients could have received an additional line of platinum-based chemotherapy if received in the adjuvant or neoadjuvant setting. Patients were also required to have a tumor biopsy specimen for determination of MMR status, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Patients were excluded if they had carcinosarcoma, endometrial leiomyosarcoma, or endometrial stromal sarcomas. Previous treatment with agents targeting VEGF, programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 or ligand 2 (PD-L1 or PD-L2) was prohibited. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and all patients provided written informed consent.
2. Study treatment
Patients were randomized 1:1 to receive lenvatinib 20 mg orally every day plus pembrolizumab 200 mg intravenously (IV) every 3 weeks or TPC consisting of either doxorubicin 60 mg/m2 IV every 3 weeks or paclitaxel 80 mg/m2 IV every week (3 weeks on/1 week off). Randomization was first stratified by MMR status (pMMR vs. mismatch repair deficient [dMMR]), then only within the pMMR stratum, patients were further stratified by ECOG performance status (0 vs. 1), geographic region (Europe, United States, Canada, Australia, New Zealand, and Israel vs. rest of world), and history of pelvic radiation (yes vs. no). Treatment continued until disease progression confirmed by blinded independent central review (BICR), unacceptable toxicity, withdrawal of consent, receipt of 35 cycles of pembrolizumab (up to 2 years), or a lifetime cumulative dose of doxorubicin of 500 mg/m2. Discontinuation of pembrolizumab was considered if patients achieved a confirmed complete response (CR), were treated for ≥8 cycles, and received ≥2 cycles of pembrolizumab following CR.
3. Endpoints
The primary endpoints were PFS (time from randomization to first documented disease progression per RECIST version 1.1 by BICR or death from any cause) and OS (time from randomization to death from any cause). Key secondary endpoints were ORR (proportion of patients who have best overall response of CR or partial response [PR] per RECIST version 1.1 by BICR) and safety.
4. Assessments
Tumor imaging was performed at baseline, every 8 weeks after randomization until the primary analysis, and every 12 weeks thereafter. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. AEs were monitored throughout the study until 30 days (120 days for serious AEs) after the last dose of study treatment.
Archived tumor tissue from the most recent biopsy or from a fresh biopsy (if no archival tumor tissue was available) was collected from all enrolled patients to assess MMR status. A sample collected following the latest systemic treatment was preferred. MMR proteins were chromogenically labeled for automated immunohistochemistry staining on the Ventana Benchmark Ultra using mouse and rabbit antibodies (Roche Diagnostics, Indianapolis, IN, USA). The MLH1 (clone M1, mouse monoclonal, Ventana Cat #790-5091), PMS2 (clone A16-4, mouse monoclonal, Ventana Cat# 790-5094), MSH2 (clone G219-1129, mouse monoclonal, Ventana Cat# 790-5093), and MSH6 (clone SP93, rabbit monoclonal, Ventana Cat# 790-5092) were used for immunohistochemical staining.
5. Statistical analysis
Analyses in the East Asia subgroup were exploratory and not powered to test hypotheses. No alpha was assigned to these analyses. Efficacy was assessed in the pMMR and all-comer populations, and safety was analyzed in all treated patients. PFS and OS were evaluated using the Kaplan-Meier method; HRs (95% CIs) were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate. For best overall response, 95% CIs were based on the binomial exact CI method.
RESULTS
1. Patients
The intention-to-treat population for the global Study 309/KEYNOTE-775 included 827 patients (pMMR, n=697; dMMR, n=130). Of these patients, 155 were included in the East Asia subgroup (Japan [n=104], Republic of Korea [n=29], and Taiwan [n=22]; Fig. 1). Baseline characteristics were similar between the treatment groups in both the all-comer (Table 1) and pMMR (Table S1) populations. In the all-comer population, 66 patients (85.7%) had pMMR tumors and 11 (14.3%) had dMMR tumors in the lenvatinib plus pembrolizumab group. In the TPC group, 68 patients (87.2%) had pMMR tumors and 10 (12.8%) had dMMR tumors. Median follow-up time (randomization to data cutoff date of March 1, 2022) was 34.3 months (range, 25.1–43.0 months). Median duration of treatment was 7.4 months (range, 0–43.0 months) with lenvatinib plus pembrolizumab and 3.5 months (range, 0–38.7 months) with TPC. The median cumulative dose of lenvatinib received was 2,002 mg (range, 20–20,788 mg). Among patients in the pembrolizumab plus lenvatinib group, 32 (41.6%) received subsequent systemic anticancer therapy, including 3 (3.9%) who received any anti-PD-(L)1 treatment (pembrolizumab, n=3) and 2 (2.6%) who received lenvatinib plus pembrolizumab (Fig. 1). Among patients in the TPC group, 38 (48.7%) received subsequent systemic anticancer therapy, including 12 (15.4%) who received any anti-PD-(L)1 treatment (pembrolizumab, n=10; nivolumab, n=2) and 5 (6.4%) who received lenvatinib plus pembrolizumab.
Fig. 1. Treatment disposition in the all-comer population.
AE, adverse event; PD, progressive disease; TPC, treatment of physician’s choice chemotherapy.
Table 1. Demographics and baseline disease characteristics in all-comer population.
| Characteristics | Lenvatinib+pembrolizumab (n=77) | TPC (n=78) | ||
|---|---|---|---|---|
| Age (yr) | 62 (35–76) | 61 (36–77) | ||
| <65 years | 48 (62.3) | 53 (67.9) | ||
| MMR status | ||||
| pMMR | 66 (85.7) | 68 (87.2) | ||
| dMMR | 11 (14.3) | 10 (12.8) | ||
| ECOG performance status | ||||
| 0 | 61 (79.2) | 61 (78.2) | ||
| 1 | 16 (20.8) | 17 (21.8) | ||
| History of pelvic radiation | 21 (27.3) | 13 (16.7) | ||
| Histology at initial diagnosis | ||||
| Endometrioid carcinoma | 49 (63.6) | 48 (61.5) | ||
| High grade | 17 (22.1) | 20 (25.6) | ||
| Low grade | 26 (33.8) | 19 (24.4) | ||
| Not specified | 6 (7.8) | 9 (11.5) | ||
| Serous carcinoma | 16 (20.8) | 20 (25.6) | ||
| High-grade serous | 0 (0.0) | 7 (9.0) | ||
| Mixed | 5 (6.5) | 4 (5.1) | ||
| Clear cell carcinoma | 5 (6.5) | 3 (3.8) | ||
| Undifferentiated | 1 (1.3) | 1 (1.3) | ||
| Neuroendocrine | 1 (1.3) | 0 (0.0) | ||
| High-grade mucinous carcinoma | 0 (0.0) | 1 (1.3) | ||
| Other | 0 (0.0) | 1 (1.3) | ||
| FIGO stage at initial diagnosis | ||||
| I | 21 (27.3) | 18 (23.1) | ||
| II | 4 (5.2) | 5 (6.4) | ||
| III | 24 (31.2) | 24 (30.8) | ||
| IV | 28 (36.4) | 31 (39.7) | ||
| Metastasis | ||||
| Lymph node | 40 (51.9) | 45 (57.7) | ||
| Intra-abdominal | 33 (42.9) | 38 (48.7) | ||
| Lung | 31 (40.3) | 24 (30.8) | ||
| Liver | 19 (24.7) | 13 (16.7) | ||
| Bone | 9 (11.7) | 4 (5.1) | ||
Data are median (range) or number (%).
dMMR, mismatch repair deficient; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; MMR, mismatch repair; pMMR, mismatch repair proficient; TPC, treatment of physician’s choice chemotherapy.
2. Efficacy
In the pMMR population, median PFS (95% CI) was 6.7 months (3.7–7.6 months) in the lenvatinib plus pembrolizumab group and 3.8 months (3.6–5.6 months) in the TPC group, with an HR of 0.74 (95% CI=0.49–1.10; Fig. 2). The 6-month PFS rates were 51% and 37%, respectively. In the all-comer population, median PFS (95% CI) was 7.2 months (3.8–9.0 months) in the lenvatinib plus pembrolizumab group and 3.7 months (3.6–5.6 months) in the TPC group, with an HR of 0.64 (95% CI=0.44–0.94). The 6-month PFS rates were 54% and 36%, respectively. In the dMMR subgroup, median PFS (95% CI) was not reached (2.0 months–not reached) in the lenvatinib plus pembrolizumab group and 3.7 months (1.2–7.2 months) in the TPC group (HR=0.25; 95% CI=0.07–0.89). The 6-month PFS rates were 70% and 30%, respectively.
Fig. 2. Kaplan-Meier estimates of PFS per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review in the (A) pMMR population and (B) all-comer population.
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; pMMR, mismatch repair proficient; TPC, treatment of physician’s choice chemotherapy.
In the pMMR population, median OS (95% CI) was 17.7 months (11.2–31.5 months) in the lenvatinib plus pembrolizumab group and 13.2 months (10.5–15.5 months) in the TPC group, with an HR of 0.68 (95% CI=0.45–1.02; Fig. 3). The 12-month OS rates were 59% and 54%, respectively. In the all-comer population, median OS (95% CI) was 20.6 months (12.1–34.6 months) in the lenvatinib plus pembrolizumab group and 12.2 months (10.4–15.5 months) in the TPC group, with an HR of 0.61 (95% CI=0.41–0.90). The 12-month OS rates were 62% and 52%, respectively. In the dMMR subgroup, median OS (95% CI) was not reached (11.3 months–not reached) in the lenvatinib plus pembrolizumab group and 6.7 months (1.2 months–not reached) in the TPC group (HR=0.31; 95% CI=0.08–1.26). The 12-month OS rates were 82% and 40%, respectively.
Fig. 3. Kaplan-Meier estimates of OS in the (A) pMMR population and (B) all-comer population.
CI, confidence interval; HR, hazard ratio; OS, overall survival; pMMR, mismatch repair proficient; TPC, treatment of physician’s choice chemotherapy.
In the pMMR population, ORR was 36% (95% CI=25%–49%) in the lenvatinib plus pembrolizumab group, with 6 patients (9.1%) experiencing CR and 18 (27.3%) experiencing PR, and 22% (95% CI=13%–34%) in the TPC group, with 3 patients (4.4%) experiencing CR and 12 (17.6%) experiencing PR (Table 2). Median (range) duration of response (DOR) was 14.4 months (1.6–39.5+ months) and 5.2 months (2.1+ to 37.1+ months), respectively (‘+’ indicates no progressive disease at the time of last assessment). In the all-comer population, ORR was 39% (95% CI, 28%–51%) in the lenvatinib plus pembrolizumab group, with 9 patients (11.7%) experiencing CR and 21 (27.3%) experiencing PR, and 21% (95% CI=12%–31%) in the TPC group, with 4 patients (5.1%) experiencing CR and 12 (15.4%) experiencing PR. Median (range) DOR was 16.5 months (1.6–39.5+ months) and 5.2 months (1.9+ to 37.1+ months), respectively. In the dMMR subgroup, ORR was 55% (95% CI=23%–83%) in the lenvatinib plus pembrolizumab group and 10% (95% CI=0%–45%) in the TPC group. Median (range) DOR was not reached (27.0+ to 34.9+ months) and not reached (1.9+ to 1.9+ months), respectively.
Table 2. Tumor response in pMMR and all-comer populations.
| Tumor response | pMMR | All-comer | ||||
|---|---|---|---|---|---|---|
| Lenvatinib+pembrolizumab (n=66) | TPC (n=68) | Lenvatinib+pembrolizumab (n=77) | TPC (n=78) | |||
| ORR* | ||||||
| % (95% CI) | 36 (25–49) | 22 (13–34) | 39 (28–51) | 21 (12–31) | ||
| BOR* | ||||||
| No. (%) | ||||||
| CR | 6 (9.1) | 3 (4.4) | 9 (11.7) | 4 (5.1) | ||
| PR | 18 (27.3) | 12 (17.6) | 21 (27.3) | 12 (15.4) | ||
| SD | 25 (37.9) | 25 (36.8) | 28 (36.4) | 30 (38.5) | ||
| PD | 17 (25.8) | 22 (32.4) | 18 (23.4) | 24 (30.8) | ||
| Not evaluable† | 0 (0.0) | 1 (1.5) | 0 (0.0) | 1 (1.3) | ||
| No assessment‡ | 0 (0.0) | 5 (7.4) | 1 (1.3) | 7 (9.0) | ||
| DOR (mo) | ||||||
| Median (range) | 14.4 (1.6 to 39.5+) | 5.2 (2.1+ to 37.1+) | 16.5 (1.6 to 39.5+) | 5.2 (1.9+ to 37.1+) | ||
+, no PD by time of last assessment; BOR, best overall response; CR, complete response; DOR, duration of response; ORR, objective response rate; PD, progressive disease; pMMR, mismatch repair proficient; PR, partial response; SD, stable disease; TPC, treatment of physician’s choice chemotherapy.
*Per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review.
†Postbaseline assessment(s) available but not evaluable.
‡No postbaseline assessment available for response evaluation.
3. Safety
All patients experienced ≥1 AE of any grade. AEs occurring in ≥50% of patients included hypertension (66.2%), hypothyroidism (62.3%), and proteinuria (54.5%) in the lenvatinib plus pembrolizumab group and decreased neutrophil count (56.0%) in the TPC group (Table 3). Grade 3 to 5 AEs were experienced by 68 patients (88.3%) in the lenvatinib plus pembrolizumab group and 57 patients (76.0%) in the TPC group. AEs of any grade led to dose reduction in 58 patients (75.3%) in the lenvatinib plus pembrolizumab group (reduction in lenvatinib only) and 10 patients (13.3%) in the TPC group. Treatment-related AEs of any grade were experienced by 75 patients (97.4%) in the lenvatinib plus pembrolizumab group and 72 patients (96.0%) in the TPC group; 57 (74.0%) and 54 (72.0%), respectively, experienced grade 3 to 5 treatment-related AEs (Table S2). Three patients (4.0%) in the TPC group died because of treatment-related AEs (cardiac failure, cardiogenic shock, and toxic cardiomyopathy); there were no deaths due to treatment-related AEs in the lenvatinib plus pembrolizumab group.
Table 3. AEs in all-comer population.
| AE | Lenvatinib+pembrolizumab (n=77) | TPC (n=75) | ||||
|---|---|---|---|---|---|---|
| Any | 77 (100.0) | 75 (100.0) | ||||
| Grade 3–5 | 68 (88.3) | 57 (76.0) | ||||
| Led to dose reduction | 58 (75.3)* | 10 (13.3) | ||||
| Led to dose interruption | 53 (68.8)† | 17 (22.7) | ||||
| Led to discontinuation | 29 (37.7)† | 5 (6.7) | ||||
| Lenvatinib | 28 (36.4) | - | ||||
| Pembrolizumab | 13 (16.9) | - | ||||
| Lenvatinib and pembrolizumab | 7 (9.1) | - | ||||
| Led to death | 1 (1.3) | 4 (5.3) | ||||
| Occurring in ≥25% of patients | Any grade | Grade 3–5 | Any grade | Grade 3–5 | ||
| Hypertension | 51 (66.2) | 23 (29.9) | 0 (0.0) | 0 (0.0) | ||
| Hypothyroidism | 48 (62.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||
| Proteinuria | 42 (54.5) | 9 (11.7) | 7 (9.3) | 1 (1.3) | ||
| Diarrhea | 37 (48.1) | 7 (9.1) | 6 (8.0) | 0 (0.0) | ||
| Decreased appetite | 34 (44.2) | 7 (9.1) | 19 (25.3) | 0 (0.0) | ||
| Nausea | 33 (42.9) | 2 (2.6) | 37 (49.3) | 3 (4.0) | ||
| Palmar-plantar erythrodysesthesia syndrome | 32 (41.6) | 5 (6.5) | 0 (0.0) | 0 (0.0) | ||
| Stomatitis | 31 (40.3) | 2 (2.6) | 23 (30.7) | 0 (0.0) | ||
| Anemia | 29 (37.7) | 9 (11.7) | 31 (41.3) | 13 (17.3) | ||
| Pyrexia | 29 (37.7) | 3 (3.9) | 7 (9.3) | 0 (0.0) | ||
| Decreased platelet count | 28 (36.4) | 9 (11.7) | 8 (10.7) | 1 (1.3) | ||
| Vomiting | 24 (31.2) | 0 (0.0) | 12 (16.0) | 0 (0.0) | ||
| Decreased weight | 21 (27.3) | 9 (11.7) | 2 (2.7) | 0 (0.0) | ||
| Arthralgia | 20 (26.0) | 1 (1.3) | 2 (2.7) | 0 (0.0) | ||
| Malaise | 20 (26.0) | 1 (1.3) | 17 (22.7) | 0 (0.0) | ||
| Increased ALT | 19 (24.7) | 7 (9.1) | 6 (8.0) | 0 (0.0) | ||
| Rash | 19 (24.7) | 0 (0.0) | 5 (6.7) | 0 (0.0) | ||
| Decreased neutrophil count | 15 (19.5) | 8 (10.4) | 42 (56.0) | 38 (50.7) | ||
| Decreased WBC count | 10 (13.0) | 5 (6.5) | 27 (36.0) | 19 (25.3) | ||
| Alopecia | 6 (7.8) | 0 (0.0) | 27 (36.0) | 0 (0.0) | ||
All data are number (%).
AE, adverse event; ALT, alanine aminotransferase; TPC, treatment of physician’s choice chemotherapy; WBC, white blood cell.
*Lenvatinib only.
†Lenvatinib, pembrolizumab, or both.
AEs of interest for pembrolizumab, regardless of attribution to study treatment by the investigators, were experienced by 60 patients (77.9%) in the lenvatinib plus pembrolizumab group and 4 patients (5.3%) in the TPC group (Table S3). All events were grade 1 to 3. Clinically significant AEs of interest for lenvatinib, regardless of attribution to study treatment by the investigators, were experienced by 74 patients (96.1%) in the lenvatinib plus pembrolizumab group and 31 patients (41.3%) in the TPC group (Table S4). In the lenvatinib plus pembrolizumab group, 4 events were grade 4 (2 gastrointestinal perforations; 2 arterial thromboembolic events) and all others were grade 1 to 3. Sixty-one patients (79.2%) in the lenvatinib plus pembrolizumab group had lenvatinib dose reductions; AEs led to the dose reduction in 58 of these patients. The median time to first lenvatinib dose reduction was 1.4 months (range, 0.3–22.8 months; Fig. S1, Table S5). AEs resulted in the discontinuation of lenvatinib in 28 patients (36.4%), pembrolizumab in 13 patients (16.9%), and both lenvatinib and pembrolizumab in 7 patients (9.1%; Table 3).
DISCUSSION
In this exploratory analysis of patients enrolled in East Asia from Study 309/KEYNOTE-775, the combination of lenvatinib plus pembrolizumab provided a clinically meaningful benefit versus TPC in patients with previously treated advanced or recurrent EC. Benefits were seen across all efficacy endpoints, including PFS and OS (primary endpoints) and ORR (secondary endpoint), and in both the pMMR and all-comer populations. The safety profile of lenvatinib plus pembrolizumab was manageable with dose modification and supportive care.
Efficacy results were generally consistent with those of the global study population [12]. Treatment with lenvatinib plus pembrolizumab resulted in similar median PFS and OS in patients enrolled in East Asia (6.7 and 17.7 months, respectively, in pMMR population; 7.2 and 20.6 months, respectively, in all-comer population) versus the global study population (6.7 and 18.0 months, respectively, in pMMR population; 7.3 and 18.7 months, respectively, in all-comer population) [12]. The proportion of patients achieving ORR and median DOR was also similar with lenvatinib plus pembrolizumab in patients enrolled in East Asia compared with the global study population [12]. Similar efficacy findings were also observed between the Japan subgroup and overall population of patients with advanced renal cell carcinoma who received lenvatinib plus pembrolizumab in the phase 3 CLEAR study [16,17]. Median PFS, the primary endpoint, was 22.1 months in the Japan subgroup and 23.9 months in the overall population. OS was not reached in either population, and ORR was 69% and 71%, respectively [16,17].
Safety findings were also generally consistent in this subgroup analysis compared with the global study population [12]. Rates of the most common AEs were similar in both analyses, although within the lenvatinib plus pembrolizumab arm, proteinuria occurred in 55% of patients enrolled in East Asia and 31% of patients in the global study population. The limited sample size of the East Asia subgroup does not allow us to make any definitive conclusions, although similar findings were observed in phase 3 studies involving patients with other cancer types [16,17,18]. In patients with advanced renal cell carcinoma, treatment with lenvatinib plus pembrolizumab led to proteinuria in 55% of patients enrolled in Japan (n = 42) [16] compared with 30% in the global study population (n = 352) [17]. In patients with radioiodine-refractory differentiated thyroid cancer, treatment with lenvatinib alone resulted in proteinuria in 63% of patients enrolled in Japan (n = 30) compared with 31% in the global study population (n = 261) [18]. Although most AEs of proteinuria were grade 1 or 2 across these subgroup analyses, the data could possibly suggest that patients from East Asia may be at increased risk for this known lenvatinib-related AE and may require closer monitoring with dose modification, as appropriate. The reason for a potential increased risk is uncertain but might be due to differences in lenvatinib pharmacokinetics, body weight, or other unknown factors. In our analysis, a slightly greater proportion of patients enrolled in East Asia versus the global study population also required lenvatinib dose reductions (75% vs. 67%) and discontinuations (36% vs. 31%) because of AEs.
Limitations of this exploratory analysis included that it was not powered to determine statistical significance in this population. Additionally, this analysis included the subgroup of patients from Study 309/KEYNOTE-775 enrolled in East Asia (Japan, Republic of Korea, and Taiwan), with the inclusion criterion being geographically specific. Therefore, the generalizability of these results beyond these countries should be approached with caution. The sample size only allowed for analysis of overall trends. The ongoing phase 3 ENGOT-en9/LEAP-001 study is evaluating the combination of lenvatinib plus pembrolizumab versus standard of care chemotherapy (paclitaxel and carboplatin) in the first-line setting in patients with advanced or recurrent EC [19]. The primary endpoints are PFS and OS in both the pMMR and all-comer populations. This global study includes sites in China, Japan, Republic of Korea, and Taiwan and therefore may provide further insights on any potential regional differences in outcomes with lenvatinib plus pembrolizumab [19].
In conclusion, this exploratory analysis of patients enrolled in East Asia with previously treated advanced or recurrent EC suggests that lenvatinib plus pembrolizumab provides clinically meaningful benefit compared with TPC. Both PFS and OS were prolonged, ORR was higher, and DOR was longer with combination therapy in both the pMMR and all-comer populations; these efficacy results were consistent with those of the global population [11]. AEs associated with the combination were generally manageable, and the safety profile was generally consistent with that reported for the global population and the established safety profiles of lenvatinib and pembrolizumab. Taken together with the global results from Study 309/KEYNOTE-775, these findings support the use of lenvatinib plus pembrolizumab in East Asian patients with previously treated advanced or recurrent EC.
ACKNOWLEDGEMENTS
We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. We would also like to thank Gursel Aktan, Gianmaria Barresi, Yusuke Kajimoto, Steve Keefe, Akihito Shito, and Chinyere E. Okpara for their contributions to the study. Medical writing assistance was provided by Kathleen Estes, PhD, and Michael S. McNamara, MS, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Footnotes
Funding: Funding for this research was provided by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Presentation: This research was presented at 2022 European Society for Medical Oncology (ESMO) Asia, December 2–4, 2022 in Singapore.
Conflict of Interest: Kan Yonemori has received lecture fees from Eisai, Pfizer, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR pharma, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), Boeringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, Sanofi, and AstraZeneca; is a member of the advisory board for Eisai, AstraZeneca, Sanofi, Genmab, Gilead, OncXerna, Takeda, Novartis, and MSD; research funding from MSD, Daiichi-Sankyo, Merck Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe; and is principle investigator for MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Merk Biopharma, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe.
Keiichi Fujiwara has received research funding from MSD and Eisai; and honoraria from MSD, Takeda, Seagen, and Genmab.
Kosei Hasegawa has received grants from Daiichi Sankyo, Eisai, MSD, and Takeda; consulting fees from Chugai, Eisai, Takeda, MSD, Roche, Genmab, and Snofi; has received honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai, Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, and Kaken; and support for attending meetings from Regenron.
Kimio Ushijima has received research funding from MSD, AstraZeneca, Chugai, Takeda, and Eisai; and honoraria from AstraZeneca, MSD, and Kyowa Kirin.
Shiro Suzuki has received honoraria from Eisai Co., Ltd, and MSD, K.K.
Ayumi Shikama has received speaker fees from Medtronic Co, Ltd, AstraZeneca K.K., Takeda Pharmaceutical CO., Ltd, Eisai Co., Ltd, Johnson & Johnson, Tiaho Pharmaceutical Co., Ltd, Merck & Co., Inc., and Sanofi S.A. Co., Ltd.
Shinichiro Minobe has received research funding from MSD.
Ting-Chang Chang has received grants from National Science and Technology Council, Taiwan; honoraria from AstraZeneca Taiwan, Merck Sharp & Dohme (I.A.) LLC Taiwan Branch, ACT Genomics, Takeda Pharmaceuticals Taiwan; and is a board member of Taiwan Association of Gynecologic Oncologists, Taiwan Precision Medicine Society, Association of Gynecologic Oncology, ROC, and Taiwan Society of Cancer Registration.
Keiko Yamamoto is employee of MSD K.K., Tokyo, Japan.
Shirong Han is employee of MSD K.K., Tokyo, Japan.
Jodi McKenzie is employee of Eisai Inc., Nutley, NJ, USA.
Robert J. Orlowski is employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and owns stock in Merck & Co., Inc. Rahway, NJ, USA.
Takuma Miura is employee of Eisai Co., Ltd, Tokyo, Japan.
Vicky Makker has received research support (all funding to institution) from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Cullinan, Duality, Eisai, Faeth Therapeutics, Karyopharm Therapeutics, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Takeda, and Zymeworks; and support for attending meetings or travel from AstraZeneca, Eisai, and MSD.
Dr. Makker is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. She has provided unpaid consulting/advisory support to ArQule, AstraZeneca, Clovis Oncology, Cullinan, Duality, Eisai, Faeth Therapeutics, GlaxoSmithKline, IDEAYA, Immunocore, ITeos Therapeutics, Jazz, Kartos Therapeutics, Karyopharm Therapeutics, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Moreo, Morphosys, Novartis, Prelude, Takeda, and Zymeworks.
Yong Man Kim has received research funding from MSD, AstraZeneca, and Zentalis; and honoraria from MSD and Chugai.
Mayu Yunokawa, Tomoka Usami, Jae-Weon Kim, Byoung-Gie Kim, and Peng-Hui Wang have no potential conflict of interest relevant to this article.
Data Sharing Statement: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
- Conceptualization: M.J., O.R.J., M.T.
- Data curation: Y.K., F.K., H.K., U.K., S.S., S.A., M.S., U.T., K.J.W., K.B.G., W.P.H., C.T.C., Y.K., H.S., M.J., O.R.J., M.V., K.Y.M.
- Formal analysis: H.S., M.J., O.R.J.
- Investigation: Y.K., F.K., H.K., Y.M., U.K., S.S., S.A., M.S., U.T., K.J.W., K.B.G., W.P.H., C.T.C., Y.K., M.V., K.Y.M.
- Resources: Y.M., W.P.H.
- Writing - original draft: M.J.
- Writing - review & editing: Y.K., F.K., H.K., Y.M., U.K., S.S., S.A., M.S., U.T., K.J.W., K.B.G., W.P.H., C.T.C., Y.K., H.S., M.J., O.R.J., M.T., M.V., K.Y.M.
SUPPLEMENTARY MATERIALS
Demographics and baseline disease characteristics in pMMR population
Treatment-related AEs in all-comer population
AEs of interest for pembrolizumab in all-comer population*
Clinically significant AEs for lenvatinib in all-comer population*
Summary of lenvatinib dose reductions in all-comer population
Lenvatinib dose reductions in the East Asia subgroup by month in the (A) all-comer population, (B) pMMR population, and (C) dMMR population.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Demographics and baseline disease characteristics in pMMR population
Treatment-related AEs in all-comer population
AEs of interest for pembrolizumab in all-comer population*
Clinically significant AEs for lenvatinib in all-comer population*
Summary of lenvatinib dose reductions in all-comer population
Lenvatinib dose reductions in the East Asia subgroup by month in the (A) all-comer population, (B) pMMR population, and (C) dMMR population.