Abstract
Purpose
Adjuvant pembrolizumab improved disease-free survival (DFS) and overall survival (OS) versus placebo in participants with renal cell carcinoma (RCC) at increased risk of recurrence after nephrectomy in the global phase 3 KEYNOTE-564 study. This post hoc subgroup analysis evaluated the efficacy and safety of adjuvant pembrolizumab in East Asian (Japan, South Korea, and Taiwan) participants enrolled in KEYNOTE-564.
Materials and Methods
Eligible participants were randomly assigned 1:1 to receive adjuvant pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≤ 17 cycles. The primary endpoint was DFS by investigator assessment. OS was a key secondary endpoint. Safety was a secondary endpoint.
Results
The East Asian subgroup included 126 participants (pembrolizumab, n=58; placebo, n=68). Median follow-up was 62.1 months (range, 49.6 to 73.0 months). Hazard ratio for DFS with pembrolizumab versus placebo was 0.70 (95% confidence interval 0.41 to 1.20). Median DFS was not reached with pembrolizumab versus 58.8 months with placebo; estimated 48-month rate was 61.3% versus 51.2%. Hazard ratio for OS was 0.47 (95% confidence interval, 0.15 to 1.49). Median OS was not reached with pembrolizumab and placebo; estimated 48-month rate was 94.8% versus 91.2%. Treatment-related adverse events occurred in 70.7% of participants (29.3% grade 3 or 4) receiving pembrolizumab and 36.8% of participants (0.0% grade 3 or 4) receiving placebo. No pembrolizumab-related deaths occurred.
Conclusion
In the KEYNOTE-564 East Asian subgroup, adjuvant pembrolizumab provided DFS and OS benefits versus placebo and had a safety profile consistent with the global results. These results further support pembrolizumab as adjuvant treatment for East Asian patients with RCC at increased risk of recurrence after nephrectomy.
Keywords: Asia, Immunoadjuvant, PD-1 inhibitor, Pembrolizumab, Renal cell carcinoma
Introduction
According to the Pan-Asian adapted European Society for Medical Oncology Clinical Practice Guidelines agreed on by the oncological societies of China (Chinese Society of Clinical Oncology), India (Indian Society of Medical and Pediatric Oncology), Japan (Japanese Society of Medical Oncology), Korea (Korean Society of Medical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology), and Taiwan (Taiwan Oncology Society), the primary treatment for localized renal cell carcinoma (RCC) is surgical resection (partial or radical nephrectomy) [1]. Nearly 50% of patients globally experience disease recurrence after surgery [2], and recurrence most often occurs during the first 5 years after surgery [3]. Adjuvant therapy has been investigated to improve disease-free survival (DFS) and overall survival (OS) in these patients; however, no consensus exists regarding appropriate adjuvant therapy for patients with localized RCC in Asia. A retrospective observational study of Japanese patients showed that those with pT2b-3cN0 RCC derived some benefit from adjuvant immunotherapy with interferon-alpha [4]. Adjuvant radiotherapy also has not shown benefit in past investigations [5], including in a retrospective study of Korean patients with localized clear cell renal cell carcinoma (ccRCC) and recurrent disease following nephrectomy [6]. Although adjuvant sunitinib for the treatment of ccRCC is approved by the U.S. Food and Drug Administration, this approval is not supported by high-level evidence because of concerns about toxicity and a lack of OS benefit, and sunitinib currently is not approved in Europe or Asia in this setting [7]. An effective adjuvant therapy should decrease the likelihood of disease recurrence following nephrectomy while minimizing toxicity; however, until recently, there was no globally approved therapy that met these criteria.
The global phase 3 KEYNOTE-564 study (NCT03142334) investigated the efficacy and safety of adjuvant pembrolizumab monotherapy in participants with RCC at increased risk of recurrence after nephrectomy [8,9]. The primary endpoint was met at the protocol-specified first interim analysis (median follow-up, 24.1 months); pembrolizumab significantly improved DFS versus placebo (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.53 to 0.87; 2-sided p=0.002); however, OS data were immature [8]. The Ministry of Health, Labour and Welfare of Japan as well as the U.S. Food and Drug Administration [10,11] and the European Union’s European Medicines Agency [12] recommended or approved adjuvant pembrolizumab for patients with RCC at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions based on these results [10]. With an additional 6 months of follow-up in KEYNOTE-564, the DFS benefit was maintained with pembrolizumab compared with placebo (HR, 0.63; 95% CI, 0.50 to 0.80) [9]. Pembrolizumab also delayed progression on next-line therapy (progression-free survival 2) versus placebo (HR, 0.57; 95% CI, 0.39 to 0.85) [9]. At the protocol-specified third interim analysis with a median follow-up of 57.2 months, adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in OS versus placebo (HR, 0.62; 95% CI, 0.44 to 0.87; p=0.005) and the DFS benefit remained consistent with that of previous analyses [8,9,13].
The National Comprehensive Cancer Network Guidelines recommend (category 1) adjuvant pembrolizumab in patients with stage 2 ccRCC with grade 4 and/or sarcomatoid features, patients with stage 3 ccRCC, and patients with stage 4 ccRCC after metastasectomy within 1 year of nephrectomy based on the results of KEYNOTE-564 [14]; however, the Pan-Asian adapted European Society for Medical Oncology Guidelines have not reached a consensus regarding adjuvant therapy post-nephrectomy [1]. Determining whether outcomes in the East Asian subgroup of KEYNOTE-564 are consistent with those of the global study population is of interest to further support the use of pembrolizumab monotherapy as adjuvant treatment for East Asian patients with RCC at increased risk of recurrence post-nephrectomy. Here, we report on the efficacy and safety of adjuvant pembrolizumab after a median study follow-up of 62 months in the subgroup of participants enrolled in East Asia in KEYNOTE-564.
Materials and Methods
1. Study design and participants
KEYNOTE-564 is an ongoing, double-blind, randomized, phase 3 study performed at 213 sites globally; details of the study design and eligibility criteria were previously described [8,9,13]. The present subgroup analysis included participants from KEYNOTE-564 who were enrolled at 29 sites in East Asia (Japan, South Korea, and Taiwan). Briefly, eligible participants were adults with histologically confirmed RCC with a clear cell component who had undergone surgery within 12 weeks prior to randomization, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, with no prior systemic therapy for advanced RCC, and with disease-free status per investigator assessment at baseline. Participants were categorized as having intermediate-high risk of disease recurrence (pathological tumor stage 2 [pT2] with nuclear grade 4 or sarcomatoid differentiation, no nodal involvement [N0], and no metastasis [M0]; or pT3, any grade, N0, M0), high risk of disease recurrence (pT4, any grade, N0, M0; or any pT, any grade, N+, M0), or M1 category with no evidence of disease (M1 no evidence of disease [NED]) after complete resection of oligometastatic sites synchronously with nephrectomy or within 1 year of nephrectomy.
The study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All participants provided written informed consent prior to enrollment and could withdraw from the trial at any time for any reason if they or a legally acceptable representative withdrew consent.
2. Treatment and assessments
Treatment randomization was stratified by metastatic stage (M0 vs. M1 NED), and the M0 group was further stratified by ECOG performance status score (0 vs. 1) and United States location (yes vs. no). Participants were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg intravenously every 3 weeks or placebo every 3 weeks for ≤ 17 cycles (approximately 1 year). Imaging assessments of the chest, abdomen, and pelvis were performed using computed tomography (strongly preferred) or magnetic resonance imaging every 12 weeks during years 1 to 2; every 16 weeks during years 3 to 5; and every 24 weeks thereafter until withdrawal of consent, pregnancy, start of new anticancer treatment, disease recurrence, death, or the end of the trial, whichever occurred first. Adverse events (AEs) were recorded through 30 days after the last dose of study treatment (90 days for serious AEs).
The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 was used for AE reporting. Immune-mediated AEs and infusion reactions were reported based on a list of preferred terms intended to capture known risks of pembrolizumab and were considered regardless of attribution to study treatment by the investigator.
3. Outcomes
The primary endpoint was DFS (defined as the time from randomization to the first documented local or distant recurrence of RCC, secondary systemic malignancy, or death from any cause, whichever occurred first) by investigator assessment. Secondary endpoints included OS (defined as the time from randomization to death from any cause) and safety.
4. Statistical analyses
Efficacy analyses were performed in the East Asian intention-to-treat (ITT) population, which included all participants randomly assigned at sites in East Asia. Safety analyses were performed in the all-participants-as-treated (APaT) population, defined as all participants randomly assigned on site in East Asia who received ≥ 1 dose of study treatment. DFS and OS were estimated using the nonparametric Kaplan-Meier method. HRs and 95% CIs were estimated using a Cox proportional hazards model with the Efron method of handling ties, with the treatment group as a covariate. No formal statistical hypothesis testing was performed for this subgroup analysis; data were presented descriptively.
Results
1. Participants
A total of 126 participants (pembrolizumab, n=58; placebo, n=68) were included in the present analysis for both the ITT and APaT populations (12.7% of the global ITT population [n=994]). The East Asian subgroup included 59 participants from Japan, 40 participants from South Korea, and 27 participants from Taiwan. The majority of participants were classified as having M0 intermediate-high risk of recurrence (49 participants [84.5%] in the pembrolizumab group and 62 participants [91.2%] in the placebo group) (Table 1). Most participants had pT3 category disease (53 participants [91.4%] in the pembrolizumab group and 64 participants [94.1%] in the placebo group) and had undergone radical nephrectomy (49 participants [84.5%] in the pembrolizumab group and 58 participants [85.3%] in the placebo group). There were nine participants each in the pembrolizumab (15.5%) and placebo (13.2%) groups with sarcomatoid features. Participant demographics and disease characteristics at baseline were generally balanced across the treatment groups and were consistent with the global population [8]. A greater percentage of participants in the placebo group compared with the pembrolizumab group had tumors with programmed cell death ligand 1 combined positive score of < 1 (25.0% vs. 15.5%) and a grade 2 tumor at baseline (44.1% vs. 34.5%). Overall, 26 participants (44.8%) and 16 participants (23.5%) discontinued treatment in the pembrolizumab and placebo groups, respectively (Fig. 1). The most common reasons for treatment discontinuation were AEs (n=15, 25.9%) and disease relapse (n=8, 13.8%) in the pembrolizumab group and disease relapse in the placebo group (n=14, 20.6%). A total of 32 participants (55.2%) in the pembrolizumab group and 52 participants (76.5%) in the placebo group completed study treatment.
Table 1.
Baseline demographics and characteristics of the East Asian ITT population
| Pembrolizumab (n=58) | Placebo (n=68) | |
|---|---|---|
| Sex | ||
| Male | 43 (74.1) | 47 (69.1) |
| Female | 15 (25.9) | 21 (30.9) |
| Age (yr) | ||
| Median (range) | 61.0 (29-78) | 61.0 (25-82) |
| < 65 | 36 (62.1) | 39 (57.4) |
| ≥ 65 | 22 (37.9) | 29 (42.6) |
| Geographic location | ||
| Japan | 27 (46.6) | 32 (47.1) |
| South Korea | 19 (32.8) | 21 (30.9) |
| Taiwan | 12 (20.7) | 15 (22.1) |
| ECOG PS | ||
| 0 | 57 (98.3) | 63 (92.6) |
| 1 | 1 (1.7) | 5 (7.4) |
| Type of nephrectomy | ||
| Partial | 9 (15.5) | 10 (14.7) |
| Radical | 49 (84.5) | 58 (85.3) |
| PD-L1 statusa) | ||
| CPS < 1 | 9 (15.5) | 17 (25.0) |
| CPS ≥ 1 | 47 (81.0) | 51 (75.0) |
| Missing | 2 (3.4) | 0 |
| Presence of sarcomatoid features | 9 (15.5) | 9 (13.2) |
| Disease risk categoryb) | ||
| M0 intermediate-high risk | 49 (84.5) | 62 (91.2) |
| M0 high risk | 5 (8.6) | 5 (7.4) |
| M1 NED | 4 (6.9) | 1 (1.5) |
| Primary tumor stage | ||
| T1 | 2 (3.4) | 1 (1.5) |
| T2 | 1 (1.7) | 1 (1.5) |
| T3 | 53 (91.4) | 64 (94.1) |
| T4 | 2 (3.4) | 2 (2.9) |
| Tumor grade | ||
| Grade 1 | 0 | 1 (1.5) |
| Grade 2 | 20 (34.5) | 30 (44.1) |
| Grade 3 | 26 (44.8) | 24 (35.3) |
| Grade 4 | 12 (20.7) | 13 (19.1) |
| Lymph node stage | ||
| N0 | 54 (93.1) | 63 (92.6) |
| N1 | 4 (6.9) | 5 (7.4) |
| Metastatic staging | ||
| M0 | 54 (93.1) | 67 (98.5) |
| M1 | 4 (6.9) | 1 (1.5) |
Values are presented as number (%). Percentages may not all sum to 100 due to rounding. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention to treat; M0, no metastasis; N0, no nodal involvement; NED, no evidence of disease; PD-L1, programmed cell death ligand 1; pT, pathological tumor.
PD-L1 CPS was defined as the number of PD-L1–staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100,
M0 intermediate-high risk was defined as pT2 (grade 4 or sarcomatoid), N0, M0; or pT3 (any grade), N0, M0. M0 high risk was defined as pT4, any grade, N0, M0; or any pT, any grade, N+, M0. M1 NED was defined as participants with solid, isolated, soft tissue metastases that were completely resected at the time of nephrectomy (synchronous) or ≤ 1 year from nephrectomy (metachronous) in addition to the primary kidney tumor.
Fig. 1.
Participant disposition in the East Asian intention-to-treat population.
The median time from randomization to the database cutoff date (September 15, 2023) was 62.1 months (range, 49.6 to 73.0 months). The median duration on therapy (defined as the time between the dates of the first and last doses) in the APaT population was 11.0 months (range, 0.0 to 13.8 months) for the pembrolizumab group and 11.1 months (range, 1.4 to 12.5 months) for the placebo group. Among 22 participants with documented disease recurrence in the pembrolizumab group, 17 participants (77.3%) received any subsequent systemic anticancer drug therapy for RCC compared with 25 of 33 participants (75.8%) with documented disease recurrence in the placebo group (S1 Table). Among participants who received any systemic anticancer drug therapy, subsequent vascular endothelial growth factor (receptor) inhibitor therapy was received by 16 of 17 participants (94.1%) in the pembrolizumab group and 22 of 25 participants (88.0%) in the placebo group. In addition, among participants who received any systemic anticancer drug therapy, subsequent programmed cell death protein/ligand 1 inhibitor therapy was received by seven of 17 participants (41.2%) in the pembrolizumab group and 16 of 25 participants (64.0%) in the placebo group (S1 Table).
2. Efficacy
At the data cutoff date, 23 participants (39.7%) in the pembrolizumab group experienced disease recurrence or died (22 recurrences and 1 death without documented recurrence) compared with 34 participants (50.0%) in the placebo group (33 recurrences and 1 death without documented recurrence). The HR for DFS was 0.70 (95% CI, 0.41 to 1.20). The median DFS was not reached (NR) (95% CI, 44.2 months to NR) in the pembrolizumab group and 58.8 months (95% CI, 25.8 months to NR) in the placebo group. Per Kaplan-Meier estimates, the percent of participants alive and disease free at 48 months was 61.3% (95% CI, 46.9 to 72.8) in the pembrolizumab group and 51.2% (95% CI, 38.5 to 62.5) in the placebo group (Fig. 2).
Fig. 2.
Kaplan-Meier estimates of disease-free survival in the East Asian intention-to-treat population. CI, confidence interval; HR, hazard ratio; NR, not reached.
At the data cutoff date, four participants (6.9%) in the pembrolizumab group and 10 participants (14.7%) in the placebo groups had died. The HR for OS was 0.47 (95% CI, 0.15 to 1.49). Median OS was NR in the pembrolizumab group (95% CI, NR to NR) or the placebo group (95% CI, NR to NR). Per Kaplan-Meier estimates, 94.8% (95% CI, 84.8 to 98.3) of participants in the pembrolizumab group and 91.2% (95% CI, 81.4 to 95.9) of participants in the placebo group were alive at 48 months (Fig. 3).
Fig. 3.
Kaplan-Meier estimates of overall survival in the East Asian intention-to-treat population. CI, confidence interval; HR, hazard ratio; NR, not reached.
3. Safety
AEs of any cause occurred in 56 participants (96.6%) in the pembrolizumab group and 61 participants (89.7%) participants in the placebo group (S2 Table). Grade 3 or 4 AEs of any cause occurred in 21 participants (36.2%) in the pembrolizumab group and nine participants (13.2%) in the placebo group. No deaths from AEs occurred.
Treatment-related AEs occurred in 41 participants (70.7%) in the pembrolizumab group and 25 participants (36.8%) in the placebo group (Table 2). The most common treatment-related AEs in the pembrolizumab group were rash (n=13, 22.4%) and fatigue (n=9, 15.5%); in the placebo group, the most common treatment-related AEs were pruritus (n=7, 10.3%) and rash (n=6, 8.8%). Grade 3 or 4 treatment-related AEs occurred in 17 participants (29.3%) in the pembrolizumab group; no grade 3 or 4 treatment-related AEs occurred in the placebo group. Treatment-related AEs led to treatment discontinuation in 13 participants (22.4%) in the pembrolizumab group and no participant (0.0%) in the placebo group.
Table 2.
Treatment-related adverse eventsa) and corresponding grade 3 or 4 eventsb) in the East Asian APaT population
| Pembrolizumab (n=58) |
Placebo (n=68) |
|||
|---|---|---|---|---|
| Any grade | Grade 3 or 4 | Any grade | Grade 3 or 4 | |
| Any | 41 (70.7) | 17 (29.3) | 25 (36.8) | 0 |
| Incidence of ≥ 5% in either treatment group | ||||
| Rash | 13 (22.4) | 1 (1.7) | 6 (8.8) | 0 |
| Fatigue | 9 (15.5) | 0 | 4 (5.9) | 0 |
| Pruritus | 7 (12.1) | 0 | 7 (10.3) | 0 |
| Myalgia | 5 (8.6) | 0 | 2 (2.9) | 0 |
| Adrenal insufficiency | 4 (6.9) | 3 (5.2) | 0 | 0 |
| Hypothyroidism | 4 (6.9) | 0 | 2 (2.9) | 0 |
| Increased alanine aminotransferase level | 4 (6.9) | 0 | 0 | 0 |
| Increased aspartate aminotransferase level | 4 (6.9) | 0 | 0 | 0 |
| Nausea | 4 (6.9) | 0 | 1 (1.5) | 0 |
| Urticaria | 4 (6.9) | 0 | 2 (2.9) | 0 |
| Arthralgia | 3 (5.2) | 0 | 1 (1.5) | 0 |
| Decreased appetite | 3 (5.2) | 0 | 0 | 0 |
| Diarrhea | 3 (5.2) | 1 (1.7) | 2 (2.9) | 0 |
| Dizziness | 3 (5.2) | 0 | 1 (1.5) | 0 |
| Edema | 3 (5.2) | 0 | 1 (1.5) | 0 |
Values are presented as number (%). APaT, all participants as treated.
Determined by the investigator to be related to the drug,
No deaths occurred from a treatment-related adverse event in either group.
Immune-mediated AEs and infusion reactions occurred in 20 participants (34.5%) in the pembrolizumab group, the most common of which were hypothyroidism (n=5, 8.6%) and adrenal insufficiency (n=4, 6.9%). Grade 3 or 4 immune-mediated AEs and infusion reactions occurred in 12 participants (20.7%) in the pembrolizumab group, the most common of which were adrenal insufficiency, pneumonitis, severe skin reactions, and type 1 diabetes mellitus in three participants each (5.2%) (Table 3).
Table 3.
Immune-mediated adverse events and infusion reactions in the East Asian APaT population
| Pembrolizumab (n=58) |
Placebo (n=68) |
|||
|---|---|---|---|---|
| Any grade | Grade 3 or 4 | Any grade | Grade 3 or 4 | |
| Any | 20 (34.5) | 12 (20.7) | 3 (4.4) | 0 |
| Hypothyroidism | 5 (8.6) | 0 | 2 (2.9) | 0 |
| Adrenal insufficiency | 4 (6.9) | 3 (5.2) | 0 | 0 |
| Pneumonitis | 3 (5.2) | 3 (5.2) | 0 | 0 |
| Severe skin reactions | 3 (5.2) | 3 (5.2) | 0 | 0 |
| Type 1 diabetes mellitus | 3 (5.2) | 3 (5.2) | 0 | 0 |
| Hepatitis | 2 (3.4) | 1 (1.7) | 0 | 0 |
| Hyperthyroidism | 2 (3.4) | 0 | 0 | 0 |
| Thyroiditis | 2 (3.4) | 0 | 1 (1.5) | 0 |
| Colitis | 1 (1.7) | 1 (1.7) | 0 | 0 |
| Infusion reaction | 1 (1.7) | 0 | 0 | 0 |
| Myasthenic syndrome | 1 (1.7) | 0 | 0 | 0 |
| Nephritis | 1 (1.7) | 1 (1.7) | 0 | 0 |
| Uveitis | 0 | 0 | 1 (1.5) | 0 |
Values are presented as number (%). APaT, all participants as treated.
Discussion
Adjuvant pembrolizumab monotherapy demonstrated antitumor activity and manageable safety in a global population of participants with RCC at increased risk of recurrence after nephrectomy in the first interim analysis of KEYNOTE-564 at 24 months of follow-up [8]. This initial benefit observed with pembrolizumab continued through updated analyses at 57 months of follow-up [9,13].
In the current analysis, we evaluated whether outcomes in the East Asian subgroup of KEYNOTE-564 are consistent with those of the global participant population. Consistent with the global results of the KEYNOTE-564 study [9,8,13], the HRs for DFS and OS favored pembrolizumab versus placebo in the East Asian participant subgroup. In the global population, 55 participants in the pembrolizumab group and 86 participants in the placebo group had died at the database cutoff date of September 15, 2023, with a significant improvement in OS observed with pembrolizumab versus placebo (HR, 0.62; 95% CI, 0.44 to 0.87; p=0.005) [13]. The safety profile of pembrolizumab was consistent between the East Asian and global populations of KEYNOTE-564, with similar rates of treatment-related AEs (70.7% and 79.1%, respectively) (S2 Table). However, a lower rate of hypothyroidism (6.9% vs. 17.4%) and diarrhea (5.2% vs. 15.8%) was observed in participants treated with pembrolizumab in the East Asian subgroup compared with the overall APaT population (S3 Table) [8,9]. The safety profile of pembrolizumab in this East Asian subgroup was also consistent with the profile of the agent in other studies in Asian participants, with no new safety signals [15]. These results suggest that adjuvant pembrolizumab monotherapy does not present any additional safety risks to East Asian participants than were observed in the global study population.
At present, pembrolizumab is the only adjuvant immunotherapy indicated for the treatment of patients with RCC with an increased risk of recurrence after nephrectomy. To our knowledge, this is the first study focused on the efficacy and safety of adjuvant immunotherapy in an East Asian population. Results from this subgroup analysis show that the efficacy and safety of adjuvant pembrolizumab monotherapy did not appear to be impacted by East Asian ethnicity. However, these results are limited by the post hoc nature of the analysis, the lack of formal hypothesis testing, wide DFS and OS HR 95% CIs, and the small number of participants enrolled in East Asia. Therefore, results should be interpreted with caution.
In conclusion, results from the global KEYNOTE-564 population demonstrated significant improvements in DFS and OS with adjuvant pembrolizumab versus placebo in participants with RCC at an increased risk of recurrence following nephrectomy. Consistent with the global results, DFS and OS favored adjuvant pembrolizumab over placebo in the KEYNOTE-564 East Asian subgroup. Additionally, adjuvant pembrolizumab had a safety profile consistent with the global KEYNOTE-564 population. These results further support the use of pembrolizumab as adjuvant treatment for East Asian patients with RCC at increased risk of recurrence following nephrectomy. These findings should be considered when updating regional treatment guidelines for patients with RCC in East Asia.
Footnotes
Ethical Statement
The study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards (the SMC IRB 2017-03-099; Samsung Medical Center, Sungkyunkwan University School of Medicine) and regulatory agencies. All participants provided written informed consent prior to enrollment and could withdraw from the trial at any time for any reason if they or a legally acceptable representative withdrew consent.
Author Contributions
Conceived and designed the analysis: Park SH, Choueiri TK, Elfiky A.
Collected the data: Park SH, Chang YH, Lee JL, Choueiri TK, Kimura G, Chung J, Lin J, Elfiky A, Burgents JE.
Contributed data or analysis tools: Park SH, Chang YH, Lee JL, Kimura G, Chung J, Masumori N, Nishimura K, Kato M, Numakura K, Chang CH, Anai S, Tsunemori H, Chen CH, Lin J, Burgents JE, Kitamura H.
Performed the analysis: Park SH, Lin J, Burgents JE.
Wrote the paper: Park SH, Chang YH, Lee JL, Choueiri TK, Kimura G, Chung J, Masumori N, Nishimura K, Kato M, Kato H, Numakura K, Chang CH, Anai S, Tsunemori H, Chen CH, Lin J, Elfiky A, Burgents JE, Kitamura H.
Acknowledgments
This study and assistance with manuscript development were funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The authors thank the participants, their families, and caregivers for their involvement in this trial and all investigators and site personnel. The authors also thank Christian H. Poehlein (Merck & Co., Inc., Rahway, NJ, USA) for study design support; Megan Brasch, Scott Chambers, Veronica Burdusel, Michelle Smith, and Karen A. Muldowney (Merck & Co., Inc., Rahway, NJ, USA) for study support; Lei Xu, Sabrina Wan, and Christine Gause (Merck & Co., Inc., Rahway, NJ, USA) for statistical support; Rodolfo F. Perini, Kentaro Imai, Scot W. Ebbinghaus, and S. Peter Kang (Merck & Co., Inc., Rahway, NJ, USA) for study support and critical review; and Shane Walton, PhD, Obinna T. Ezeokoli, PhD, and Robert Steger, PhD, of ApotheCom (Yardley, PA, USA) for medical writing assistance.
Conflict of Interest
Jae Lyun Lee owns stock in Amgen, Black Diamond Therapeutics, Innovent Biologics, Johnson & Johnson, Karyopharm Therapeutics, Merck & Co, Inc., and Zymeworks; has received honoraria from AstraZeneca, Bristol Myers Squibb, MSD Korea, and Novartis Korea; and has received research funding from Amgen, Arcus Biosciences, AstraZeneca, Bayer Schering Pharma, Boryung, Bristol Myers Squibb, Eutilex, GI Innovation, Ipsen, Janssen, Loxo, Merck & Co, Inc., MSD, Novartis, Pfizer, Roche/Genentech, Samjin, Seagen, and Oscotec. Toni K. Choueiri reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria in the past 5 years, ongoing or not, from Alkermes, Arcus Biosciences, AstraZeneca, Aravive, Aveo, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Calithera Biosciences, Circle Pharma, Deciphera Pharmaceuticals, Eisai, Eli Lilly and Company, EMD Serono, Exelixis, Gilead, GlaxoSmithKline, HiberCell, IQVIA, Infinity, Ipsen, Janssen, Kanaph Therapeutics, L’institut Servier, Merck & Co, Inc., Neomorph, Nikang Therapeutics, Novartis, Nuscan/PrecedeBio, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, UpToDate, and continuing medical education events (Clinical Care Options, MJH Life Sciences, OncLive, Peerview, and others), outside the submitted work; institutional patents filed on molecular alterations and immunotherapy response/toxicity, and circulating tumor DNA; equity: Bicycle, CureResponse, InnDura Therapeutics, Osel, Pionyr Immunotherapeutics, PrecedeBio, Primium, and Tempest; committees: Academic and Community Cancer Research United, European Society for Medical Oncology, KidneyCAN, the American Society of Clinical Oncology (BOD 6-2024), the National Cancer Institute Genitourinary Cancers Steering Committee, and the National Comprehensive Cancer Network; medical writing and editorial assistance support may have been funded by communications companies in part; mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; and support in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DanaFarber Cancer Institute. Go Kimura has received lecture fees or honoraria from Astellas, Bayer, Bristol Myers Squibb, Eisai, Janssen, Kissei Pharmaceutical, Merck Biopharma, MSD, ONO Pharmaceutical, and Takeda. Naoya Masumori has received lecture fees or honoraria from ONO Pharmaceutical and Takeda and has received research funding from MSD. Kazuo Nishimura has received honoraria from Merck Biopharma and MSD. Minoru Kato reports an advisory role and has received lecture fees from Merck KGaA and MSD. Jianxin Lin, Aymen Elfiky, and Joseph E Burgents are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA.
Hiroshi Kitamura reports employment, leadership position, or advisory role for MSD, Astellas, Bristol Myers Squibb, and Merck Biopharma; honoraria from Astellas, Bristol Myers Squibb, Merck Biopharma and MSD; and research funding from Bristol Myers Squibb and MSD.
Se Hoon Park, Yen-Hwa Chang, Jinsoo Chung, Haruaki Kato, Kazuyuki Numakura, Chao-Hsiang Chang, Satoshi Anai, Hiroyuki Tsunemori, and Chung-Hsin Chen declare no conflicts of interest.
Funding
This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Data Availability 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: https://externaldatasharing-msd.com/) 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 United States and the European Union 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 f ile with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
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Associated Data
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