Efficacy and safety of lenvatinib plus pembrolizumab vs sunitinib in the East Asian subset of patients with advanced renal cell carcinoma from the CLEAR trial

In the CLEAR trial, lenvatinib plus pembrolizumab met study endpoints of superiority vs sunitinib in the first‐line treatment of patients with advanced renal cell carcinoma. We report the efficacy and safety results of the East Asian subset (ie, patients in Japan and the Republic of Korea) from the CLEAR trial. Of 1069 patients randomly assigned to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, 213 (20.0%) were from East Asia. Baseline characteristics of patients in the East Asian subset were generally comparable with those of the global trial population. In the East Asian subset, progression‐free survival was considerably longer with lenvatinib plus pembrolizumab vs sunitinib (median 22.1 vs 11.1 months; HR 0.38; 95% CI: 0.23‐0.62). The HR for overall survival comparing lenvatinib plus pembrolizumab vs sunitinib was 0.71; 95% CI: 0.30‐1.71. The objective response rate was higher with lenvatinib plus pembrolizumab vs sunitinib (65.3% vs 49.2%; odds ratio 2.14; 95% CI: 1.07‐4.28). Dose reductions due to treatment‐emergent adverse events (TEAEs) commonly associated with tyrosine kinase inhibitors occurred more frequently than in the global population. Hand‐foot syndrome was the most frequent any‐grade TEAE with lenvatinib plus pembrolizumab (66.7%) and sunitinib (57.8%), a higher incidence compared to the global population (28.7% and 37.4%, respectively). The most common grade 3 to 5 TEAEs were hypertension with lenvatinib plus pembrolizumab (20%) and decreased platelet count with sunitinib (21.9%). Efficacy and safety for patients in the East Asian subset were generally similar to those of the global population, except as noted.

the Republic of Korea) from the CLEAR trial. Of 1069 patients randomly assigned to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib, 213 (20.0%) were from East Asia. Baseline characteristics of patients in the East Asian subset were generally comparable with those of the global trial population. In the East Asian subset, progression-free survival was considerably longer with lenvatinib plus pembrolizumab vs sunitinib (median 22.1 vs 11.1 months; HR 0.38; 95% CI: 0.23-0.62).
Hand-foot syndrome was the most frequent any-grade TEAE with lenvatinib plus pembrolizumab (66.7%) and sunitinib (57.8%), a higher incidence compared to the global population (28.7% and 37.4%, respectively). The most common grade 3 to 5 TEAEs were hypertension with lenvatinib plus pembrolizumab (20%) and decreased platelet count with sunitinib (21.9%). Efficacy and safety for patients in the East Asian subset were generally similar to those of the global population, except as noted.

What's new?
Despite the emergence of lenvatinib plus pembrolizumab as an effective treatment for renal cell carcinoma (RCC), Asians, among whom RCC incidence is increasing, may exhibit heightened sensitivity to adverse effects from treatment with tyrosine kinase inhibitors. Here, efficacy and safety of lenvatinib plus pembrolizumab were evaluated and compared against that of sunitinib in patients from East Asian sites (Japan and the Republic of Korea) with previously untreated RCC. Similarities in efficacy and safety were observed between patients from East Asian sites and patients from other sites. Moreover, survival and response rates were significantly better with lenvatinib plus pembrolizumab, supporting the use of this therapeutic approach in East Asian populations.

| INTRODUCTION
The highest incidence rates of renal cell carcinoma (RCC) globally are in Europe and North/South America 1,2 ; however, the incidence of RCC is increasing in Asian countries. South Korea and Japan are among the Asian countries with the highest standardized incidence rates (8 and 5.3 per 100 000, respectively). 3,4 The combination of lenvatinib, a multitargeted tyrosine kinase inhibitor, plus pembrolizumab, an immune checkpoint inhibitor, has been approved in the United States, Europe, Japan, South Korea and several other countries for the first-line treatment of adult patients with advanced RCC (aRCC). 5 1.69-2.29). 9 In the global population of the CLEAR trial, the safety profile of lenvatinib plus pembrolizumab was manageable and generally consistent with the established profiles of each monotherapy. 5,9,10 In prior studies of patients who received treatment with tyrosine kinase inhibitors, the incidence rates of certain adverse events (AEs) (eg, hand-foot syndrome, proteinuria) were higher in Asian populations compared to rates observed in non-Asian populations, [11][12][13][14] and in some cases, the efficacy of targeted treatments differed between Japanese and non-Japanese populations. 15,16 Therefore, it is important to continue to evaluate the efficacy and safety of lenvatinib plus pembrolizumab in Asian populations. Here, we report in detail the efficacy and safety results of the patients from East Asian sites (ie, in Japan and the Republic of Korea) from the CLEAR trial for the lenvatinib plus pembrolizumab and sunitinib groups; for completeness, we also briefly report results of the lenvatinib plus everolimus group in Appendix S1.

| Patients
Patients aged 18 years or older who had previously untreated aRCC with a clear-cell carcinoma component, at least one measurable lesion according to RECIST v1.1, and a Karnofsky performance-status score of at least 70 were enrolled in the CLEAR trial. A complete list of study entry criteria has been published previously. 9 This multicenter trial included patients from East Asian sites (in Japan and the Republic of Korea). 9 In our analyses, this subset of patients is referred to as the East Asian subset because the number of East Asian patients from non-East-Asian sites (n = 12; lenvatinib plus pembrolizumab, n = 6; lenvatinib plus everolimus, n = 4; sunitinib, n = 2) was comparatively low and therefore not included.

| Study design and treatments
Study design and selected endpoints have been previously reported. 9 Briefly, patients were randomly assigned (1:1:1) to receive lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib. Randomi Duration of response was a key exploratory endpoint. Further details regarding tumor assessments have been described previously. 9 In this analysis, we examined the efficacy of lenvatinib plus pembrolizumab vs sunitinib by estimating PFS, OS, and ORR; and report safety by incidence of any grade, grade ≥3 and serious treatmentemergent adverse events (TEAEs) in the subset of patients from East Asian sites from the CLEAR trial. The data cutoff date for this subgroup analysis was 28 August 2020 (ie, the data cutoff date of the primary analysis) with a median overall survival follow-up of 26.6 months for the global study population. 9 Results from the primary analysis of the global patient population are included for context.

| Statistical methods
Median PFS and OS were calculated using the Kaplan-Meier method; HRs and 95% CIs were estimated by a stratified Cox model. Odds

| RESULTS
All results discussed are for the approved combination of lenvatinib plus pembrolizumab compared to the active control of sunitinib. For completeness, results for the lenvatinib plus everolimus group are included in the Appendix S1.

| Patients
In the CLEAR trial, 213 (20.0%) of all randomized patients (n = 1069; lenvatinib plus pembrolizumab, n = 355; sunitinib, n = 357) 9 Table 1 and were generally comparable with the global trial population across treatment groups. 9   BMI data was not reported in the primary article for the CLEAR trial. b IMDC prognostic group at baseline was based on total risk score from six prognostic factors at baseline: Karnofsky performance status, hemoglobin, corrected serum calcium, neutrophils, platelets and time from first renal cell cancer diagnosis to randomization. In the global population, the IMDC risk group for two patients in the lenvatinib-plus-pembrolizumab group and four patients in the sunitinib group could not be evaluated. 9 c PD-L1 status was determined using an investigational version of the PD-L1 IHC 22C3 pharmDx (Agilent, Santa Clara, CA) and a provisional CPS, which is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

| Efficacy
F I G U R E 1 Kaplan-Meier plot of progressionfree survival for patients in the East Asian subset of the CLEAR trial. Thirty-three patients in the lenvatinib plus pembrolizumab group and 39 patients in the sunitinib group had events of progressive disease or death during PFS analysis. CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.
odds ratio 2.14; 95% CI: 1.07-4.28; Figure 3). The percentage of patients with complete response was 17.3% with lenvatinib plus pembrolizumab and 7.7% with sunitinib ( Figure 3). High-dose systemic corticosteroids (≥40 mg prednisone daily equivalent) were used to treat AEs of special interest for pembrolizumab in nine (12.0%) patients of the East Asian subset (Table S1), comparable with results from patients in the global trial population. 9,17 The duration of high-dose corticosteroid treatment for AEs of special interest for pembrolizumab was ≥14 days in 2 (2.7%) patients of the East Asian subset (Table S1).
TEAEs, by preferred terms (those with an incidence rate of at Efficacy results for patients in the East Asian subset were generally consistent with those of the global trial population 9  likely attributable to small sample size and lower number of events. 9 The ORR was also improved with lenvatinib plus pembrolizumab vs sunitinib in both the East Asian subset (65.3% vs 49.2%, respectively) and the global population (71.0% vs 36.1%, respectively). 9 Although the ORR observed in the East Asian subset of the sunitinib group was higher relative to that of the global population of the sunitinib group, the odds ratio of 2.14 (95% CI: 1.07-4.28) remains indicative of greater benefit with lenvatinib plus pembrolizumab vs sunitinib. The percentage of patients with progressive disease was lower with lenvatinib plus pembrolizumab vs sunitinib in both populations (East Asian subset: 6.7% vs 12.3%, respectively; global population: 5.4% vs 14.0%, respectively). 9 Data on subsequent therapies in the East Asian subset were generally consistent with data from the global population, 9 with fewer patients in the lenvatinib plus pembrolizumab group receiving PD-1/PD-L1 checkpoint inhibitors as subsequent therapies compared to the sunitinib group.
In a recent publication analyzing the Japanese subgroup from As observed previously in studies involving patients treated with tyrosine kinase inhibitors, the incidence of certain TEAEs (eg, handfoot syndrome, proteinuria) is higher in Asian vs non-Asian populations. [11][12][13][14] In this analysis, hand-foot syndrome was the most frequent any-grade TEAE in both treatment groups (lenvatinib plus pembrolizumab, 66.7%; sunitinib, 57.8%), with a higher incidence than the global population (lenvatinib plus pembrolizumab, 28.7%; sunitinib, 37.4%). 9 The incidence of proteinuria was higher among patients in the East Asian subset treated with lenvatinib plus pembrolizumab (any-grade, 56.0%; grade ≥ 3, 18.7%) compared to the global population (anygrade, 29.5%; grade ≥ 3, 7.7%). 9 Hand-foot syndrome and proteinuria AEs were mostly grade 1 or grade 2 in severity and were generally manageable with study-drug interruption and/or dose reduction The increase in dose reductions seen in the East Asian subset may be attributable to a combination of factors including differences in body mass index, tolerability of AEs and ability to absorb and metabolize the drug between Asian and non-Asian populations. 12,20 A prior study in thyroid cancer concluded that body weight and increased exposure may contribute to some of these differences, but further pharmacokinetic studies are warranted. 20 The variation in the occurrence of certain TEAEs between Asian and non-Asian sites is unlikely due to drug exposure alone, but may be due to variations in tyrosine kinase receptor sensitivity in normal tissue, the cause of which is unknown but possibly related to genetic or environmental factors such as diet or gut microbiota. 21,22 Caution should also be taken in extrapolating the data presented in this analysis to the entire Asian population because the patients included here were only from Japan and the Republic of Korea, and both genetic and nongenetic factors can contribute to differences within Asian populations. 12 Overall, the safety profile of lenvatinib plus pembrolizumab in the East Asian subset of the CLEAR trial was manageable and generally consistent with that of the global trial population. The efficacy of the combination in the East Asian subset was also similar to that in the global trial population. 9 These data support the use