RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis

Background RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. Methods RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Results Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0–85.3) for Asian patients and 74.7% (95% CI 63.6–83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%). Conclusions This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small patient numbers in some subpopulations. Trial registration Everolimus as Second-line Therapy in Metastatic Renal Cell. Carcinoma (RECORD-4); ClinicalTrials.gov identifier: NCT01491672. Registration date: December 14, 2011. Electronic supplementary material The online version of this article (10.1186/s12885-018-4091-5) contains supplementary material, which is available to authorized users.


Background
Everolimus, a mammalian target of rapamycin inhibitor, is a second-line treatment option for patients with metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor (VEGF) receptor inhibitors [1,2]. Approval of everolimus was based on results of the phase 3 RECORD-1 study of patients who had previously received sunitinib, sorafenib, or both [3]. The phase 2 RECORD-4 study was subsequently designed to assess everolimus as a purely second-line therapy in patients with mRCC [4]. Because 41% of RECORD-4 patients were from China, and some differences in responses to certain targeted agents between Chinese and Western patients have been reported [5], this subanalysis evaluated outcomes in Asian patients compared with non-Asian patients.

Patients
In the Asian (n = 55) and non-Asian (n = 79) populations, respectively, 98% and 84% had good/intermediate Memorial Sloan Kettering Cancer Center (MSKCC) prognosis, 73% and 65% were men, and 85% and 73% were < 65 years of age (Additional file 1: Table S1). Median duration of exposure was 5.5 and 6.0 months for Asian and non-Asian patients, respectively.

Discussion
There have been some reported differences in responses to certain targeted agents between Chinese and Western patients with RCC [5]. However, our findings support the comparable efficacy of everolimus in Asian and non-Asian patients with RCC. In this RECORD-4 subanalysis of second-line everolimus, median PFS was 7.4 and 7.8 months in Asian and non-Asian patients, respectively, and the clinical benefit rate was 75% in both patient populations. These findings suggest that secondline everolimus has comparable efficacy in Asian and non-Asian patients with RCC. These results are supported by a phase 1b study of everolimus in 64 Chinese mRCC patients who were intolerant to, or progressed on, prior VEGFR-TKI therapy, in which median PFS was 6.9 months and the clinical benefit rate was 66% [6].
Median PFS was comparatively shorter (4.9 months) in the pivotal phase 3 RECORD-1 trial of everolimus in VEGFR-TKI pretreated mRCC patients from centers across Australia, Canada, Europe, the USA, and Japan [3]. However, patients in RECORD-1 were more heavily pretreated, having received a median of 2 prior antineoplastic therapies, and had a poorer risk profile per MSKCC criteria, which may negatively affect outcomes in RECORD-1 compared with RECORD-4 [3,4].
Five targeted drugs (pazopanib, everolimus, axitinib, sorafenib, and sunitinib) are currently approved for the treatment of advanced RCC in China, and everolimus and axitinib carry the highest level of evidence for second-line treatment after failure of first-line TKI in Chinese and Asia consensus treatment guidelines [7][8][9]. Thus, results of our study are important to physicians who treat these populations of patients, and support the use of everolimus following progression on first-line TKI therapy in Asian patients with mRCC. It is important that outcomes by prior therapy should be interpreted with caution because of the small patient numbers in some subpopulations.

Conclusions
In conclusion, second-line everolimus had comparable efficacy and safety in Asian and non-Asian patients with mRCC.

Additional files
Additional files 1: Table