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Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)

Open AccessPublished:November 30, 2022DOI:https://doi.org/10.1016/j.ejca.2022.10.025

      Highlights

      • The combination of vorolanib and everolimus showed promising efficacy.
      • Vorolanib plus everolimus was well-tolerated with manageable safety profile.
      • This study provided a new option for previously treated patients with metastatic renal cell carcinoma.

      Abstract

      Background

      Vorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC).

      Patients and methods

      Patients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1.

      Results

      Between 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively.

      Conclusions

      The addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile.

      Trial registration

      ClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

      Keywords

      1. Introduction

      Renal cell carcinoma (RCC) accounts for approximately 85% of kidney cancers [
      • Barata P.C.
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      Treatment of renal cell carcinoma: current status and future directions.
      ]. Recently, immune-based combinations have become the standard of care as front-line therapy in patients with metastatic RCC (mRCC) [
      • Motzer R.J.
      • Tannir N.M.
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      Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
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      Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.
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      • Rini B.I.
      • Plimack E.R.
      • Stus V.
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      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
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      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426.
      ,
      • Motzer R.
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      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ,
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      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
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      • Burotto M.
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      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Powles T.
      • Atkins M.B.
      • et al.
      Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma.
      ]. Notwithstanding, tyrosine kinase inhibitor (TKI) monotherapy is still used in clinical practice as a first-line therapy for patients with selected mRCC [
      National Comprehensive Cancer Network [Internet]
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      ,
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger.
      ]. These subpopulations include patients with favourable risk factors or a low tumour burden, patients with specific comorbidities (i.e. concomitant autoimmune diseases) or those who may benefit from avoiding periodic access to the hospital for intravenous administration (as in the case of the ongoing severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] pandemic). Furthermore, immune combinations as first-line treatment for mRCC are only approved in some countries only. Vascular endothelial growth factor receptor (VEGFR)-TKIs remain a recommended option as first-line therapy in China.
      Single agents, such as everolimus, other TKIs or PD-1 inhibitors, showed limited benefit with a median progression-free survival (PFS) of 4.0–7.4 months when served as the standardised second-line therapy after patients with mRCC failed to respond to VEGFR-TKIs [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      ,
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Rini B.I.
      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      ]. Increasing evidence suggests that combination therapy may result in a relevant clinical benefit and represent a trend in the second-line treatment of mRCC [
      • Wiele A.J.
      • Ross J.
      • Chahoud J.
      • et al.
      964P-Lenvatinib (Len) alone or in combination with everolimus (Eve) in heavily pretreated patients (pts) with metastatic renal cell carcinoma (mRCC) after immune checkpoint inhibitors (ICI) and VEGFR-targeted therapies: a single-institution experience.
      ,
      • Motzer R.J.
      • Hutson T.E.
      • Glen H.
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      ,
      • Lee C.H.
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      • et al.
      Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC).
      ]. However, these studies were phase 2 studies. Cabozantinib or axitinib is still the standard of care for patients who fail first-line therapy with VEGFR-TKIs. Additionally, for patients with RCC who are considered to have a favourable risk, VEGFR-TKIs are an important treatment option.
      Vorolanib shows a strong inhibitory activity against VEGFR2 (KDR), platelet-derived growth factor receptor-β, rearranged during transfection and stem cell factor receptor [
      • Liang C.
      • Yuan X.
      • Shen Z.
      • et al.
      Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity.
      ]. In a phase 1 study, vorolanib plus everolimus had a promising therapeutic effect with a median PFS of 10.2 months under the recommended dose among patients treated with only one prior VEGFR-TKI [
      • Sheng X.
      • Yan X.
      • Chi Z.
      • et al.
      Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma.
      ,
      • Moore K.N.
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      • Kurkjian C.
      • et al.
      Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) x-82 in patients (pts) with advanced solid tumors.
      ]. Based on these findings, we implemented a randomised, double-blind, three-arm, phase 3, registered study in late 2016 to evaluate the efficacy and safety of vorolanib plus everolimus versus monotherapies as second-line treatment in patients with mRCC.

      2. Patients and methods

      2.1 Study design and participants

      This is a randomised, double-blind, multicentre phase 3 study conducted at 36 centres in China. Eligible patients were 18–75 years of age and diagnosed with advanced or mRCC with a clear-cell component confirmed by histology or cytology. All patients must have experienced disease progression after one previous treatment with a VEGFR-TKI. Eligible patients were required to have an Eastern Cooperative Oncology Group performance status score of 0–1, a life expectancy of more than 3 months, adequate haematologic, hepatic and renal function, and measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Patients with brain metastases and those who received any anticancer treatment or major surgery within 4 weeks before the first dose of the study drug were excluded.
      The study was approved by the institutional ethics committees and followed the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all patients.

      2.2 Procedures

      The patients were characterised and stratified according to the Memorial Sloan-Kettering Cancer Centre (MSKCC) prognostic risk score (favourable [score of 0], intermediate [score of 1 or 2] or poor [score of 3–6]) [
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • et al.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      ]. The patients were randomised at a 1:1:1 ratio to orally receive vorolanib (200 mg/day) plus everolimus (5 mg/day), vorolanib (200 mg/day) plus placebo or everolimus (10 mg/day) plus placebo in 28-day continuous cycles until disease progression, death, unacceptable toxicity or withdrawal of consent. Dose reduction was not allowed due to the double-blind nature of the trial, while dose interruption (no more than 28 days) was allowed for the management of toxicity. Crossover between treatment groups was not allowed.
      Tumour response was assessed at baseline and week 4 and then every 8 weeks by the investigator and independent review committee (IRC) per RECIST version 1.1. Adverse events were assessed by the investigators and graded according to the Common Terminology Criteria for Adverse Events (version 4.03).

      2.3 Outcomes

      The primary end-point was PFS assessed by the IRC. The secondary end-points included overall survival (OS), objective response rate (ORR) and safety. PFS was defined as the time from the date of randomisation to the date of the first documentation of disease progression (according to RECIST version 1.1) or death. OS was defined as the time from the date of randomisation to the date of death from any cause. The ORR was defined as the proportion of patients with a best overall response of complete or partial response.

      2.4 Statistical analysis

      We designed the study to have 85% power to detect a statistically significant difference in PFS at a two-sided α level of 0.05 based on the primary comparison between the vorolanib plus everolimus arm (or single-agent vorolanib) and single-agent everolimus arm, assuming median PFS times of 6.5 months for everolimus and 10.5 months for each vorolanib-containing arm. For the primary analysis, we needed 231 progression events or deaths in a total of 384 patients for the three arms.
      PFS analysis was based on a stratified log-rank test at a two-sided α level of 0.05, with the MSKCC score as the stratification factor. The Kaplan–Meier method was used to estimate the median PFS for each treatment group with 95% confidence intervals (CIs). Hazard ratios (HRs) and 95% CIs were estimated using the stratified Cox proportional hazards regression model. There was no interim analysis for PFS. A fixed-sequence statistical strategy was used for multiplicity correction. PFS was compared between the vorolanib arm and everolimus arm only after the vorolanib plus everolimus arm and everolimus arm were positive.
      As of 30th April 2020, the number of events for disease progression or death triggered the final PFS analysis. Statistics analysis system (SAS) version 9.4 and power analysis and sample size (PASS) version 14.0 software were used.
      This study is registered with ClinicalTrials.gov (NCT03095040) and chinadrugtrials.org.cn (CTR20160987).

      3. Results

      3.1 Patient characteristics

      From 10th March 2017 to 30th May 2019, 513 patients were screened, of whom, 399 patients (133 patients in each group) were randomised. All patients received at least one dose of the study treatment and composed the efficacy and safety population (Fig. 1). At the cut-off date, 164 patients had died, while 56 patients remained on the study treatment. The baseline characteristics were generally similar across the treatment groups (Table 1).
      Fig. 1
      Fig. 1Trial flowchart. The data cutoff was 23rd October 2020.
      Table 1Baseline characteristics (ITT population).
      Vorolanib plus everolimus (n = 133)Vorolanib (n = 133)Everolimus (n = 133)
      Age (median, range)58.0 (30–74)59.0 (28–74)59.0 (35–74)
       <65 years103 (77.4%)101(75.9%)99 (74.4%)
       ≥65 years30 (22.6%)32(24.1%)34 (25.6%)
      Sex
       Male102 (76.7%)107 (80.5%)103 (77.4%)
       Female31 (23.3%)26 (19.5%)30 (22.6%)
      ECOG performance status score
       050 (37.6%)62 (46.6%)67 (50.4%)
       183 (62.4%)71 (53.4%)66 (49.6%)
      MSKCC prognostic risk category
       Favourable30 (22.6%)33 (24.8%)36 (27.1%)
       Intermediate94 (70.7%)91 (68.4%)89 (66.9%)
       Poor8 (6.0%)9 (6.8%)8 (6.0%)
      Metastatic site
       Lung95 (71.4%)99 (74.4%)105 (78.9%)
       Bone50 (37.6%)52 (39.1%)48 (36.1%)
       Lymph node62 (46.6%)71 (53.4%)61 (45.9%)
       Liver24 (18.0%)26 (19.5%)26 (19.5%)
      Previous VEGFR-targeted therapy
       Sunitinib41 (30.8%)44 (33.1%)43 (32.3%)
       Sorafenib67 (50.4%)66 (49.6%)67 (50.4%)
       Pazopanib5 (3.8%)6 (4.5%)5 (3.8%)
       Other20 (15.0%)17 (12.8%)18 (13.5%)
      Best response by previous VEGFR-targeted therapy
       CR/PR12 (9.0%)19 (14.3%)17 (12.8%)
       SD/PD59 (44.4%)52 (39.1%)48 (36.1%)
       Unknown62 (46.6%)62 (46.6%)68 (51.1%)
      PFS of previous VEGFR-targeted therapy
       <12 months47 (35.3%)52 (39.1%)52 (39.1%)
       ≥12 months45 (33.8%)40 (30.1%)39 (29.3%)
       UK41 (30.8%)41 (30.8%)42 (31.6%)
      Visceral metastasis
       No8 (6.8%)7 (5.3%)6 (6.0%)
       Yes125 (93.2%)126 (94.7%)127 (94.0%)
      Data are the number of patients (%) or the median (range). ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center; ITT, intention-to-treat.

      3.2 Efficacy

      At the data cut-off, 270 PFS events were recorded. The median follow-up durations were 22.1 months (95% CI, 18.7–23.5), 21.5 months (95% CI, 20.1–23.3) and 21.9 months (95% CI, 19.8–23.5) for the vorolanib plus everolimus, single-agent vorolanib and single-agent everolimus groups, respectively. The median PFS times were 10.0 months (95% CI, 8.2–10.4) for vorolanib plus everolimus, 6.4 months (95% CI, 4.6–8.3) for single-agent vorolanib and 6.4 months (95% CI, 4.7–8.3) for single-agent everolimus (Table 2; Fig. 2A). The combination of vorolanib plus everolimus demonstrated a significantly prolonged PFS compared with single-agent everolimus (HR, 0.70; 95% CI, 0.52–0.94; P = 0.0171) and a longer but not significant median PFS than single-agent vorolanib (HR, 0.76; 95% CI, 0.56–1.03; P = 0.0738). The median PFS of patients treated with single-agent vorolanib was similar to that of patients treated with single-agent everolimus (HR, 0.94; 95% CI, 0.70–1.26; P = 0.6856). The results were similar to the investigator-assessed PFS (vorolanib plus everolimus versus single-agent everolimus, 9.3 months [95% CI, 8.1–10.1] versus 6.4 months [95% CI, 4.6–6.6]; HR, 0.70; 95% CI, 0.53–0.93; P = 0.0138; single-agent vorolanib versus single-agent everolimus, 6.5 months [95% CI, 4.6–8.2] versus 6.4 months [95% CI, 4.6–6.6]; HR, 0.92; 95% CI, 0.70–1.22; P = 0.5552) (Fig. 2B).
      Table 2Efficacy outcomes (ITT population).
      Vorolanib plus everolimus (n = 133)Vorolanib (n = 133)Everolimus (n = 133)
      Progression-free survival
      Events (%)82 (61.7%)92 (69.2%)96 (72.2%)
      Median PFS (months)

      (95% CI)
      10.0 (8.2–10.4)6.4 (4.6–8.3)6.4 (4.7–8.3)
      Overall survival
      Events (%)54 (40.6%)54 (40.6%)56 (42.1%)
      Median OS (months)

      (95% CI)
      30.4 (16.5–NE)30.5 (22.8–NE)25.4 (19.1–NE)
      Objective response
      Complete response0 (0)0 (0)0 (0)
      Partial response33 (24.8%)14 (10.5%)11 (8.3%)
      Stable disease79 (59.4%)75 (56.4%)88 (66.2%)
      Progressive disease9 (6.8%)29 (21.8%)24 (18.0%)
      Not assessed12 (9.0%)15 (11.3%)10 (7.5%)
      ORR (95% CI)24.8 (17.7–33.0)10.5 (5.9–17.0)8.3 (4.2–14.3)
      DCR (95% CI)84.2 (76.9–90.0)66.9 (58.2–74.8)74.4 (66.2–81.6)
      Data are numbers (%). NE denotes could not be estimated. PFS, progression-free survival; OS, overall survival; ORR, objective response rate; DCR, disease control rate.
      Fig. 2
      Fig. 2Kaplan–Meier estimate of progression-free survival and subgroup analysis. Panels A and B show the Kaplan–Meier curves for progression-free survival in each treatment group assessed by an independent review committee and investigator. Panel C shows the analysis of progression-free survival in subgroups of patients in the vorolanib plus everolimus arm versus single-agent everolimus arm. Panel D shows the analysis of progression-free survival in subgroups of patients in the single-agent vorolanib arm versus the single-agent everolimus arm. Tick marks indicate censored data. The subgroup of patients without visceral metastasis was not presented due to the small simple size.
      A consistent PFS benefit from vorolanib plus everolimus over single-agent everolimus was evident across the relevant subgroups, including Eastern Cooperative Oncology Group performance status score, sex, age, MSKCC risk score, bone metastasis and PFS from first-line VEGFR inhibitor subgroups (Fig. 2C). PFS did not differ between patients who received single-agent vorolanib and those who received single-agent everolimus (Fig. 2D).
      At the data cut-off, 164 deaths (41.1%) occurred. As the OS data were not mature, no significant difference was found for the estimated OS either between the vorolanib plus everolimus group and the single-agent everolimus group (HR, 0.94; 95% CI, 0.64–1.37; P = 0.7369; Fig. 3) or between the single-agent vorolanib group and the single-agent everolimus group (HR, 0.92; 95% CI, 0.63–1.34; P = 0.6646). The median OS times were 30.4 months (95% CI, 16.5-NE) for vorolanib plus everolimus, 30.5 months (22.8-NE) for single-agent vorolanib, and 25.4 months (19.1-NE) for single-agent everolimus (Table 2). A total of 239 (59.9%) patients received subsequent anticancer therapies. The most common subsequent anticancer therapies were VEGFR inhibitors, followed by anti-PD-1/PD-L1 antibodies (Supplementary Table S1). Survival follow-up is continuing.
      Fig. 3
      Fig. 3Kaplan–Meier estimate of overall survival. Tick marks indicate censored data. NE denotes could not be estimated.
      A significantly higher ORR was observed in the vorolanib plus everolimus group (24.8%, 33/133) than in the everolimus group (8.3%, 11/133) (P = 0.0003), whereas no significant difference in ORR was observed between the vorolanib group (10.5%, 14/133) and the everolimus group (P = 0.5278). The median durations of response were 11.1 months (95% CI, 5.6–12.9), 13.3 months (3.8–22.1) and 10.9 months (1.8-NE) in the three respective groups (Supplementary Table S2). Considering that patients in the favourable risk group are now the main beneficiaries of first-line VEGF-TKIs, we performed a post hoc analysis on the responders in this subgroup. A total of 11/30, 4/33 and 4/36 patients responded in the combination arm, vorolanib arm and everolimus arm, respectively, with ORRs of 36.7%, 12.1% and 11.1%. The baseline characteristics of these patients are summarised in Supplementary Table S3.

      3.3 Safety

      The median durations of treatment were 33.0 weeks (interquartile range, 16.1–54.7) for the combination group, 28.1 weeks (12.0–52.1) for the single-agent vorolanib group and 28.0 weeks (12.1–52.0) for the single-agent everolimus group. Fifteen (11.3%) patients from the combination group, 7 (5.3%) patients from the single-agent vorolanib group and 19 (14.3%) patients from the single-agent everolimus group discontinued the study treatment due to drug-related adverse events. Dose interruptions due to drug-related adverse events were observed in 59 (44.4%), 11 (8.3%) and 37 (27.8%) patients in the three respective groups.
      The overall incidence rates of treatment-related adverse events (TRAEs) were 99.2%, 95.5% and 98.5% in the three respective groups. Grade 3 or higher TRAEs occurred less frequently in the single-agent vorolanib group (52 [39.1%]) than in the single-agent everolimus group (71 [53.4%]) or the vorolanib plus everolimus combination group (96 [72.2%]). The most common TRAEs in the combination group were proteinuria, anaemia, leukopenia, hair colour changes and thrombocytopaenia (Table 3). The frequency of hair colour changes was high in the vorolanib-containing groups. The most common grade 3 or higher TRAEs were anaemia and proteinuria in the combination group; hair colour changes and leukopenia in the single-agent vorolanib group; anaemia in the single-agent everolimus group. TRAE-related death occurred in 5 patients in the combination group, 4 in the vorolanib group and 3 in the everolimus group.
      Table 3Treatment-related adverse events (safety set population).
      Vorolanib plus everolimus (n = 133)Vorolanib (n = 133)Everolimus (n = 133)
      Any gradeGrade ≥3Any gradeGrade ≥3Any gradeGrade ≥3
      Hair colour changes68 (51.1)064 (48.1)08 (6.0)0
      Diarrhoea53 (39.8)8 (6.0)35 (26.3)3 (2.3)20 (15.0)0
      Oral ulcer44 (33.1)2 (1.5)7 (5.3)046 (34.6)5 (3.8)
      Facial oedema43 (32.3)06 (4.5)06 (4.5)0
      Weight loss41 (30.8)2 (1.5)15 (11.3)1 (0.8)36 (27.1)1 (0.8)
      Fatigue37 (27.8)1 (0.8)24 (18.0)028 (21.1)1 (0.8)
      Peripheral oedema37 (27.8)1 (0.8)16 (12.0)016 (12.0)0
      Oral mucositis27 (20.3)2 (1.5)8 (6.0)027 (20.3)1 (0.8)
      Hypertension25 (18.8)6 (4.5)22 (16.5)6 (4.5)21 (15.8)3 (2.3)
      Cough22 (16.5)017 (12.8)022 (16.5)1 (0.8)
      Elevated blood pressure20 (15.0)4 (3.0)17 (12.8)3 (2.3)16 (12.0)3 (2.3)
      Rash19 (14.3)08 (6.0)1 (0.8)21 (15.8)0
      Decreased appetite18 (13.5)015 (11.3)1 (0.8)21 (15.8)1 (0.8)
      Pulmonary inflammation16 (12.0)2 (1.5)4 (3.0)010 (7.5)3 (2.3)
      Eyelid oedema16 (12.0)014 (10.5)1 (0.8)7 (5.3)0
      Taste disorders16 (12.0)05 (3.8)000
      Nausea14 (10.5)010 (7.5)013 (9.8)1 (0.8)
      Laboratory abnormality
       Proteinuria77 (57.9)13 (9.8)43 (32.3)4 (3.0)52 (39.1)6 (4.5)
       Anaemia77 (57.9)20 (15.0)28 (21.1)5 (3.8)77 (57.9)22 (16.5)
       Leukopenia74 (55.6)8 (6.0)53 (39.8)028 (21.1)0
       Thrombocytopaenia67 (50.4)1 (0.8)19 (14.3)1 (0.8)22 (16.5)0
       Neutropenia63 (47.4)14 (10.5)36 (27.1)2 (1.5)11 (8.3)0
       Elevated AST44 (33.1)2 (1.5)31 (23.3)1 (0.8)35 (26.3)0
       Hypertriglyceridemia42 (31.6)8 (6.0)23 (17.3)6 (4.5)41 (30.8)9 (6.8)
       Elevated blood triglycerides39 (29.3)10 (7.5)19 (14.3)4 (3.0)29 (21.8)7 (5.3)
       Elevated blood cholesterol38 (28.6)1 (0.8)9 (6.8)028 (21.1)0
       Hypercholesterolaemia34 (25.6)013 (9.8)2 (1.5)38 (28.6)1 (0.8)
       Elevated serum creatinine30 (22.6)020 (15.0)1 (0.8)37 (27.8)3 (2.3)
       Elevated ALT27 (20.3)1 (0.8)31 (23.3)2 (1.5)33 (24.8)0
       Detected urinary protein26 (19.5)10 (7.5)14 (10.5)3 (2.3)18 (13.5)1 (0.8)
       Hypokalaemia24 (18.0)11 (8.3)3 (2.3)012 (9.0)3 (2.3)
       Elevated LDL19 (14.3)04 (3.0)012 (9.0)0
       Hypoalbuminaemia19 (14.3)012 (9.0)3 (2.3)15 (11.3)1 (0.8)
       Elevated blood glucose18 (13.5)1 (0.8)13 (9.8)022 (16.5)2 (1.5)
       Hyperglycaemia18 (13.5)2 (1.5)8 (6.0)1 (0.8)30 (22.6)3 (2.3)
       Elevated CPK18 (13.5)2 (1.5)11 (8.3)07 (5.3)1 (0.8)
       Elevated GGT17 (12.8)3 (2.3)10 (7.5)2 (1.5)34 (25.6)4 (3.0)
       Hypophosphatemia17 (12.8)5 (3.8)7 (5.3)1 (0.8)13 (9.8)4 (3.0)
       Elevated LDH15 (11.3)3(2.3)4 (3.0)2(1.5)9 (6.8)4(3.0)
       Lymphocytopenia15 (11.3)5 (3.8)4 (3.0)1 (0.8)8 (6.0)2 (1.5)
       Decreased serum albumin14 (10.5)013 (9.8)06 (4.5)0
       Decreased blood phosphorus14 (10.5)3 (2.3)5 (3.8)2 (1.5)9 (6.8)4 (3.0)
      Data are numbers (%). TRAEs (any grade) with a frequency of 10% or higher in any treatment group are presented.

      4. Discussion

      The establishment of second-line treatments for mRCC is an unmet need in the clinic. In this phase 3, double-blind, three-arm, randomised study in patients with mRCC, our findings show PFS and ORR benefits from the vorolanib plus everolimus combination over everolimus alone for second-line treatment. The PFS in the current study was 10.0 months, which was comparable to the historical data.
      The combination of VEGF and mTOR inhibitors yielded promising results in STUDY 205 with a median PFS of 14.6 months in the combination group of lenvatinib with everolimus [
      • Motzer R.J.
      • Hutson T.E.
      • Glen H.
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      ]. We noted that the ORR and PFS of vorolanib plus everolimus (ORR: 24.8%; PFS: 10.0 months) in our study were not better than those of lenvatinib plus everolimus (IRC data: ORR: 35%; PFS: 12.8 months) in the second-line treatment of patients with advanced mRCC [
      • Motzer R.J.
      • Hutson T.E.
      • Ren M.
      • Dutcus C.
      • Larkin J.
      Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma.
      ]. However, this study was a randomised phase 2 trial with a modest sample size and was not double-blinded. In comparison, the current study is the first double-blinded, randomised, phase 3 study evaluating the combination of VEGFR/mTOR targeting therapies in the second-line treatment of advanced or mRCC. Furthermore, the PFS in the vorolanib plus everolimus group in our study was comparable to that in the CLEAR study (10.0 versus 14.7 months) [
      • Motzer R.
      • Alekseev B.
      • Rha S.Y.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ]. In the METEOR study, the ORR and PFS were 17% and 7.4 months, respectively [
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
      ]. Therefore, the ORR and PFS for vorolanib plus everolimus were numerically better than those for cabozantinib. Although no head-to-head trials exist, our study still provides a novel option in the VEGFR-TKI refractory setting. In the subgroup analysis for PFS, the HRs for all subgroups favoured the combination treatment over everolimus (point estimate of HRs <1). The wide CIs of the HRs in some subgroups, including 1, may be due to the small sample size. We must acknowledge that the median duration of response was not superior in the combination arm. Regarding the two monotherapy arms, only 14 (10.5%) and 11 (8.3%) patients in the vorolanib arm and everolimus arm, respectively, responded; this may be because the sample size was small, causing large individual differences. In the combination arm, the sample size was larger than that in the two monotherapy arms, with 33 (24.8%) patients who responded, showing a robust result.
      The OS data are not yet mature, and no difference has been observed thus far. However, although across-trial comparisons are difficult and should be made with caution, this is the first study that demonstrated the longest OS duration, which was more than 30 months, in patients with RCC in the 2nd-line setting, which was longer than that reported in other pivotal phase 3 trials of sorafenib (17.8 months) [
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial.
      ], everolimus (14.8 months) [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors.
      ], axitinib (20.1 months) [
      • Motzer R.J.
      • Escudier B.
      • Tomczak P.
      • et al.
      Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.
      ], nivolumab (25.8 months) [
      • Motzer R.J.
      • Tykodi S.S.
      • Escudier B.
      • et al.
      Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with> 5 years of follow-up in patients with advanced renal cell carcinoma (aRCC).
      ] and cabozantinib (21.4 months) [
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
      ]. This is possibly due to the inclusion of more patients with favourable and intermediate MSKCC risk scores and subsequent therapies. Therefore, a longer follow-up is warranted for OS benefit. Another reason may be that vorolanib showed an inhibitory effect on platelet-derived growth factor receptor β with an IC50 of 0.13 nmol/L [
      • Liang C.
      • Yuan X.
      • Shen Z.
      • et al.
      Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity.
      ]. At the time of 164 death events (41.1%), the median OS was 5.0 months longer with vorolanib plus everolimus (30.4 months versus 25.4 months) than with everolimus alone. The disappointing result of similar OS between the combination group and vorolanib group may be partly due to the high number of treatment interruptions related to toxicity (44.4%).
      The safety profile of vorolanib plus everolimus was consistent with the known toxic effects of each individual agent [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      ,
      • Sheng X.
      • Yan X.
      • Chi Z.
      • et al.
      Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma.
      ]. Grade 3 or higher TRAEs occurred in 72.2% of patients receiving the combination, which was notably less than that of patients who received lenvatinib plus everolimus [
      • Motzer R.J.
      • Hutson T.E.
      • Glen H.
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      ]. The most common lenvatinib-related TRAEs were diarrhoea, fatigue or asthenia, hypertension and hypertriglyceridaemia, which are known classic effects of VEGFR-targeting agents [
      • Eskens F.A.
      • Verweij J.
      The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review.
      ]. However, the most common TRAEs in the vorolanib-containing groups were hair colour changes and leukopenia. Meanwhile, the occurrence of TRAEs was lower in the single-agent vorolanib group than in the combination group or single-agent everolimus group. Everolimus-related toxic effects were similar between patients allocated single-agent everolimus and vorolanib plus everolimus. The most frequent adverse events in the combination regimen group were proteinuria, anaemia, leukopenia and hair colour changes. The incidence of proteinuria seemed higher in this study (40.6–70.2%); one possible explanation is that abnormal but non-significant urine protein was reported in approximately half of the patients at baseline. The discontinuation rates due to TRAEs in this study were less than those reported by STUDY 205 [
      • Motzer R.J.
      • Hutson T.E.
      • Glen H.
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      ]. TRAEs were more frequent in the combination group than in the single-agent group. It is important to note that the incidence of serious adverse events was not significantly different between the combination group and the everolimus group (44.4% versus 38.3%, P = 0.3835). Additionally, the TRAEs leading to drug discontinuation were similar in the combination group and everolimus group (8.3% versus 12.0%, P = 0.4172).
      The mRCC treatment paradigm is rapidly evolving, and the standard of care in mRCC has shifted in the front-line setting from VEGF-targeting therapies to immune checkpoint inhibitor (ICI) combination therapies. The OS benefit of lenvatinib plus pembrolizumab further confirmed that ICI/TKI combination therapy is important in the first-line treatment of patients with advanced RCC [
      • Motzer R.
      • Alekseev B.
      • Rha S.Y.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ]. Before that time, immuno-oncology (IO) combinations were not the mainstream strategies in the first-line setting. The first indication of IO combination (nivolumab plus ipilimumab) in mRCC was approved in April 2018, and the second indication (pembrolizumab plus axitinib) was approved in April 2019, which was near the end of the enrolment period of the current study. In this study, the enrolled patients all failed first-line TKI therapy, which may not be consistent with the current clinical practice. However, TKI therapy was still one of the choices for the first-line treatment of favourable patients.
      When the current study was designed in late 2016, everolimus was one of the choices of the standard of care for the second-line treatment of mRCC after prior VEGFR targeted therapy [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      ,
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Alyasova A.
      • Ye D.
      • et al.
      Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).
      ]. Therefore, everolimus was selected as a comparator in this study. Interestingly, the PFS and ORR of everolimus in our study were higher than those reported in several pivotal trials. In a single-arm study in Chinese patients with mRCC who were intolerant to or experienced cancer progression after previous VEGFR-TKIs, everolimus achieved a median PFS of 6.9 months and an ORR of 5% [
      • Guo J.
      • Huang Y.
      • Zhang X.
      • et al.
      Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study.
      ]. In the RECORD-4 subanalysis of second-line everolimus, the median PFS and ORR were 7.4 months and 11% in Asian patients, respectively [
      • Yang L.
      • Alyasova A.
      • Ye D.
      • et al.
      RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis.
      ]. These results suggested that everolimus may prolong the PFS and ORR in the Chinese patient population compared with the Western patient population.
      This study has several limitations. First, patients who received an ICI alone or in combination as first-line therapy were not included in this study because ICIs were not commercially available in China during the study period. Second, we were unable to control for selection bias or other immeasurable confounders. A difference in the patient distribution among the three risk groups has long been recognized. In our study, 6.3% of patients had poor MSKCC risk scores, while approximately 10–17% of patients had poor MSKCC risk scores in other trials [
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
      ,
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors.
      ,
      • Hutson T.E.
      • Escudier B.
      • Esteban E.
      • et al.
      Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma.
      ,
      • Rini B.I.
      • Bellmunt J.
      • Clancy J.
      • et al.
      Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial.
      ]. However, the baseline characteristics of the patients were well balanced among the three arms. In addition, no specific management was performed because our study was blinded. Third, there may be a regional bias, and our results may not be generalizable in other populations owing to differences in medical practices. Nevertheless, this phase 3 study reported the favourable outcomes of a VEGFR-TKI in the IO era.
      To the best of our knowledge, our registered trial is the first phase 3 trial to investigate the efficacy and safety of the combination of mTOR- and VEGF-targeting agents as second-line treatments for mRCC. This study demonstrated that the combination of vorolanib plus everolimus was associated with significant improvements in PFS, ORR and DCR compared with everolimus monotherapy as second-line treatment for patients with VEGFR inhibitor-refractory RCC. The safety profile of each drug was well-tolerated and manageable, consistent with its class and targeting profile.

      Role of the funding source

      This study was sponsored by Betta Pharmaceuticals Co. Ltd. Data were collected by investigators and analysed by the sponsor. All authors, including those employed by the funder, were involved in data interpretation. The sponsor had a role in the study design, as well as collection, analysis and interpretation of data in collaboration with the study investigators. The sponsor also collaborated with the investigators to write the report.

      Author contributions

      Xinan Sheng: Conceptualization, Methodology, Validation, Formal Analysis, Investigation, Resources, Writing – Review and Editing. Dingwei Ye: Investigation, Resources, Writing – Review and Editing. Aiping Zhou: Investigation, Resources, Writing – Review and Editing. Xin Yao: Investigation, Resources, Writing – Review and Editing. Hong Luo: Investigation, Resources, Writing – Review and Editing. Zhisong He: Investigation, Resources, Writing – Review and Editing. Zengjun Wang: Investigation, Resources, Writing – Review and Editing. Yingchao Zhao: Investigation, Resources, Writing – Review and Editing. Zhigang Ji: Investigation, Resources, Writing – Review and Editing. Qing Zou: Investigation, Resources, Writing – Review and Editing. Chaohong He: Investigation, Resources, Writing – Review and Editing. Jianming Guo: Investigation, Resources, Writing – Review and Editing. Xinhua Tu: Investigation, Resources, Writing – Review and Editing. Ziling Liu: Investigation, Resources, Writing – Review and Editing. Benkang Shi: Investigation, Resources, Writing – Review and Editing. Ben Liu: Investigation, Resources, Writing – Review and Editing. Peng Chen: Investigation, Resources, Writing – Review and Editing. Qiang Wei: Investigation, Resources, Writing – Review and Editing. Zhiquan Hu: Investigation, Resources, Writing – Review and Editing. Yanqiao Zhang: Investigation, Resources, Writing – Review and Editing. Kui Jiang: Investigation, Resources, Writing – Review and Editing. Fangjian Zhou: Investigation, Resources, Writing – Review and Editing. Dapeng Wu: Investigation, Resources, Writing – Review and Editing. Cheng Fu: Investigation, Resources, Writing – Review and Editing. Xingya Li: Investigation, Resources, Writing – Review and Editing. Bin Wu: Investigation, Resources, Writing – Review and Editing. Lijie Wang: Investigation, Resources, Writing – Review and Editing. Shukui Qin: Investigation, Resources, Writing – Review and Editing. Gang Li: Investigation, Resources, Writing – Review and Editing. Yunpeng Liu: Investigation, Resources, Writing – Review and Editing. Hongqian Guo: Investigation, Resources, Writing – Review and Editing. Kehe Chen: Investigation, Resources, Writing – Review and Editing. Dahong Zhang: Investigation, Resources, Writing – Review and Editing. Gongxian Wang: Investigation, Resources, Writing – Review and Editing. Lieming Ding: Conceptualization, Supervision, Project Administration, Data Curation, Writing – Review and Editing. Yang Wang: Conceptualization, Supervision, Project Administration, Data Curation, Writing – Review and Editing. Xiaobin Yuan: Investigation, Methodology, Validation, Formal Analysis, Writing – original draft, Writing – review and editing. Jun Guo: Conceptualization, Validation, Formal Analysis, Investigation, Supervision, Project Administration, Resources, Data Curation, Writing – Review and Editing.

      Data sharing statement

      The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

      Conflict of interest statement

      Dr. Jun Guo is the member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, and Oriengene. Lieming Ding, Yang Wang and Xiaobin Yuan are employees of Betta pharmaceuticals. Other authors declared no conflict of interests.

      Acknowledgements

      The authors express gratitude to the patients and their families; all the trial site coordinators. This work was funded by Betta Pharmaceuticals Co., Ltd., which contributes to the data analysis, study monitoring or oversight and medical-writing support. The authors also express appreciation to Tian Zhang, M.D. (UT Southwestern Medical Center) for insights and manuscript review.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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