Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine–Refractory Differentiated Thyroid Cancer: The REALITY Randomized Clinical Trial

Key Points

Question  Does apatinib prolong the progression-free survival of patients with progressive locally advanced or metastatic, radioactive iodine–refractory differentiated thyroid cancer compared with placebo?

Findings  In this phase 3 randomized clinical trial of 92 eligible patients, apatinib significantly improved progression-free survival and overall survival compared with placebo. Hypertension was the most common grade 3 or higher-level adverse event.

Meaning  The findings of this trial indicate that apatinib might provide a new treatment option for patients with radioactive iodine–refractory differentiated thyroid cancer.

Importance  Patients with radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options.

Objective  To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC.

Design, Setting, and Participants  This randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020.

Interventions  Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib.

Main Outcomes and Measures  The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy.

Results  Of the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])—none of which occurred in the placebo group.

Conclusions and Relevance  The REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC.

Trial Registration  ClinicalTrials.gov Identifier: NCT03048877

The global annual new cases of thyroid cancer were estimated at 567 000 based on the GLOBOCAN 2018 database, and China accounted for approximately 34% of all incident cases worldwide.^1,2 Differentiated thyroid cancer (DTC) is the most common type, accounting for more than 90% of all thyroid cancers, and is composed of papillary, follicular, Hürthle cell, and poorly differentiated cancers.³ Up to 30% of patients with DTC experience disease recurrence, and 30% of the cancers eventually become refractory to radioactive iodine therapy.^4-6 Patients with radioactive iodine–refractory DTC (RAIR-DTC) have a poor prognosis, with a 10-year survival rate of 10%.^6,7 Sorafenib and lenvatinib, angiogenesis inhibitors,⁸ were found to prolong progression-free survival (PFS) in patients with RAIR-DTC in the DECISION and SELECT trials.^9,10 However, no significant benefit on overall survival (OS) was observed, except for a subgroup of patients older than 65 years in the SELECT trial.¹¹ Sorafenib and lenvatinib were not available for treatment of thyroid cancer in China until 2017 (sorafenib) and 2020 (lenvatinib). In addition, a relatively high proportion of patients with advanced disease, especially for RAIR-DTC, might also lead to the poor prognosis in China.^1,2 A large number of unmet clinical needs and the limited treatment options warrant the exploration of alternative strategies for patients with RAIR-DTC.

Apatinib is a small-molecule angiogenesis inhibitor with high selectivity for VEGFR-2.¹² In a previous preliminary study, the efficacy and safety of apatinib was assessed in patients in China with RAIR-DTC.¹³ Ten eligible patients were administered apatinib, 750 mg, orally once daily for 8 weeks. The objective response rate (ORR) reached 90%, and the total diameter of the target lesions was reduced by 41%. All adverse events were acceptable and controllable. However, 5 patients developed grade 3 hand-foot syndrome, indicating a relatively high incidence of treatment-related adverse events. In a subsequently study, 10 patients with RAIR-DTC were enrolled and treated with apatinib, 500 mg/d.¹⁴ After 6 cycles of treatment, apatinib showed a similar disease control rate (DCR), tumor shrinkage, and decrease of the thyroglobulin level compared with apatinib, 750 mg/d, but the incidence of treatment-related adverse events was lower with 500 mg/d than with apatinib, 750 mg/d. Based on the findings of those studies, we performed a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to evaluate the efficacy and safety of apatinib in patients with progressive locally advanced or metastatic RAIR-DTC at an initial dose of 500 mg/d.

This randomized, double-blind, placebo-controlled phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was performed at 21 sites in China (eTable 5 in Supplement 2). This study was conducted in accordance with the Declaration of Helsinki,¹⁵ Good Clinical Practice guidelines, and relevant Chinese laws. The study protocol (Supplement 1) and amendments were approved by the Hospital Ethics Committee of Peking Union Medical College Hospital and Bayi Hospital Nanjing Chinese Medicine University. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. All patients provided written informed consent prior to any study procedure and were provided financial compensation.

Key eligibility criteria included the following: age 18 years or older; locally advanced or metastatic RAIR-DTC (papillary, follicular, Hürthle cell, and poorly differentiated carcinoma) that progressed within 12 months after the last treatment according to the Response Evaluation Criteria in Solid Tumors, version 1.1; 1 measurable lesion identified with computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1; adequate organ function; an Eastern Cooperative Oncology Group performance status of 0 to 2; and a life expectancy of 3 months or more. Patients with RAIR-DTC had at least 1 of the following conditions: (1) the target lesion had completely lost iodine uptake function; (2) the target lesion progressed within 12 months after receiving a single radioactive iodine treatment greater than or equal to 3.7 gigabecquerels (GBq) (≥100 mCi); (3) patients were given continuous radioactive iodine with an interval of less than 12 months between every 2 radioactive iodine treatments at a dose greater than or equal to 3.7 GBq, but the disease progressed 12 months after receiving 1 dose of radioactive iodine; and (4) patients received a cumulative dose of radioactive iodine greater than or equal to 22.2 GBq (≥600 mCi). Patients with RAIR-DTC who had received chemotherapy, small-molecule vascular endothelial growth factor tyrosine kinase inhibitors, or radiotherapy more than 1 month before the first use of study treatment were also included in this study. Complete inclusion and exclusion criteria are described in the trial protocol (Supplement 1).

Patients were randomly assigned (1:1) to the apatinib group or the placebo group via the minimization randomization method through randomization and trial supply management by the PLA Second Military Medical University, Shanghai, China, and stratified by sex (male or female). Both apatinib and placebo were assigned in a double-blind manner. Patients, investigators, and sponsors were blinded to the treatment assignment.

Apatinib, 500 mg, or placebo was administered orally once daily until disease progression or intolerable toxic effects occurred, withdrawal of consent, or investigators’ decision to discontinue treatment. When grade 3 or higher-level adverse events occurred during treatment, dose interruption, reduction, and discontinuation were carried out. The minimum dose of apatinib was 250 mg once daily.

Tumor assessment with computed tomography or magnetic resonance imaging was performed at the end of the first and second treatment cycles and every 2 cycles thereafter. Efficacy evaluations were performed as per Response Evaluation Criteria in Solid Tumors, version 1.1, by the investigators. Complete response (CR) and partial response (PR) were confirmed by 2 successive radiographic examinations within a minimum of 4-week intervals. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria, version 4.0, and classified by MedDRA-preferred terms. Survival was determined every 2 months until death or loss to follow-up.

During the extension phase, patients with progressive disease (PD) in the placebo group received apatinib, using an open-label approach; patients in the apatinib group could continue to receive apatinib after progression at the discretion of the investigators. Further details about these procedures are provided in the protocol (Supplement 1).

The primary end point was investigator-assessed PFS (defined as the time from randomization to disease progression or death from any cause). Secondary end points were OS (time from randomization to death from any cause), ORR (proportion of patients with a confirmed CR or PR from randomization to disease progression or death from any cause), DCR (proportion of patients with a confirmed CR, PR, or stable disease from randomization to disease progression or death from any cause), duration of response (DOR) (time from the first confirmed response to disease progression or death from any cause), time to objective response (time from randomization to the first confirmed response), and safety.

Sample size determination was performed using PASS, version 11 (NCSS Statistical Software) with group sequential log-rank test settings. We assumed that the median PFS was 5.8 months for the placebo group and 12 months for the apatinib group. A total of 83 disease progression or death events were needed to provide 90% power to detect a difference in PFS between the apatinib and placebo group under a significance level of a 2-sided value of P < .05. With an enrollment period of 24 months and a follow-up period of 12 months, a total of 118 enrolled patients were needed, after accounting for a dropout rate of 15%.

An interim analysis was planned to be conducted when approximately 50 (60%) events were observed. The O’Brien-Fleming boundaries approximated by the Lan-DeMets α spending function were used to control the familywise type I error rate. Moreover, these boundaries were recalculated by the actual number of observed events in the interim analysis. At this analysis, the actual information fraction was 61% (51 of 83) for PFS; therefore, the α significance threshold at the interim analysis was adjusted to 0.0085.

Efficacy analyses were performed in the full analysis set based on the intention-to-treat principle, which included all patients randomized in the study. For time-to-event end points (ie, PFS, OS, DOR, and time to objective response), the Kaplan-Meier method was used to estimate the rates, median time, and their corresponding 95% CIs. An unstratified log-rank test was performed to compare the difference between the apatinib group and placebo group. In addition, hazard ratios (HRs) and their 95% CIs were obtained by unstratified Cox proportional hazards regression models. For binary outcomes (ORR and DCR), the Clopper-Pearson method was used to calculate the 95% CIs, and the Fisher exact test was performed for between-group comparisons.

Prespecified subgroup analyses included age (≤65 or >65 years), sex (male or female), Eastern Cooperative Oncology Group performance status (0 or ≥1), histologic subtype (papillary or others), site of metastases (lung or others), and iodine uptake (uptake or no uptake). Data on race and ethnicity were not collected. The HRs and corresponding 95% CIs of subgroup analyses were estimated by an unstratified Cox proportional hazards regression model. Because 2 patients with the poorly differentiated subtype and 1 patient with the mixed papillary-poorly differentiated subtype were enrolled in the placebo group at this analysis, we performed post hoc analyses on survival end points by excluding these 3 patients to avoid potential bias. We also performed post hoc analyses of the association between PFS and baseline thyroglobulin level, which were split according to a median value (>289.4 or ≤289.4 ng/mL [1 to 1 conversion to micrograms per liter]). The post hoc analysis methods followed time-to-event analysis.

Safety analyses were based on all randomized patients who received at least 1 dose of the study drug (safety set). The numbers and percentages of participants with each adverse event were summarized by treatment group. All analyses were performed using SAS, version 9.4 (SAS Institute Inc).

Between February 17, 2017, and March 2, 2020, 92 patients from 21 sites were randomized and treated with apatinib (n = 46) or placebo (n = 46) (Figure 1). Of the 92 patients, 56 were women (60.9%) and 36 were men (39.1%); mean (SD) age at baseline was 57.7 (10.6) years. All patients received treatment and were included in the full analysis set and the safety set. By the data cutoff time (March 25, 2020), 51 PFS events had occurred. The interim analysis was conducted by an independent statistical team, and the results were assessed by the independent data monitoring committee . The baseline characteristics are reported in Table 1. Eight patients (8.7%) had previously received targeted therapy (4 patients with sorafenib and 4 with donafenib: 5 patients in the apatinib group and 3 in the placebo group); 3 patients in the apatinib group had previously received chemotherapy. There were 2 patients with the poorly differentiated subtype and 1 patient with mixed papillary-poorly differentiated subtype in the placebo group.

With a median follow-up duration of 18.1 (IQR, 12.7-22.2) months, the median PFS was 22.2 (95% CI, 10.91-not reached) months in the apatinib group and 4.5 (95% CI, 1.94-9.17) months in the placebo group, with an HR of 0.26 (95% CI, 0.14-0.47) (log-rank P < .001; ie, lower than the prespecified significance level of P = .0085) (Figure 2A). The 12-month PFS rate was 60.3% (95% CI, 40.8%-75.2%) in the apatinib group and 12.4% (95% CI, 3.4%-27.4%) in the placebo group, and the 24-month PFS rate decreased to 37.2% (95% CI, 15.1%-59.7%) in the apatinib group and 4.1% (95% CI, 0.3%-17.2%) in the placebo group (Table 2). Moreover, the median OS was not reached in the apatinib group (95% CI, 26.25- not reached) and was 29.9 months (95% CI, 18.96-not reached) in the placebo group (HR, 0.42; 95% CI, 0.18-0.97; P = .04) (Figure 2B).

In the apatinib group, 25 patients achieved a confirmed PR with an ORR of 54.3% (95% CI, 39.0%-69.1%), and 1 patient in the placebo group achieved a confirmed PR with an ORR of 2.2% (95% CI, 0.1%-11.5%) (P < .001). Seven patients in the apatinib group had unconfirmed PR; 6 patients were deemed to have stable disease because the response was not confirmed by the cutoff date, and 1 patient was deemed to have PD owing to a new lesion observed through the radiographic examination for response confirmation. The DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group and 58.7% (95% CI, 43.2%-73.0%) in the placebo group (P < .001) (Table 2). Three patients did not receive the first efficacy evaluation; tumor shrinkage in target lesions occurred in 89 patients (Figure 3). The median tumor shrinkage rate with apatinib was 51.7% (IQR, 43.8%-62.7%) in 25 patients with a confirmed response. Furthermore, the median time to objective response was 1.9 (IQR, 1.2-3.7) months and DOR was 22.4 (95% CI, 17.7-27.1) months in 25 patients with a confirmed response.

In the extension phase of the trial, 35 patients with PD in the placebo group received apatinib, and 11 patients in the apatinib group continued apatinib after progression according to the discretion of the investigators. During the extension phase, an ORR of 51.4% was observed in the placebo group. Five patients in the apatinib group achieved stable disease (eTable 1 in Supplement 2).

Subgroup analyses showed that the median PFS was longer with apatinib than with placebo in all prespecified subgroups (eFigure 1A in Supplement 2). The median OS of all subgroups did not differ significantly between 2 treatments but numerically favored apatinib (all HRs, <1) (eFigure 1B in Supplement 2). After exclusion of 2 patients with the poorly differentiated subtype and 1 patient with the mixed papillary-poorly differentiated subtype in the placebo group, the median PFS and OS of the 2 groups were similar to those from the full analysis set (eFigure 2 in Supplement 2). Furthermore, apatinib significantly improved the median PFS in post hoc subgroups of high (>289.4 ng/mL: 20.1; 95% CI, 7.62-not reached months with apatinib vs 4.0; 95% CI, 1.91-9.20 months with placebo; HR, 0.23; 95% CI, 0.09-0.47; P <  .001) and low (≤289 ng/mL: 25.8; 95% CI, 9.10-not reached months with apatinib vs 7.5; 95% CI, 0.95-9.33 months with placebo; HR, 0.27; 95% CI, 0.11-0.47; P =  .003) baseline thyroglobulin levels (eFigure 3 in Supplement 2).

The median duration of treatment was 7.8 (range, 1.0-25.9) months in the apatinib group and 2.6 (range, 0.2-25.6) months in the placebo group. Of the 46 patients treated with apatinib, 17 individuals (37.0%) had a dose reduction due to treatment-related adverse events of any grade, mainly including 6 patients (13.0%) with hand-foot syndrome, 3 (6.5%) with proteinuria, and 2 (4.3%) with hypertension. Three patients (6.5%) discontinued apatinib owing to hand-foot syndrome, proteinuria, and epistaxis. The dose was not reduced for any patient in the placebo group, but 3 patients discontinued placebo owing to hematuria, neck pain, and presence of blood in the urine. During the extension phase, the median duration of apatinib therapy was 6.1 (range, 0.5-31.4) months in the placebo group and 1.6 (range, 0.0-20.3) months in the apatinib group. The dose was reduced in 13 of 35 patients (37.1%) and 2 patients (5.7%) discontinued apatinib due to treatment-related adverse events in the placebo group, whereas no dose reductions or discontinuations occurred in the apatinib group.

Adverse events that occurred in 10% or more patients during the randomization phase occurred in all patients (46 [100%]) in the apatinib group and 42 patients (91.2%) in the placebo group. In the apatinib group, 36 adverse events (78.3%) were grade 3 or a higher level, and 8 of (17.4%) adverse events in the placebo group were grade 3 or higher (eTable 2 in Supplement 2). The incidence of treatment-related adverse events was 100% in the apatinib group and 63.0% in the placebo group (eTable 3 in Supplement 2). Grade 3 or higher-level treatment-related adverse events occurred in 34 patients (73.9%) who received apatinib, with hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%]) being the most common events. During the extension phase, similar treatment-related adverse events were observed (eTable 4 in Supplement 2). No patients died from treatment-related adverse events during the whole treatment period. However, 1 patient in the placebo group died from non–treatment-related dyspnea.

This randomized phase 3 trial showed that patients with progressive locally advanced or metastatic RAIR-DTC could derive clinical benefits from apatinib. Among placebo-controlled trials in patients with progressive RAIR-DTC, PFS was prolonged by 17.6 months with apatinib (HR, 0.26; 95% CI, 0.14-0.47; P < .001), 5.0 months by sorafenib (HR, 0.59; 95% CI, 0.45-0.76; P < .001), and 14.7 months with lenvatinib (HR, 0.21; 99% CI, 0.14-0.31; P < .001).^9,10 Progression-free survival was prolonged by 20.2 months in Chinese patients treated with lenvatinib (HR, 0.16; P < .001).¹⁶ Apatinib and lenvatinib presented high selectivity for VEGFR-2 in preclinical studies.^12,17,18 Moreover, the median DOR was 22.4 months in the present study. These factors may underlie the PFS benefit of apatinib. In addition, although the serum thyroglobulin level is a marker of persistent disease and a factor used in estimation of clinical outcomes, apatinib treatment improved PFS regardless of the level of thyroglobulin. The results were consistent with those of sorafenib.⁹

Current clinical benefits have been demonstrated in the form of improved PFS, but no available data on OS in the intention-to-treat populations were reported in other phase 3 randomized trials,^9,10,16 apart from the prolonged OS in the prespecified subgroup of patients older than 65 years in the SELECT trial.¹¹ Therefore, therapeutic decisions regarding the use of tyrosine kinase inhibitors are somewhat controversial and based on the convergence of expert opinions and patient preference. Herein, apatinib increased the median OS compared with placebo in the full analysis set, and improved OS could potentially be underestimated owing to patients with PD in the placebo group crossing over to apatinib therapy. An improvement in OS compared with placebo was also observed in a phase 2 study of anlotinib.¹⁹ Moreover, although all patients with poorly differentiated subtypes, which are associated with poor prognosis,²⁰ were in the placebo group, the median PFS and OS determined through post hoc analyses after excluding these patients were consistent with those in the full analysis set. This study suggests that apatinib offers a favorable benefit-risk profile in patients with RAIR-DTC.

Among patients who had previously received chemotherapy in the apatinib group, 1 patient achieved PR and 2 achieved stable disease. For 8 patients who had previously received antiangiogenesis therapy, 3 individuals achieved PR and 2 achieved stable disease in the apatinib group; 1 patient in the placebo group achieved stable disease. Lenvatinib and cabozantinib treatment also showed that patients who had previously received angiogenesis inhibitors could respond to subsequent antiangiogenesis therapy.^10,21 Furthermore, patients in the placebo group who crossed over to apatinib achieved an ORR similar to that of the apatinib group.

The safety profile of apatinib was consistent with the adverse events associated with other antiangiogenic therapy,^22-24 including the most common hypertension, hand-foot syndrome, proteinuria, diarrhea, and asthenia. The incidence of grade 3 or higher-level treatment-related adverse events was 73.9%, which was similar to the result of SELECT trial.¹⁰ No patient died from treatment-related adverse events during the randomization phase. Overall, apatinib therapy was manageable in this study.

This study has some limitations. The results were obtained only in the Chinese population. Furthermore, we used placebo as a control rather than active agents owing to no availability of sorafenib and lenvatinib for patients in China with thyroid cancer until 2017 and 2020. Therefore, based on ethical considerations and limited drug accessibility, patients in the placebo group could cross over to apatinib after disease progression. In addition, this study did not perform biomarker analysis for efficacy owing to a lack of tumor samples for genotype testing.

In this randomized clinical trial, apatinib exhibited significant clinical benefits in terms of both prolonged PFS and OS with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC. Apatinib should be considered as a new treatment option for patients with RAIR-DTC.

Accepted for Publication: September 7, 2021.

Published Online: December 16, 2021. doi:10.1001/jamaoncol.2021.6268

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Lin Y et al. JAMA Oncology.

Corresponding Authors: Yansong Lin, MD, PhD, Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China (linyansong1968@163.com); Shukui Qin, MD, PhD, Department of Oncology, Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China, No. 34 Biao, 34 Hao, Yanggongjing Road, Qinhuai District, Nanjing 210002, Jiangsu Province, China (qinsk@csco.org.cn).

Author Contributions: Drs Y. Lin and Qin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Y. Lin, Qin.

Acquisition, analysis, or interpretation of data: Z. Li, Yang, Fu, S. Li, W. Chen, Gao, Miao, Xu, Q. Zhang, Zhao, Bao, L. Li, Ren, C. Lin, Jing, Ma, Liang, G. Chen, H. Zhang, Y. Zhang, Zhou, Sang, Hou.

Drafting of the manuscript: Y. Lin, Hou.

Critical revision of the manuscript for important intellectual content: Qin, Z. Li, Yang, Fu, S. Li, W. Chen, Gao, Miao, Xu, Q. Zhang, Zhao, Bao, L. Li, Ren, C. Lin, Jing, Ma, Liang, G. Chen, H. Zhang, Y. Zhang, Zhou, Sang, Hou.

Statistical analysis: Zhou.

Obtained funding: Y. Lin.

Administrative, technical, or material support: Y. Lin, Z. Li, Yang, Fu, S. Li, W. Chen, Gao, Miao, Xu, Q. Zhang, Zhao, Bao, L. Li, Ren, C. Lin, Jing, Ma, Liang, G. Chen, H. Zhang, Y. Zhang.

Supervision: Y. Lin, Qin, Gao, Hou.

Conflict of Interest Disclosures: Drs Zhou and Sang and Hou were employees of Jiangsu Hengrui Pharmaceuticals Co Ltd. during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by the National Natural Science Foundation of China (grant 81771875), the Project on Inter-Governmental International Scientific and Technological Innovation Cooperation in the National Key Projects of Research and Development Plan (grant 2019YFE0106400) and Jiangsu Hengrui Pharmaceuticals Co Ltd; in addition, apatinib and placebo were provided by Jiangsu Hengrui Pharmaceuticals Co Ltd.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: The trial results were presented at the European Society for Medical Oncology Virtual Congress 2020; September 18, 2020.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and their families for participating in the study. Yitao Wang, MS, and Ni Guan, MS, provided statistical support, and Wending Sun, PhD, and Fangzhou Xia, MD, provided medical writing support (Jiangsu Hengrui Pharmaceuticals Co Ltd); no financial compensation outside of salary was provided.