Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial

Abstract

Importance: There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored.

Objective: To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC.

Design, setting, and participants: The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021.

Interventions: Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily).

Main outcomes and measures: The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population.

Results: In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas.

Conclusions and relevance: This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting.

Trial registration: Clinicaltrials.gov Identifier: NCT04348032.

Conflict of interest statement

Conflict of Interest Disclosures: Drs She, Guan, and Hou reported personal fees from Jiangsu Hengrui Pharmaceutical Co outside the submitted work. Dr Wu reported grants from National Key R&D Program of China during the conduct of the study as well as nonfinancial support from Jiangsu Hengrui Pharmaceuticals Co Ltd and the CSPC Pharmaceutical Group Co Ltd outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

aOne patient discontinued treatment with pegylated liposomal doxorubicin (PLD) but was still receiving treatment with apatinib at the data cutoff date.

Figure 2.. Progression-Free Survival (PFS) and Overall Survival (OS)

Kaplan-Meier analysis of PFS (A) and OS (B) in the intent-to-treat population. Stratification factors included platinum-free interval (≤3 months vs 3-6 months) and prior platinum-sensitive relapse (yes vs no). HR indicates hazard ratio; NR, not reached; PLD, pegylated liposomal doxorubicin.

Figure 3.. Best Percentage of Change in Target Lesions

PLD indicates pegylated liposomal doxorubicin. The horizontal dashed lines represent the criteria of progrssive disease or partial response according to Response Evaluation Criteria in Solid Tumours, version 1.1.