Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety

Abstract

Apatinib (YN968D1) is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a single-arm, nonrandomized phase II study (NCT03121846) to assess the efficacy and safety of apatinib in patients with stage IV sarcoma. We recruited 64 patients with stage IV sarcoma who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. Fifty-nine patients were assessed for efficacy and 64 patients for AEs. The median PFS was 7.93 months. At 12 weeks, the PFR was 74%, the ORR was 16.95% (10/59), and the DCR was 86.44% (51/59). The final ORR was 15.25% (9/59) and the DCR was 57.63% (34/59). Notably, 22 patients (34.38%) who developed hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (18.20 vs. 10.73 months; P = 0.002). We conclude that apatinib is effective and well tolerated in patients with advanced sarcoma. The development of hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in sarcoma patients.

Fig. 1. Maximum changes and all changes from baseline in target lesions in patients with stage IV sarcomas treated with apatinib.

a Maximum changes in target lesions in patients with stage IV sarcoma treated with apatinib. Among 64 patients, 51 were evaluated for response to apatinib (RECIST 1.1). No patients achieved CR, 13 (25.49%) achieved PR once, and 36 (70.59%) achieved SD once. Only two (3.9%) patients suffered from PD, and 49 (96.1%) responded to apatinib monotherapy. b Changes from baseline in target lesions after apatinib treatment in 51 patients with measurable sarcoma lesions. Green lines: target lesions shrank ≥ 30% from baseline; red lines: target lesions increased ≥ 20% from baseline; yellow lines: target lesions initially decreased ≥ 30% and then increased ≥ 20% from baseline; black lines: target lesions changed from 20%–30%

Fig. 2. Efficacy and toxicity of apatinib in sarcoma patients.

a Overall responses of 59 patients with stage IV sarcoma treated with apatinib. Among 59 patients, 51 had measurable lesions and eight patients had unmeasurable lesions. Responses were PR in nine (15.25%), SD in 25 (42.37%), and PD in 25 (42.37%). b, c PFS and OS in 59 patients treated with apatinib. b Median PFS was 7.93 months; PFR at 12 weeks was 74%. c Median OS was 17.27 months. d, e Frequency and prognostic role of apatinib toxicity in sarcoma patients. d Severe adverse events (AEs) included no grade 4 AEs and grade 3 AEs in nine patients (14.06%), mainly hypertension (HTN), hand-foot syndrome (HFS), proteinuria, fatigue, and dysgeusia. e: HTN, proteinuria, and HFS were significantly correlated with longer OS in this cohort, and patients who suffered from any of these three AEs during treatment had significantly longer OS than those without these AEs

Fig. 3. Typical responses to apatinib treatment in two sarcoma patients.

a, b Metastatic undifferentiated pleomorphic sarcoma lesions showed significant decrease in size and pulmonary cavities after apatinib treatment. Positron emission tomography-computed tomography (PET-CT) showed decreased tumor size, metabolic activity, pulmonary cavities, and severe pneumothorax after apatinib treatment. a Before apatinib treatment (2016.11.2). b After apatinib treatment (2017.5.19). c–f Stable lung metastatic lesion in patient with synovial sarcoma treated with apatinib. Chest CT scan showed long-term stable disease. c: CT scan before treatment (2015.12.26). d CT scan after treatment (2016.5.11). e CT scan after treatment (2016.11.23). f CT scan after treatment (2017.3.27)