Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

Objective: Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objectiveresponse in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. Thisstudy aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. Inaddition, we detected gene variants in ctDNA to explore the therapeutic implications. Methods: This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients weretreated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1, 8, and 15 of every cycle (3 weeks). Theprimary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection wereevaluated before and during treatment. Results: Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4–7.0 months), and the median OS was 17.4months (95% CI, 8.0–27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs includedgastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs. detected baseline ctDNA (13.9 months vs. 3.6 months, P = 0.018). Conclusions: All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allelefrequencies in ctDNA at baseline showed longer PFS.