Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study

Eligible patients were female, ≥18 years, with documented locally advanced, metastatic breast cancer, both previously treated or chemotherapy-naïve. Other inclusion criteria included HER2-negative disease (IHC 0-1 or IHC 2, confirmed as FISH negative), ≥1 measurable lesion according to RECIST 1.0 criteria and a life expectancy of ≥16 weeks. Previous endocrine therapy for advanced disease was allowed. Patients were required to have adequate bone marrow, hepatic, and renal functions, indicated by hemoglobin ≥10 g × 100 mL, absolute neutrophil count ≥2 × 10⁹/L, platelet count ≥100 × 10⁹/L, total serum bilirubin <1.5× upper normal limit (UNL), AST/ALT <2.5× UNL, (<3.5× UNL for liver metastases), and alkaline phosphatase <2.5× UNL (<5× UNL for bone metastases).

Patients were ineligible if they had only local relapse, previous exposure to a vinca alkaloid or CAPE, serious comorbidities such as cardiac disease, uncontrolled diabetes or hypercalcemia, severe peripheral neuropathy, active infection, or previous organ allograft. Patients were also excluded if they were pregnant or lactating; had clinical central nervous system or leptomeningeal metastases, a malabsorption disease, hypersensitivity to fluoropyrimidine therapy; had participated in another clinical trial with any investigational drug within 30 days before study inclusion; or had a history of another malignancy. Drugs acting on P450 cytochrome were not allowed during the study.

Patients were divided in two groups, according to treatment line (first-line = Group 1; ≥ second-line = Group 2).

Treatment consisted of VNR 40 mg each alternative day of the week (Monday, Wednesday, and Friday) and CAPE 500 mg three times a day (TID) after meals, given continuously without drug-free periods, until disease progression, unacceptable toxicity, or patient’s refusal. Patients’ compliance was evaluated by a diary given at the beginning of each cycle (1 cycle = 3 weeks). The dose of VNR was temporarily reduced to 30 mg three times a week at the first appearance of Grade 2 neutropenia or thrombocytopenia; the dose was increased to the previous level (40 mg) only if a complete recovery was observed at the beginning of the subsequent cycle. If a second episode of Grade 2 neutropenia or thrombocytopenia occurred, the dose was maintained at 30 mg until the end of the study with no further reduction. In the case of Grade 3–4 neutropenia or thrombocytopenia, VNR was interrupted for a maximum of 3 weeks, until recovery of neutrophil count at 1.0 × 10⁹/L; the dose administered upon resuming treatment was determined according to the toxicity grade. CAPE was reduced to 1000 mg/day in case of Grade 3–4 neutropenia or thrombocytopenia, or Grade 2–3 diarrhea or hand-foot syndrome, until recovery to Grade 1. For any other Grade 3–4 toxicity, both drugs were interrupted until recovery to lower grade.

The primary endpoint of the study was CBR, defined as the proportion of patients with complete (CR) or partial response (PR) or with stable disease (SD) at 24 weeks from the start of treatment. Patients without a computed tomography (CT) re-evaluation at week 24 were considered non-responder if they discontinued treatment for medical decision, clinical progression, death, or toxicity.

Secondary endpoints were the objective response rate (ORR) and disease control rate (DCR), defined as the percentage of patients with CR + PR or CR + PR + SD, respectively, according to RECIST criteria. Further assessments included disease-free interval (DFI), progression-free survival (PFS), and time to progression (TTP). For patients achieving a CR or PR, the time to response and duration of response were also assessed.

Blood tests evaluating hepatic and renal function together with CEA and CA 15.3 were conducted at baseline and every 3 cycles, until study end. For each cycle white blood cells, erythrocyte count, hemoglobin, and platelets were assessed, before chemotherapy delivery. Tumor status was assessed according to RECIST 1.0 criteria, every 3 cycles (9 weeks) until disease progression, interruption of the treatment for toxicity, or patient’s refusal.

A sample size for each group has been defined according to the Fleming approach, modified by A’Hern [11]. We assumed the treatment had no therapeutic interest with a CBR ≤ 40 % for Group 1 and ≤20 % for Group 2, while a CBR ≥ 55 % and ≥35 %, respectively, was required to consider the treatment active. With a one-sided alpha level of 10 % and a power of 85 %, a total of 61 patients in Group 1 and 49 patients in Group 2 had to be enrolled. Considering a possible drop-out of about 10 %, 120 patients were required to have 105 patients evaluable for the primary endpoint (60 in Group 1 and 45 in Group 2).

CBR, ORR, and DCR were given as point estimate and 95 % confidence interval (CI). CIs were computed using exact binomial methods. Subjects who were not reported as having died or with progression/relapse at the time of the analysis were censored at their last available contact date. Survival data were summarized by median and interquartile range (IQR), computed with the Kaplan–Meier method. A Cox proportional hazard model was used to assess the impact of clinical factors on survival endpoints and results were expressed as hazard ratios (HR) and 95 % CI. Compliance with treatment and toxicity were evaluated using both cycle and patient as units of analysis. All analyses were conducted on the whole population and according to treatment line. Exploratory analyses were conducted on subgroups defined by HR status and metastatic site. Analyses were carried out with SAS (Version 9.2).