Induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin in Japanese patients with HER2-negative metastatic breast cancer: a multicenter, collaborative, open-label, phase II clinical study for the SBCCSG 35 investigators

The present multicenter, collaborative, open-label, Phase II clinical study of ISMT (SBCCSG 35; University Hospital Medical Information Network identifier: 000015971) was conducted in Japanese patients with MBC. Patients were recruited centrally. All patients provided written informed consent before enrollment. The study protocol was approved by the Institutional or Central Ethics Committee, and the study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and local ethical and legal regulations.

The primary endpoint for ISMT was time to treatment failure (TTF). The secondary endpoints for ISMT were progression-free survival (PFS), the overall response rate (ORR), overall survival (OS), safety, peripheral neuropathy, and the assessment of QOL.

At the time of entry, female patients were checked for age, height, body weight, history, complications, HER2/neu expression, hormone status, hematology, and blood chemistry.

Patients were eligible if they met the following requirements: 1) a female diagnosed with histologically or cytologically confirmed breast cancer; 2) a definite diagnosis of MBC; 3) 20 to 74 years of age; 4) Eastern Cooperative Oncology Group (ECOG) performance status, 0 to 2; 5) measurable lesions according to the response evaluation criteria in solid tumors (RECIST) [23]; 6) major organs of well-conserved functions (bone marrow, liver, kidney, and lungs), i.e., neutrophil count: ≥ 1500/μL, platelet count: 80,000/μL, hemoglobin: ≥ 9.0 g/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and serum creatinine: ≤ 2.5-fold the upper limit at the site; 7) grade ≤ 1 peripheral neuropathy at screening; 8) HER2-negative breast cancer; 9) an expected survival period of ≥ 3 months since the day of administration onset; 10) no clinical concerns about electrocardiograms; 11) no history of treatment with paclitaxel, bevacizumab, or eribulin after metastasis; and 12) written informed consent provided by the patient herself. The key exclusion criteria were as follows: systemic infection involving fever (≥ 38.0°C), history of hypersensitivity to investigational drugs and their solvents, metastasis to the brain requiring treatment, interstitial pneumonia, pulmonary fibrosis, poorly controlled hypertension or diabetes mellitus, active double cancer, history of mental impairment, central nervous system impairment, or cerebrovascular neuropathy, pregnancy, breast-feeding, or women of childbearing age, and patients whom the investigator or subinvestigator considered ineligible.

Patients, who achieved disease control, underwent ISMT until disease progression, development of intolerable toxicities, consent withdrawal, or investigator’s discretion to discontinue study treatment. Patients, who showed progressive disease (PD), underwent post therapy.

Patients received 3 cycles of induction therapy with paclitaxel (90 mg/m² intravenously, once daily, on days 1, 8, and 15 followed by 1-week drug holiday) and bevacizumab (10 mg/kg intravenously after the completion of paclitaxel administration on days 1 and 15) as PB therapy, followed by 1-week drug holiday on day 22. In patients whose status was rated to be stable disease (SD) or better during cycle 3 of the PB regimen, switch maintenance therapy with eribulin 1.4 mg/m² alone was conducted for 2 consecutive weeks during which they underwent infusion, once weekly, on days 1 and 8, as well as 1-week drug holiday at week 3. This cycle was repeated to the extent possible.

The following anticancer therapies were prohibited during the study period because of their potential effects on the assessment of the present clinical study: hormone therapy, immunotherapy, chemotherapy, radiotherapy, surgery, and systemic steroid therapy.

Between January 23, 2015, and February 25, 2016, a total of 53 Japanese female patients with MBC were recruited to the present clinical study at 4 medical institutions in Japan. Two of these patients were ineligible (one patient underwent 4 regimens of chemotherapy and another had systemic infection involving fever of 38°C). Therefore, 51 were enrolled in the study; 19 (37.3%) and 32 (62.7%) had stage IV and recurrence, respectively. Patient characteristics at baseline are shown in Table 1. The number of patients who underwent first-line chemotherapy was 34; and the number of patients who underwent second-line chemotherapy was 17, of whom 6 and 11 received anthracycline and oral 5-fluorouracil, respectively. None of them received both classes of anticancer drugs (Table 1). Among them, 43 (84.3%) were postmenopausal, 32 (62.7%) had MBC, 42 (82.4%) had visceral metastases, 16 (31.4%) had 5 or more metastases, 27 (53.0%) underwent hormone therapy previously, as well ass 42 (82.4%), 38 (74.5%), and 9 (17.6%) had estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, and triple-negative breast cancer, respectively. The most predominant site of metastases was the liver, followed by the lung and local lesion. Fifty-one and 45 patients were assessable for the efficacy and safety of the PB regimen and eribulin maintenance therapy, respectively.

Fifty-one and 45 patients in the PB regimen and eribulin maintenance therapy received the investigational drugs, respectively; the median of cycles delivered in the latter was 10 cycles (range: 1–29 cycles). The relative dose intensity (RDI) in the former was 97.7% (range: 33.3–100.0), with 3 dose reductions, 17 dose delays, and 9 dose discontinuations. In contrast, the RDI in the latter was 83.3% (49.3–100.6%), with 16 dose reductions, 35 dose delays, 38 dose discontinuations, and 2 combinations with pegylated granulocyte colony-stimulating factor.

Among 51 enrolled patients, 45 (88.2%) underwent maintenance treatment with eribulin alone—38 of whom had disease progression during a median follow-up of 17 months and 7 did not. The following best response rates were obtained (Table 2), and a flow diagram showing best overall responses to ISMT is shown (Fig. 1). In the PB regimen, the ORR was 51.0% (95% CI: 36.6–65.3) and the disease control rate (DCR: CR + PR + SD) was 90.2% (95% CI: 78.6–96.7). In eribulin maintenance therapy, the ORR was 64.4% (95% CI: 48.8–78.1) and the DCR was 93.3% (95% CI: 81.7–98.6). Furthermore, the following best overall responses were obtained with respect to 17 patients who underwent second-line chemotherapy: for 6 patients who received anthracycline, 3 each were rated to PR and SD; and 11 patients who received oral 5-fluorouracil, PR, SD, and PD were 8, 2, and 1, respectively. The Kaplan-Meier curves for TTF, PFS, and OS in ISMT are shown in Fig. 2. Median TTF was 9.2 months (95% CI: 7.3–11.1) (Fig. 2a), median PFS was 10.7 months (95% CI: 9.6–11.8) (Fig. 2b), and median OS was 20.0 months (95% CI: 16.0–24.0) (Fig. 2c). Waterfall plots (Fig. 3a-c) indicate percent changes in metastatic tumor size (total sum of the longest single dimension for measurable target lesions) from baseline to the maximal tumor shrinkage. In the vast majority of patients with MBC whose best tumor response was rated to be SD or better, consequently, tumor shrinkage was greater for eribulin maintenance therapy than for the PB regimen with respect to the following principal organs that showed the elevated incidences of visceral metastases: overall (Fig. 3a), liver (Fig. 3b), and lung (Fig. 3c). The shrinkage rates in the overall, liver, lung, and soft tissue were 93.3% (42/45), 96.4% (27/28), and 100.0% (18/18), respectively.

Among 38 patients who had disease progression, 10 had new lesions (6 in the central nervous system and 1 each in the liver, bone, peritoneum, and distal lymph nodes) and 28 had the deterioration of existing lesions.

Forty patients (78.4%), who showed disease progression in ISMT, underwent post therapy; 23 of these patients again underwent the PB regimen (Table 3). The DCR was 75.0% (15/20) for the PB regimen.

All of 51 patients who underwent the PB regimen and more than 80% of patients who underwent eribulin maintenance therapy experienced AEs (Table 4). All the AEs were clinically manageable by dose modifications (dose interruptions/delays or dose reductions) or symptomatic treatment. The most common hematologic AE was anemia in the PB regimen and eribulin maintenance therapy, being found in 58.8% (30/51) and 57.8% (26/45) of patients, respectively. Among nonhematologic AEs, alopecia (100%, 51/51) and all-grade peripheral sensory neuropathy (82.2%, 37/45) were most common in patients who underwent the PB regimen and eribulin maintenance therapy, respectively. The grade of peripheral sensory neuropathy deteriorated and improved in 14 and 3 patients who underwent eribulin maintenance therapy, respectively. Grade 3 peripheral sensory and motor neuropathies in the PB regimen and eribulin monotherapy were 15.7 and 37.8%, respectively. Grade 4, hematologic or nonhematologic AEs did not develop. No patient died in ISMT.