Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial

Abstract

The study was designed to evaluate efficacy and superiority of capecitabine/bevacizumab + vinorelbine (CAP/BEV/VIN) compared to CAP/BEV alone. Main purpose was to introduce a taxane-/anthracycline-free first-line treatment in advanced breast cancer (ABC), in order to avoid long-term toxicities. In this open-label, superiority, phase 3 trial, patients with HER2-negative ABC were randomized 1:1 to receive either oral CAP at 1000 mg/m2 [twice daily, days 1–14, q3w] plus intravenous BEV at 15 mg/kg [day 1, q3w] (arm A) or in addition to this protocol intravenous VIN at 25 mg/m2 [days 1 + 8, q3w] (arm B) until disease progression, unacceptable toxicity or withdrawal of consent. Between 26 February 2009 and 26 October 2012, we randomised 600 patients (arm A N = 300; arm B N = 300) from 57 German outpatient-centres and 2 university hospitals. Median progression-free survival (PFS) (primary endpoint) was not improved with VIN (CAP/BEV, 8.8 months; CAP/BEV/VIN, 9.6 months; HR 0.84 [95 % CI 0.70–1.01], P = 0.058). Median overall survival (OS) (secondary endpoint) was 25.1 and 27.2 months for CAP/BEV and CAP/BEV/VIN, respectively, average HR 0.85 [95 % CI 0.70–1.03], P = 0.104). The 1- and 2-year OS rates appeared to be similar (78.0 and 77.0 %; 53.0 and 54.0 %). Toxicity profiles were generally mild and manageable. Adverse events occurred more frequently in arm B. Regarding the balance between clinical efficacy (PFS, OS) and toxicity, the CAP/BEV combination provides a favourable treatment option in first-line ABC avoiding taxane- and/or anthracycline-induced long-term toxicity. Superiority of CAP/BEV/VIN was not met, and side effects were even enhanced. Nevertheless, no safety issues occurred.

Weekly paclitaxel, capecitabine, and bevacizumab with maintenance capecitabine and bevacizumab as first‐line therapy for triple‐negative, metastatic, or locally advanced breast cancer: Results from the GINECO A‐TaXel phase 2 study

“…An alternative approach to improve tolerability, evaluated in a German randomized phase 3 trial, was to replace the combination regimen of a taxane and capecitabine with a vinorelbine and capecitabine doublet combined with bevacizumab. The PFS was slightly (but not significantly) improved with the addition of vinorelbine to capecitabine plus bevacizumab, with a more pronounced effect observed in patients with TNBC (median PFS, 7.0 months) . Unlike our A‐TaXel study, both chemotherapy agents and bevacizumab were continued until disease progression or unacceptable toxicity.…”

“…The PFS was slightly (but not significantly) improved with the addition of vinorelbine to capecitabine plus bevacizumab, with a more pronounced effect observed in patients with TNBC (median PFS, 7.0 months). 26 Unlike our A-TaXel study, both chemotherapy agents and bevacizumab were continued until disease progression or unacceptable toxicity. Adverse events led to the discontinuation of bevacizumab in 31% of patients, capecitabine in 30% of patients, and vinorelbine in 34% of patients.…”

Tumour growth and immune evasion as targets for a new strategy in advanced cancer

“…Despite the availability of new biological drugs and a more rational use of therapies, the clinical outcome remains poor. Thus, the life expectancy of patients with advanced disease is dismal, and the median survival of a mixed population of metastatic breast cancer patients has not substantially improved in the last decades (Chia et al 2007, Dawood et al 2008, Welt et al 2016, Toss et al 2017.…”

Efficacy of bevacizumab combined with chemotherapy in the treatment of HER2-negative metastatic breast cancer: a network meta-analysis

“…In contrast to previous studies, other study suggested that bevacizumab plus capecitabine and taxanes did not show an improvement of PFS and safety in patients with HER2negative metastatic breast cancer [15]. Another concern has been the addition of second-line chemotherapy agents, such as vinorelbine, everolimus and trebananib, did not improve the efficacy of bevacizumab and taxanes, while adverse events were even enhanced [16][17][18].…”

“…Finally, sixteen studies were identified involving 589 patients that fulfilled the inclusion criteria in Fig. 1 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Figure 2 demonstrates all available direct comparisons across outcomes in this network meta-analysis.…”