Abstract P1-12-01: Evaluation on efficacy and safety of capecitabine plus docetaxel versus docetaxel monotherapy in metastatic breast cancer patients pretreated with anthracycline: Results from a randomized phase III study (JO21095)

Abstract

Introduction: A previous large-scale phase III study demonstrated that, compared with docetaxel (T) alone, capecitabine (X) and T in combination (XT) offered significantly superior progression free survival (PFS) and overall survival (OS) in metastatic breast cancer (MBC). However, XT increased Grade 3/4 adverse events (AEs) which led to more frequent dose reductions than with T alone. Optimal dose of XT in Japanese was examined in a phase Ib study. Based on the background, we conducted a phase III randomized study in Japanese HER2 negative MBC patients pre-treated with anthracycline to compare efficacy and safety of XT therapy and T therapy. Methods: Eligible pts were HER2-negative MBC pts with anthracycline-pretreatment, a measurable tumor, and ECOG performance status of 0 or 1. Pts were randomly assigned to the XT group or the T→X group. The XT group received concurrent therapy of X (1650 mg/m2/day from day 1 to 14) and T (60 mg/m2) in 3-week cycle. The T→X group received sequential therapy of T (70 mg/m2) in 3-week cycle followed at disease progression by X (2500 mg/m2/day from day 1 to 14 followed by 1-week rest). Primary endpoint was PFS. Secondary endpoints were OS, overall response rate (ORR), time to treatment failure (TTF), safety, and quality of life. The XT group and the T phase of the T→X group (T group) were compared in our evaluation. Results: Of 163 pts enrolled, 156 were eligible. Baseline characteristics of all pts in each group were well balanced. The median delivered dose was 79.0% and 95.1% of the planned dose respectively for X and T in the XT group, and it was 97.2% in the T group. Median PFS in the XT group was 10.5 months compared to 9.8 months in the T group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40–0.97). The ORR was 70% and 61%; the median TTF was 9.6 months and 7.0 months in the XT group and the T group, respectively. Median OS has not been reached yet. Subgroup analysis showed PFS was longer in pts with liver metastasis (HR, 0.39; 95% CI, 0.19–0.84) and in pts with lung metastasis (HR, 0.43; 95% CI, 0.21–0.90) in the XT group. Incidence of treatment related AEs (TR-AEs) ≥Grade 3 was 74.4% (61 pts) in the XT group and 76.3% (61 pts) in the T group. Frequently reported TR-AEs ≥Grade 3 were; decrease in neutrophil count (XT, 57.3%; T, 60.0%), neutropenia (XT, 8.5%; T, 12.5%) and febrile neutropenia (XT, 6.1%; T, 10.0%). TR-AE ≥Grade 3 in the XT group with incidence at least 5% higher than the T group was hand-foot syndrome (XT, 7.3%; T, 0%). On the other hand, TR-AEs ≥Grade 3 in the T group with incidence at least 5% higher than the XT group were fatigue (XT, 2.4%; T, 8.8%) and peripheral edema (XT, 1.2%; T, 6.3%). Conclusion: The concurrent therapy of XT demonstrated significant improvement of PFS compared with T alone. Superior efficacy of XT therapy was reported as same as the previously reported study on XT versus T although the dose was lower in our study. Considering the efficacy and tolerability, we consider concurrent Japanease dose XT therapy is a preferable treatment for MBC pts with liver or lung metastasis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-01.

Second-line single-agent chemotherapy in human epidermal growth factor receptor 2-negative metastatic breast cancer: A systematic review

“…A PRISMA flow diagram of the citation screening for the original and updated SRs is shown in Table 1 categorises included RCTs by treatment line, including key trial characteristics. Of the 14 second-and/or later-line papers, five [19][20][21][22][23] reported data for a purely second-line patient population, three [24][25][26] reported data from mixed-line treatment but provided results for the second-line subgroup separately, three [27][28][29] had unclear second-line status (i.e. it was unclear whether the previous therapy had been given in the adjuvant or metastatic setting), two [30,31] reported data from second-or later-line patients, and one [32] reported data from a second-or later-line subgroup separately.…”

“…Only three trials enrolled confirmed HER2-negative patients specifically [19,27,29] An overview of the patient characteristics across treatment arms is shown in Table 2. Within trials, there were some potential imbalances between treatment arms: the proportion of patients with oestrogen or progesterone receptor positivity (ER+ and/or PR+) in Baselga et al, 2012 [29] was numerically higher on sorafenib + capecitabine vs capecitabine; the proportion ER+ in Venturino et al, 2000 [20] was higher in the vinorelbine monotherapy arm; the proportion of patients with ECOG (Eastern Cooperative Oncology Group) status 0 was higher with docetaxel monotherapy vs docetaxel + gemcitabine in Papadimitriou et al, 2009 [23]; median ECOG status was lower in the vinorelbine monotherapy arm and the proportion of patients with visceral metastases also lower in Venturino et al, 2000 [20]; the proportion of patients with visceral metastases was numerically higher on mitomycin vs paclitaxel in Dieras et al, 1995 [21]; and median age was slightly higher in the epirubicin arm vs doxorubicin in Gasparini et al, 1991 [22].…”

“…The primary endpoint was OS in two trials [26,30], PFS in four [19,27,29,31], overall response in three [23,28,32] and not reported in five papers published between 1990 and 2000 [20-22, 24, 25] ( Table 1). Safety/toxicity was typically a secondary endpoint, amongst others.…”

“…Median PFS was reported in four trials [19,27,29,31,34]. Three trials demonstrated significantly longer PFS: capecitabine + sorafenib (6.4 months) vs capecitabine (4.1 months), HR 0.58 (95% CI: 0.41, 0.81), p=0.001 [29]; capecitabine + low dose DTX (10.5 months) vs DTX monotherapy before having sequential capecitabine (9.8 months), HR 0.62 (95% CI: 0.40, 0.97), p=0.0342 [27]; bevacizumab + chemotherapy (6.3 months, 95% CI: 5.4, 7.2) vs single-agent treatment of physician's choice (TPC) (approx. 60% capecitabine) (4.2 months, 95% CI: 3.9, 4.7), HR 0.75 (95% CI: 0.61, 0.93), p=0.0068 [19].…”

“…Low-dose (60mg/m 2 ) docetaxel + capecitabine concomitantly, which had shown a PFS benefit vs docetaxel 70mg/m 2 (prior to sequential capecitabine) showed non-significantly reduced haematological AEs, higher frequency of hand-foot syndrome (7.4% vs 0%, respectively) and lower frequencies of fatigue and peripheral oedema ( Table 5) [27]. Paclitaxel 3qw had shown increased TTP vs mitomycin, but the safety profile was difficult to interpret because although taxane therapy was associated with more frequent grade III/IV neutropenia & peripheral neuropathy, patients received substantially more courses of PTX than mitomycin [21].…”