CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC

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Abstract
512 Background: W P is active, well tolerated and feasible with high efficacy alone or with T (Seidman et al. JCO 1998 and 2001). The primary aims of this trial were to determine whether: 1) W P improves response rate (RR) vs. S P, regardless of HER2 status and assignment to T, and 2) T added to P improves RR vs. P alone for HER2 normal tumors. Secondary objectives were to evaluate time to progression (TTP) and overall survival (OS) with respect to the above comparisons. Methods: Patients (pts) with measurable MBC, 0–1 prior chemotherapy regimens for locally advanced or MBC, ≥ 1 year from adjuvant taxane (if any) were stratified by line of therapy and randomized unequally (40:60) to S P 175 mg/m2 or W P 80 mg/m2. After accrual of the first 171 pts, when T became accepted as standard therapy for pts with HER2 positive MBC (Slamon et al NEJM 2001), HER2 status was assessed locally, pts with HER2 positive MBC received T and pts with HER2 normal MBC were randomized for T (standard weekly dosing). 158 pts treated with S P in the prior CALGB 9342 trial (Winer et al. JCO 2004) contributed data to the S P group in C9840 by pre-designed analyses. Results: 585 pts entered (488 first-line/97 second-line), and 577 were treated (n=735 with C9342 pts). Efficacy was analyzed as prescribed in adjusted multivariate models, controlling for relevant covariates including line of therapy and trastuzumab use. W P was superior to S P with respect to RR: 40% vs. 28%, (OR=1.61, p=0.017), and TTP: 9 vs. 5 mos, (HR=1.45, p = 0.0008). In this model, OS was 24 mos for W P vs. 16 mos for S P, (HR=1.19, p = 0.17). For pts with HER2 normal MBC, T did not improve RR: 35% vs. 29%, p=0.34, TTP: 7 vs. 6 mos, p=0.09, or OS: 22 vs. 20 mos, p=0.67. W P caused more grade 3 sensory/motor neuropathy (23/8% vs. 12/4%, p=0.001/0.04), and less grade ≥ 3 granulocytopenia (8 vs. 15%, p=0.013). 5 pts (0.8%) experienced significant cardiac dysfunction, 4 on T arms. There were 2 treatment related deaths, both due to pneumonia, on W P. Conclusions: W P is superior to S P in the management of MBC. T does not improve efficacy of P in HER2 normal MBC. Characterization of tumor tissue for HER2 (immunohistochemistry and fluorescent in situ hybridization) and other potential correlates of T sensitivity is ongoing centrally, as are analyses of serial changes in serum HER2 extracellular domain and quality of life.

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