Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer

Abstract

Background: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer.

Patients and methods: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS).

Results: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms.

Conclusion(s): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials.

Clinical trial number: NCT00294996.

Keywords: anthracyclines, HER2, cardiac safety, Myocet, trastuzumab; breast cancer.

Figure 1.

Kaplan–Meier estimates of progression-free survival based on (A) independent central review and (B) overall survival (intent-to-treat population). MTP, nonpegylated liposomal doxorubicin + trastuzumab + paclitaxel; TP, trastuzumab + paclitaxel; HR, hazard ratio.

Figure 2.

Hazard ratios with 95% confidence intervals of progression-free survival (A) and survival (B) by prespecified stratification factors based on independent central review (intent-to-treat population). MTP, nonpegylated liposomal doxorubicin + trastuzumab + paclitaxel; TP, trastuzumab + paclitaxel; HR, hazard ratio.

Figure 3.

Kaplan–Meier estimates of progression-free survival (A) and survival (B) in patients with ER- and PR-negative tumors. Exploratory analysis excluding patients with undocumented ER and PR status from the prespecified stratum. MTP, nonpegylated liposomal doxorubicin + trastuzumab + paclitaxel; TP, trastuzumab + paclitaxel; HR, hazard ratio.