Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study

Abstract

on behalf of the Spanish Breast Cancer Cooperative Group SOLTI Abstract Purpose: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC). Experimental Design: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter. Results: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC).The recommended doses of TLC-D99 and paclitaxel were 50 mg/m 2 every 3 weeks and 80 mg/m 2 /wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to z50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1months (95% confidence interval,3) in MBC patients. Conclusions: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.

Never use anthracyclines with trastuzumab: it is time to reconsider the taboo

“…The data reported by Stickeler et al find support in other small trials in which either pegylated [19][20][21] or nonpegylated doxorubicin [22] was combined with trastuzumab. Of note, in a Phase I/II trial that built on the combination of doxorubicin, paclitaxel and trastuzumab of the NOAH study and substituted the naked anthracycline with the non-pegylated liposomal formulation TLC-D99 the Authors reported an outstanding objective response rate of 98.1% in 69 patients with HER2-positive metastatic breast cancer, and a median time to progression exceeding 22 months at the cost of very good cardiac tolerability [23].…”

“…The clinical results are so promising to justify renewed attention to the possibility of widening the indication of trastuzumab to also include the co-administration with anthracyclines. Such scenario will have to wait for the results of prospective randomized tests that in some cases are already ongoing, as in the Breast cancer Adjuvant Caelyx Herceptin (BACH) study [8], or in the announced trial that will prospectively test in women with metastatic breast cancer the combination of trastuzumab and paclitaxel verses TLC-D99, trastuzumab and paclitaxel [23]. The time for reconsidering the taboo of never combining trastuzumab with anthracyclines has come.…”

Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age

“…Echocardiography has been used to determine cardiac function before treatment with NPLD [29,40]. BNP as marker for cardiac dysfunction could be used for therapeutic monitoring [41][42][43].…”

Role of trastuzumab in the management of HER2-positive metastatic breast cancer

“…112 Moreover, most of the trials associating liposomal anthracyclines with trastuzumab in metastatic disease revealed low incidence of symptomatic cardiac events. 50,[53][54][55][56][57] The CREC also reviewed a number of trastuzumab monotherapy trials and found a 3%-7% range of cardiac dysfunction. Patients enrolled in these trials were largely unselected and many of the patients who developed cardiac dysfunction had underlying cardiac disease or had received a cumulative anthracycline dose .400 mg/m.…”