Combination with Cytotoxic Agents

Preclinical studies suggest additive or synergistic interactions between trastuzumab and multiple cytotoxic agents. These data provide the rationale for exploring combination therapy. Pegram et al. (14) found laboratory evidence of synergy for the combination of trastuzumab with carboplatin, cyclophosphamide, docetaxel, and vinorelbine and additive effect for trastuzumab with doxorubicin, epirubicin, and paclitaxel. Although preclinical data are interesting, it is most important to follow the data from clinical trials.

Two important phase III trials have evaluated the addition of trastuzumab to chemotherapy in women with HER2 overexpressing MBC.

In a pivotal clinical trial reported by Slamon et al., patients received chemotherapy with either doxorubicin and cyclophosphamide (AC) or single-agent pacli-taxel with or without trastuzumab. The combination of chemotherapy and trastuzumab resulted in significantly higher overall response rates with a longer median time to disease progression and OS time than with chemotherapy alone (15). An improvement in median OS from 20.3 to 25.1 months (P = 0.046) was seen in the trastuzumab arm. About two-thirds of the patients in the chemotherapy-alone arm crossed over to receive trastuzumab at disease progression.

Another phase III trial evaluated single-agent docetaxel with or without tras-tuzumab, as first-line therapy for MBC also showed an improvement in median OS from 22.7 to 31.2 months (P = 0.0325) (16). Patients who went on to receive trastu-zumab at progression had a worse survival, compared with those who received the combination initially.

A quality of life (QOL) study designed to compare the effects of chemotherapy with chemotherapy plus trastuzumab reported a significant improvement in fatigue and improved global QOL in patients treated with the combination (17).

An increasing number of phase II studies and a phase III study support incorporation of carboplatin as a standard agent in the management of patients eligible to receive first-line chemotherapy for MBC. The rationale for combining carboplatin with a taxane is based on their single-agent activities in MBC, their complementary mechanisms of action, and their activity in other malignancies. In addition to a possible synergistic interaction, in vitro data suggest that trastu-zumab may also reverse primary platinum resistance by modulating HER2/neu activity (18). In addition, when used in combination, paclitaxel appears to have a platelet-sparing action that reduces the thrombocytopenia seen with carboplatin alone (19).

The NCCTG protocol 98-32-52 by Perez et al. (20) was a randomized phase II trial that tested carboplatin/docetaxel/trastuzumab as first-line chemotherapy in patients overexpressing HER2 with MBC. Patients received either every three-week therapy consisting of paclitaxel 200 mg/m2, carboplatin AUC 6, and trastuzumab administered every 21 days for eight cycles, or weekly therapy consisting of paclitaxel 80 mg/m2 and carboplatin AUC 2 for three of four weeks, with weekly trastuzumab administered every four weeks for six cycles. Trastuzu-mab was continued until disease progression or toxicity. The objective response rate (ORR) with the three-week therapy versus the weekly therapy was 65% (90% CI; 51-77%) and 81% (90% CI; 70-90%), with a median time to disease progression of 9.9 versus 13.8 months and median OS of 2.1 versus 3.2 years. Toxicities occurred significantly less frequently with weekly versus three-week therapy.

A phase III randomized trial tested the addition of carboplatin to paclitaxel and trastuzumab. The trial enrolled 188 patients and showed an improvement in response rate (RR) from 36% to 52% and time to tumor progression time to tumor progression (TTP) from 6.9 to 14.6 months with a trend in the OS in favor of the triplet of 42.1 versus 30.6 months (P = 0.11) (21). However, in the absence of a statistically significant survival benefit and without a comparison arm that automatically crossed over the nonplatinum group to platinum-containing therapy, it is difficult to assess the best combination.

0 0

Post a comment