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Adding carboplatin to docetaxel (Taxotere) and trastuzumab (Herceptin) failed to lengthen the lives of women with HER2-positive metastatic breast cancer in an international phase III trial. The three-drug regimen was as effective as the combination of docetaxel (Taxotere) and trastuzumab (Herceptin). Median overall survival for both regimens was over 36 months and time to tumor progression exceeded 10 months at a median follow-up of 39 months.
The 3-year survival outcome is "among the longest yet reported," said Dr. Mark Pegram, who presented the data on behalf of the Breast Cancer International Research Group (BCIRG). Hoffmann-La Roche and Genentech, makers of trastuzumab, sponsored the study (BCIRG 007) with support from Sanofi-Aventis, maker of docetaxel.
For the trial, 263 women (average age 52) were enrolled at 58 centers. Investigators randomized 131 to docetaxel and trastuzumab, and 132 to the same two drugs plus carboplatin. Both regimens were given in eight 3-week cycles.
All women got a loading dose of 4 mg/kg of trastuzumab followed by 2 mg/kg weekly during treatment and 6 mg/kg every 3 weeks afterward until disease progression. The docetaxel dose was lower in the triplet arm, 75 mg/m² weekly, as compared with 100 mg/m² on the same schedule in the doublet arm. The carboplatin dose was AUC:6.
The trial did not rule out a contribution by carboplatin, according to Dr. Pegram of the University of California David Geffen School of Medicine. The trial was underpowered to detect small differences in clinical outcome, he said, and "asymmetry in docetaxel dosing" may have affected the outcomes.
The discussant, Dr. Luca Gianni of the Istituto Nazionale dei Tumori di Milano in Italy, concurred that the trial's small size and different docetaxel dosing "prevents a clear assessment of the role of carboplatin."
Both said differences in toxicity would influence choice of regimen. "You make your pick based on this because the activity is the same," Dr. Gianni said.
As expected, grade 3 and 4 thrombocytopenia was more prevalent in the three-drug arm: 15% vs. 2.3% (P less than .001). There were also two septic deaths vs. none in the doublet arm, but other hematological toxicities were not different. Febrile neutropenia occurred in 12% in the two-drug arm and 13% of those who also got carboplatin.
Some nonhematological toxicities were significantly greater in the two-drug arm: sensory neuropathy (57% vs. 44%), myalgia (44% vs. 31%), rash (32% vs. 15%), and nail changes (55% vs. 33%). Conversely, nausea occurred significantly more often in women receiving all three drugs (73% vs. 53%), as did emesis (44% vs. 28%).
Over three-fourths (79%) of patients completed the triplet regimen. Less than two-thirds (64%) in the doublet arm finished eight treatment cycles.n
Pegram M. et al. BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). Abstract LBA1008.
Commentary |
The updated data presented by Pegram et al. on the BCIRG 007 trial raise a few issues. The trial design and statistical plan is such that it is not implausible that the triplet of TCH (docetaxel, carboplatin, trastuzumab) could be somewhat superior to the doublet of TH (docetaxel, trastuzumab). A larger study, which will not be done, could potentially answer that question more definitively. Alternatively, TCH as given in this trial could be the same as TH (with docetaxel at 100 mg/m²) with respect to antitumor efficacy, though toxicity differs between the two regimens. The findings also raise the issue of whether TH could achieve the same risk reduction as TCH, as evaluated in adjuvant trials by the BCIRG trial. Although seemingly identical to TCH in clinical efficacy, TH did cause more neuropathy, myalgia, rash, and nail changes, whereas TCH was associated with more nausea and vomiting. — William J. Gradishar, M.D.
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