CALGB 40603 Trial Supports Adding Carboplatin to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer
The addition of carboplatin to a neoadjuvant regimen significantly increased the rate of pathologic complete response in patients with triple-negative breast cancer. The results from the CALGB/Alliance 40603 study were reported at the 2013 San Antonio Breast Cancer Symposium (Abstract S5-01).
Bevacizumab (Avastin) was also evaluated in the study and had some effect when added to chemotherapy, but, due to its toxicity, was felt to be a less promising candidate for this approach.
“Based on these results, and those of the GeparSixto trial, if you decide that a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy, then it makes sense to add carboplatin to your neoadjuvant regimen. You can comfortably do so with acceptable additional toxicities,” said William M. Sikov, MD, FACP, of Brown University, Providence, Rhode Island, who presented the findings.
The rationale for the study was the achievement of pathologic complete responses in about one-third of patients with triple-negative disease after taxane-based neoadjuvant chemotherapy, the likelihood that patients with pathologic complete responses will have improved recurrence-free and overall survival, the activity of platinum analogues in advanced triple-negative disease, and the finding that bevacizumab can increase response rates and time to progression, he said.
Study Details
The phase II CALGB 40603 study enrolled 454 patients with stage II/III triple-negative breast cancer, randomly assigning participants to standard neoadjuvant chemotherapy or chemotherapy plus either carboplatin, bevacizumab, or the combination of carboplatin/bevacizumab.
Patients were randomly assigned in a 2×2 schema to receive weekly paclitaxel for 12 courses plus dose-dense anthracycline/cyclophosphamide with or without either the addition of bevacizumab every 2 weeks for nine cycles or the addition of carboplatin AUC 6 every 3 weeks for four cycles. The primary endpoint was pathologic complete response in the breast, and a secondary endpoint was pathologic complete response in the breast and the axillae.
Highest Rate Achieved With Combination
The investigators evaluated the effect of carboplatin on all patients receiving it (alone or in combination) and the same for bevacizumab.
“The addition of carboplatin to standard neoadjuvant chemotherapy significantly increased the pathologic complete response in the breast and also in the breast plus axillae,” Dr. Sikov reported.
For patients receiving carboplatin, 60% achieved a pathologic complete response, compared to 46% of those not receiving carboplatin, an increase of 76% (P = .0018). Defined by no disease in the breast or axillae, rates were 54% with carboplatin vs 41% without carboplatin, a 71% increase (P = .0029), Dr. Sikov reported.
Bevacizumab was active as well, yielding a statistically significant difference in the breast but not the axillae. Among patients receiving bevacizumab, 59% achieved a pathologic complete response in the breast, while 48% achieved this without bevacizumab, a 58% increase (P = .0089). Absence of residual disease in both breast and axilla was observed in 52% of patients receiving bevacizumab, and in 44% of those not receiving this drug, a 36% nonsignificant increase (P = .0570).
When carboplatin and bevacizumab were used in combination in addition to chemotherapy, 67% of patients achieved a pathologic complete response, however, a significant treatment interaction between the two drugs was not shown.
Bevacizumab More Toxic
Bevacizumab was considered more toxic, as was the combination. The total number of patients with a serious adverse event was 15 in the chemotherapy-alone arm, 39 with chemotherapy plus bevacizumab, 39 with chemotherapy plus carboplatin, and 46 with chemotherapy plus carboplatin/bevacizumab. Bevacizumab was associated with more grade 3 hypertension, infections, and postsurgical complications, with a slight increase in thrombosis and bleeding problems. Patients receiving carboplatin were more likely to experience neutropenia and thrombocytopenia, Dr. Sikov said.
Bevacizumab was discontinued in 23% of assigned patients, vs 6% to 13% for other agents.
“Bevacizumab did increase pathologic complete responses but at the cost of significant toxicities, and we don’t think it should be routinely added,” Dr. Sikov said at a press briefing.
Other Studies Support Carboplatin Use
Dr. Sikov noted that several studies now show that the addition of carboplatin increases pathological complete responses in patients with triple-negative disease, although recurrence-free and overall survival benefits have not yet been observed, largely due to short follow-up and lack of statistical power. He said that the general assumption is that achievement of pathologic complete response will, indeed, improve long-term outcomes, and he said that he incorporates carboplatin in the neoadjuvant setting in his patients.
Lajos Pusztai, MD, DPhil, of Yale University, New Haven, Connecticut, the formal discussant of the paper, said there is mounting evidence for using carboplatin, but less support for bevacizumab. He and his own research team have estimated that carboplatin plus chemotherapy will result in a 15% reduction in the risk for recurrence, “but this will most likely not reach statistical significance,” largely attributed to small sample size and limited statistical power.
“This provides a valuable new treatment option for patients with high-risk triple-negative disease,” Dr. Pusztai concluded. “The impact on survival may be modest, but real, I believe. Patient-level benefits, other than survival, exist that can be derived from more effective neoadjuvant chemotherapies.”
The study was funded by the National Institutes of Health, Genentech, and the Breast Cancer Research Foundation. Dr. Sikov reported no potential conflicts of interest.
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