The achievement of a pathologic complete response in patients with triple-negative breast cancer was boosted by the addition of carboplatin to a standard neoadjuvant chemotherapy regimen, and by the addition of veliparib, an investigational oral PARP inhibitor, plus carboplatin to a standard chemotherapy regimen, in studies presented at the 2013 San Antonio Breast Cancer Symposium.
William Sikov, MD, Associate Professor of Medicine at Brown University, Providence, Rhode Island, reported the results from the Cancer and Leukemia Group B (CALGB)/Alliance 40603 study,1 concluding, “Based on these results, and those of the GeparSixto trial,2 if you decide that a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy, it would be reasonable to add carboplatin. You will increase the likelihood of response in the breast and axillary nodes, and can do so with acceptable additional toxicities, primarily an increase in neutropenia and thrombocytopenia.”
Bevacizumab (Avastin) was also evaluated in the study, and also increased pathologic responses when added to chemotherapy, but, considering its toxicity, was felt to be a less promising approach.
CALGB/Alliance 40603 Study
The phase II CALGB/Alliance 40603 study enrolled 454 patients with stage II/III triple-negative breast cancer, randomly assigning them to standard neoadjuvant chemotherapy or chemotherapy plus carboplatin, bevacizumab, or the combination. Patients received weekly paclitaxel for 12 courses plus dose-dense anthracycline/cyclophosphamide alone, or with 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. 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 in the breast, compared to 46% of those not receiving carboplatin. When defined as no disease in the breast or axillae, pathologic complete response 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 in the breast and axilla. When carboplatin and bevacizumab were used in combination in addition to chemotherapy, 67% of patients achieved a pathologic complete response in the breast. However, a significant treatment interaction between the two drugs was not shown.
Bevacizumab proved more toxic, as did chemotherapy plus both experimental agents. The total number of patients with a serious adverse event was 15 in the chemotherapy-alone arm, 39 with chemotherapy plus bevacizumab, 29 with chemotherapy plus carboplatin, and 46 with chemotherapy plus the two agents. Bevacizumab was associated with more grade 3 hypertension, infections, and postsurgical complications, as well as a slight increase in thrombosis and bleeding problems. Patients receiving carboplatin were more likely to experience neutropenia and thrombocytopenia. Most treatment discontinuations were seen with bevacizumab.
“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.
The I-SPY 2 trial is an ongoing multidrug, multicenter neoadjuvant phase II breast cancer trial. Findings reported at San Antonio included positive results for the PARP inhibitor veliparib, the first drug to complete testing in the trial. Adding carboplatin and veliparib to standard presurgery chemotherapy improved estimated pathologic complete response rates for the subset of women with triple-negative breast cancer.3
I-SPY 2, devised by Laura J. Esserman, MD, and Don Berry, PhD, uses an adaptive randomized design to learn which patients respond better to which therapies as the trial proceeds. To be eligible, patients must have a breast tumor measuring at least 2.5 cm and be considered at high risk for early breast cancer recurrence by MammaPrint evaluation, or have triple-negative or HER2-positive disease regardless of MammaPrint results.
For this portion of the trial, patients were randomly assigned to standard neoadjuvant chemotherapy—weekly paclitaxel for 12 weeks, followed by anthracycline-based chemotherapy for four courses—or to the same regimen plus veliparib at 100 mg/d plus carboplatin AUC 6 every 3 weeks during paclitaxel. Among 71 patients assigned to the veliparib-containing regimen, 38 had triple-negative breast cancer and 33 had hormone receptor–positive, HER2-negative disease.
The estimated pathologic complete response rate for patients with triple-negative breast cancer was 52% after receipt of chemotherapy plus veliparib/carboplatin and standard paclitaxel followed by anthracycline-based chemotherapy vs 26% with control chemotherapy alone, corresponding to a 99% probability that this regimen is superior to the control, reported Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.
Thus, veliparib and carboplatin arm met the threshold for graduation—meaning a 90% chance of success when tested in a 300-patient phase III neoadjuvant trial. AbbVie is planning to open such a trial early this year, Dr. Rugo told The ASCO Post.
In “signatures” other than triple-negative breast cancer, the combination was predicted to be far less successful. For example, for the hormone receptor–positive/HER2-negative group, the estimated pathologic complete response rate was 14% for the combination and 19% for controls, she said.
“These data show that the adaptive design of I-SPY 2 can generate results that will power phase III registration trials,” said Dr. Rugo. “By identifying which patients benefit, we can reduce trial size, accelerate drug development, and avoid overtreatment in the majority of patients, which is the future of drug development.”
Use of Carboplatin
Dr. Sikov noted that several studies now show that the addition of carboplatin increases pathologic complete responses in patients with triple-negative disease, though 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 he incorporates carboplatin in the neoadjuvant setting in his patients.■
Disclosure: Drs. Sikov and Rugo reported no potential conflicts of interest.
1. Sikov WM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013.
2. von Minckwitz G, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2012.
3. Rugo HS, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013.
Lajos Pusztai, MD, DPhil, Professor of Medicine and Director of Breast Medical Oncology at Yale University, New Haven, Connecticut, who was the formal discussant of the papers by Sikov et al and Rugo et al, said there is mounting evidence for using carboplatin. He and his own research team have...