Add-on agents boost neoadjuvant chemo response in triple-negative disease

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.