May 13-17Orlando, Florida Edith A. Perez, MD
Mayo Clinic, Jacksonville, Florida
Taxol® Plus Avastin® for Management of Metastatic Breast Cancer (MBC)
The results of the E2100 trial have established the role of adding Avastin (bevacizumab) to Taxol (paclitaxel) for patients with advanced breast cancer and form the main basis for this amendment to N0531.
E2100 is an Intergroup trial coordinated by ECOG, which enrolled 715 eligible patients with MBC (essentially all HER2 negative) to receive either weekly Taxol or the weekly Taxol in combination with Avastin, 10 mg/kg every 14 days. Data presented at ASCO 2005 were based on 355 events observed, which allowed for a first interim analysis. Median age was 56 years; 64% had received adjuvant chemotherapy, and 63% had ER+ breast cancer. Progression free survival (primary endpoint) was 6.11 months for Taxol and 10.97 months for the combination arm, for a hazard ratio of 0.498 (95% CI, 0.401-0.618), and a p value of <0.001. A trend for improvement in overall survival was also noted, with a hazard ratio of 0.674 (95% CI, 0.495-0.917), p= 0.01. In terms of toxicity, both regimens were well tolerated. There was no evidence that toxicities of weekly Taxol were enhanced by the addition of Avastin. Unique toxicities of Avastin were mild and included 1.2% grade 3 thromboembolic events, 0.6% grade 3 bleeding, 0.3% grade 4 bleeding, 0.9% grade 3 proteinuria and 1.5% grade 4 proteinuria. There was no evidence of cardiac toxicity. Evaluation of tissue markers to predict for efficacy is a matter of ongoing and planned research.
The recommendations after this study included continued follow up, but also that Avastin should be considered for all patients eligible to receive first line chemotherapy with Taxol for metastatic disease. Issues of cost effectiveness will need to be revisited when longer follow up is obtained. Additionally, subset analyses and correlative laboratory studies may help identify groups of patients or biological tumor characteristics to assist in patient selection for this therapy, and this work is ongoing.
Of note is that Avastin has been added to multiple other chemotherapy drugs, including 5-FU, Camptosar® (irinotecan), combination Taxol + Paraplatin® (carboplatin), Gemzar® (gemcitabine) in the setting of malignancies other than breast. Avastin has also been evaluated with Xeloda® (capecitabine) in a prior study of patients with MBC previously treated with anthracyclines and taxanes, either in the adjuvant or metastatic setting, demonstrating lack of benefit in terms of either progression free survival or survival when compared to Xeloda alone. Phase II combinations studies of Avastin with Taxotere® (docetaxel), Taxotere with Xeloda, and others are currently ongoing.
Addition of Herceptin® as Adjuvant Therapy for Patients with HER2 Positive Breast Cancer
Herceptin (trastuzumab) is a humanized monoclonal antibody targeting the extra cellular domain of the HER2 protein receptor that has been demonstrated to improve survival when used in combination with chemotherapy in patients with HER2 positive metastatic breast cancer. Several worldwide trials were initiated starting in the year 2000 evaluating the addition of this agent to chemotherapy for patients with resected breast cancer. Three presentations given at the 2005 ASCO meeting highlighted the first results of some of these trials: one of the joint analysis of NSABP B-31 with 2 of the arms of NCCTG N9831, a presentation of an unplanned interim analysis of NCCTG N9831 conducted at the request of the Data Monitoring Committee to assist in patient management, and one on the first-interim results of the HERA trial. The data from these studies merit a change in practice related to adjuvant management of patients with HER2-positive breast cancer, highlighting the critical importance of accurate HER2 testing and cardiac monitoring.
The NSABP B-31 is a phase III trial of doxorubicin and cyclophosphamide followed by Taxol (AC followed by Taxol) vs. AC
Taxol plus 52 weeks of Herceptin beginning with the first cycle of Taxol, in patients with HER2-positive, node-positive breast cancer. Although the Taxol was initially given once every 3 weeks for 4 doses, the study was later amended to allow for the use of Taxol in a weekly schedule for 12 doses.
The NCCTG N9831 study is a 3-arm study comparing AC followed by weekly Taxol (control; Arm A) to AC followed by Taxol followed by 52 weeks of Herceptin beginning after the completion of Taxol (sequential; Arm B) to AC followed by Taxol plus 52 weeks of Herceptin beginning with the first Taxol cycle (concurrent; Arm C), in HER2-positive, node-positive and high-risk node negative patients.
Although some differences exist between the trials, including Taxol schedule (q 3 week or weekly), use of hormonal treatments, and recommendations for post surgical radiotherapy, the control and investigational arms of B-31 are similar to Arms A and C of N9831. Accordingly, the two cooperative groups proposed and then conducted a joint efficacy analysis of the named arms, with disease-free survival (DFS) as primary endpoint.
In April of 2005, there were sufficient events (recurrences, second primary cancers, and deaths) on NSABP B-31 and NCCTG N9831 to trigger the first joint interim analysis assessing the impact of the addition of Herceptin to Taxol following AC chemotherapy in women with operable HER2+ breast cancer. DFS was found to be significantly increased for those who were randomized to receive Herceptin added to chemotherapy relative to those who were randomized to chemotherapy alone. The results crossed the pre-specified early-reporting boundary (2p= 0.001) and as such the B-31 DSMB and the N9831 DSMB were independently informed of the interim analysis findings. Both DSMB recommended that the findings be released.
The findings of this interim analysis were presented at the annual meeting of ASCO on May 16, 2005.
The joint analysis team reported that there was a 52% decrease in the hazard of recurrence, second primary cancer, or death for patients randomized to Taxol with concurrent Herceptin relative to Taxol alone (HR=0.48, 95%CI: 0.39 to 0.60, 2p= 2×10-12). Absolute difference in DFS was estimated to be 12% at 3 years (95%CI: 8 to 15%) and 18% (95%CI: 13 to 24%) at 4 years. There was also a 33% reduction in the hazard of death for patients randomized to Taxol with Herceptin relative to Taxol alone (p= 0.015). There was increased incidence of class III/IV CHF and cardiac death in patients who receivedHerceptin in combination with Taxol (3-4%).
The N9831 DSMB further recommended data from Arm B-the sequential schedule of Taxol and Herceptin after AC chemotherapy-be released after learning of the results of the joint analysis. The results of this unplanned comparison of DFS among the treatment arms in N9831 were also presented at the 2005 ASCO meeting.
Fewer than 25% of the events necessary for the final planned analysis had occurred at the time of this analysis. The N9831 study team reported: one, there was an estimated 13% decrease in the hazard of recurrence, second primaries and death for women randomized to Taxol followed by Herceptin relative to those women randomized to Taxol alone (2p=0.2936); two, a 36% decrease in the hazard of recurrence, second primaries and death for women randomized to Herceptin in combination with Taxol relative to those women randomized to Taxol followed by Herceptin (2p= 0.0114); and, three, the rate of cardiac events (CHF and cardiac death) in the Herceptin containing arms did not exceed that of the non-Herceptin containing arm by more that 4%. Further follow up is needed to determine whether these early trends continue.
Results of HERA Phase III Clinical Trial
The results of a planned interim analysis from HERA, another multicenter phase III clinical trial assessing the impact of the addition of Herceptin after the completion of at least 4 cycles of adjuvant chemotherapy +/- radiation therapy in women with HER2 positive breast cancer, were also presented at 2005 ASCO meeting.
The patient population was different from that enrolled in the U.S. studies, as all chemotherapy and radiotherapy had to be completed before enrollment, only 68% of patients received adjuvant anthracyclines and only 26% received both anthracyclines and taxanes.
At a median follow up of 1 year, the HERA team found a significant increase in DFS, with a 46% decrease in the hazard of recurrence, second primaries and death for women randomized to Herceptin relative to those women randomized to observation (HR= 0.54, 95%CI: 0.43-0.67, 2p<0.001). The rate of cardiac events (CHF and cardiac death) was 0.5% in the Herceptin containing arm and 0% in the non-Herceptin containing arm. These data were of the no Herceptin versus 1 year of Herceptin administered once every 3 weeks arms; data of the 2 year Herceptin arm have not been released.
The results of these studies were impressive. Although longer follow up will be important, Herceptin should be added to chemotherapy for patients eligible to receive adjuvant therapy for resected breast cancer. HER2 testing may include either evaluation for HER2 protein or the HER2 gene and should be performed at an experienced facility.
Miller KD, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenker TN, Davidson NE. E2100: A randomized phase III trial of paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005; Educational Session.
Romond EH, Perez EA, Bryant J, et al. Advances in monoclonal antibody therapy for breast cancer: Combined analysis of NSABP-B31/NCCTG-N9831. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005; Oral Presentation.
Perez EA, Suman VJ, Davidson N, et al. Advances in monoclonal antibody therapy for breast cancer: further analysis of NCCTG N9831. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005; Educational Session.
Piccart-Gebhart MJ. Advances in monoclonal antibody therapy for breast cancer: first results of the HERA trial. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005; Oral Presentation.