Paclitaxel Plus Bevacizumab for Management of Metastatic Breast Cancer

The results of the E2100 trial, an Intergroup trial coordinated by the Eastern Cooperative Oncology Group (ECOG), have established the role of adding bevacizumab to paclitaxel for patients with advanced breast cancer and form the main basis for this amendment to N0531.[1]

E2100 Study Design

E2100 enrolled 715 eligible patients with metastatic breast cancer (essentially all HER2-negative) to receive either weekly paclitaxel or the weekly paclitaxel in combination with bevacizumab, 10 mg/kg every 14 days. Data presented at the 2005 American Society of Clinical Oncology meeting 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.

Combination Regimen Shows Progression Free Survival Advantage

Progression free survival ( the study’s primary endpoint) was 6.11 months for paclitaxel 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 paclitaxel were enhanced by the addition of bevacizumab. Unique toxicities of bevacizumab 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 bevacizumab should be considered for all patients eligible to receive first line chemotherapy with paclitaxel 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 bevacizumab has been added to multiple other chemotherapy drugs, including 5-FU, irinotecan, combination paclitaxel plus carboplatin, gemcitabine in the setting of malignancies other than breast. Bevacizumab has also been evaluated with 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 capecitabine alone. Phase II combinations studies of bevacizumab with docetaxel, docetaxel with capecitabine, and others are currently ongoing.

Addition of Trastuzumab as Adjuvant Therapy for Patients with HER2-Positive Breast Cancer

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 oncology society meeting highlighted the first results of some of these trials: a joint analysis of NSABP B-31 with two 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 a 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.

B-31 and N9831 Study Designs

The NSABP B-31 is a phase III trial of doxorubicin and cyclophosphamide followed by paclitaxel (AC followed by paclitaxel) vs. ACfollowed bypaclitaxel plus 52 weeks of trastuzumab beginning with the first cycle of paclitaxel, in patients with HER2-positive, node-positive breast cancer. Although the paclitaxel was initially given once every three weeks for four doses, the study was later amended to allow for the use of paclitaxel in a weekly schedule for 12 doses.

The NCCTG N9831 study is a three-arm study comparing AC followed by weekly paclitaxel (control, Arm A) to AC followed by paclitaxel followed by 52 weeks of trastuzumab beginning after the completion of paclitaxel (sequential, Arm B) to AC followed by paclitaxel plus 52 weeks of trastuzumab beginning with the first paclitaxel cycle (concurrent, Arm C), in HER2-positive, node-positive and high-risk node negative patients.

Although some differences exist between the trials, including paclitaxel schedule (q 3 weeks 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.

Interim Analysis

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 trastuzumab to paclitaxel following AC chemotherapy in women with operable HER2-positive breast cancer. DFS was found to be significantly increased for those who were randomized to receive trastuzumab 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 May 16, 2005, at the annual meeting of the American Society of Clinical Oncology.[2]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 paclitaxel with concurrent trastuzumab relative to paclitaxel alone (HR = 0.48, 95% CI: 0.39 to 0.60, 2p = 2x10-12). 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 four years. There was also a 33% reduction in the hazard of death for patients randomized to paclitaxel with trastuzumab relative to paclitaxel alone (p= 0.015). There was increased incidence of class III/IV CHF and cardiac death in patients who received trastuzumab in combination with paclitaxel (3-4%).

The N9831 DSMB further recommended data from Arm B—the sequential schedule of paclitaxel and trastuzumab 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 American Society of Clinical Oncology meeting.[3]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 paclitaxel followed by trastuzumab relative to those women randomized to paclitaxel alone (2p=0.2936); two, a 36% decrease in the hazard of recurrence, second primaries and death for women randomized to trastuzumab in combination with paclitaxel relative to those women randomized to paclitaxel followed by trastuzumab (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 trastuzumab after the completion of at least four cycles of adjuvant chemotherapy +/- radiation therapy in women with HER2-positive breast cancer, were also presented at the May oncology meeting.[4]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 one 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 trastuzumab 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 trastuzumab containing arm and 0% in the non- trastuzumab containing arm. These data were of the no-trastuzumab versus one year of trastuzumab administered once every three weeks arms; data of the two year trastuzumab arm have not been released.

Conclusion

The results of these studies were impressive. Although longer follow up will be important, trastuzumab 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.