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First Taxane-Based Non-Anthracycline Containing Chemotherapy in Combination With Herceptin (TCH) for HER2 Positive Early Breast Cancer Patients Obtains Approval From the FDA
Date:5/29/2008

TCH (Taxotere, Carboplatin, Herceptin) showed a significant improvement in Disease-Free Survival (DFS) and Overall Survival (OS), compared to AC-T (doxorubicin and cyclophosphamide followed by docetaxel) and a 5-fold lower cardiotoxicity compared to AC-TH (AC-T + Herceptin) in women receiving

adjuvant therapy for HER2-positive ESBC

EDMONTON, Canada, May 29 /PRNewswire/ -- The Cancer International Research Group (CIRG), a division of TRIO (Translational Research in Oncology) announced today that, based on its study BCIRG 006, the U.S. Food and Drug Administration (FDA) has approved a new treatment consisting of the chemotherapeutic agents Taxotere(R) (docetaxel) and carboplatin combined with Herceptin(R) (trastuzumab) (TCH) for the adjuvant (post-surgery) treatment of HER2 (Human Epidermal growth factor Receptor 2)-positive early breast cancer. The AC-TH regimen (doxorubicin and cyclophosphamide followed by Taxotere and Herceptin), also investigated in the BCIRG 006 study, received approval at the same time.

Results from the BCIRG 006 clinical trial showed that the TCH regimen reduced the risk of disease recurrence by one third (HR=0.67, 95% CI [0.54-0.83], p=0.0003), compared to the AC-T control arm. The experimental AC-TH treatment reduced the risk of disease recurrence by 39 percent (HR=0.61, 95% CI [0.49-0.77], p<0.0001), compared to the AC-T control arm.

The DFS benefit of TCH and AC-TH was present regardless of a patient's age, the tumor responsiveness to hormones (hormone receptor status), or whether or not the cancer had spread to lymph nodes (nodal status). There was no statistically significant difference in DFS between the two experimental arms (TCH and AC-TH).

OS was also significantly improved with the TCH regimen with 34% reduction in the risk of death (HR=0.66, 95% CI [0.47-0.93], p=0.0182) compared to the AC-T control arm. Similarly, AC-TH was associated with a 42% reduction in the risk of death (HR=0.58, 95% CI [0.40-0.83], p=0.0024) compared to the AC-T control arm. There was no statistically significant difference in OS between the two experimental arms (TCH and AC-TH).

Moreover, with the TCH regimen, the risk of congestive heart failure was five-fold lower compared to that observed with AC-TH (0.4% vs 1.9% vs 0.3% in women treated with TCH, AC-TH, and AC-T respectively).

"The BCIRG 006 trial results give us a new option for the treatment of HER2 positive breast cancer. This approach exploits the most recent molecular information regarding the HER2 alteration allowing us to retain the remarkable benefits of Herceptin while leaving behind almost all of the major side effects," said Professor Dennis Slamon, Professor and Chief Hematology-Oncology UCLA Los Angeles and CIRG Chair. "The BCIRG design, while initially received controversially, was based on clean preclinical evidence that led us to test a novel combination of drugs in breast cancer."

About BCIRG 006

The BCIRG 006 was a phase III multicenter study conducted by the CIRG and sponsored by sanofi-aventis (Paris, France) with additional support from Genentech (South San Francisco, USA).

Study design

3,222 women with HER2-positive node-positive and high-risk node-negative operable breast cancer were enrolled and randomly assigned to one of the following treatments:

- AC-T (n=1,073), the anthracycline-containing control regimen consisting

of doxorubicin (A, 60 mg/m2) plus cyclophosphamide (C, 600 mg/m2) every

three weeks for four cycles followed by Taxotere(R) (T, 100 mg/m2)

every three weeks for four cycles.

- AC-TH (n=1.074), the anthracycline-containing experimental regimen

consisting of AC every three weeks for four cycles followed by

Taxotere(R) (T, 100 mg/m2) every three weeks for four cycles plus

Herceptin(R) (H, 4 mg/kg loading dose followed by 2 mg/kg per week

concurrently with T) and then Herceptin(R) monotherapy (6 mg/kg every

three weeks) to complete one year of Herceptin(R) treatment

- TCH (n=1.075), the non-anthracycline experimental regimen consisting of

Taxotere(R) (T, 75 mg/m2) plus carboplatin (C; AUC 6 mg/mL/min) every

three weeks for six cycles plus Herceptin(R) (H, 4 mg/kg loading dose

followed by 2 mg/kg per week concurrently with TC) and then Herceptin(R)

monotherapy (6 mg/kg every three weeks) to complete one year of

Herceptin(R) treatment.

The primary endpoint of the study was to compare disease-free survival (DFS) of each of the experimental regimens (TCH or AC-TH) with standard anthracycline-based chemotherapy (AC-T).

Secondary endpoints included evaluation of overall survival (OS) and cardiac toxicity. The first analysis (considered as the primary) was presented at the SABCS in 2006 and the updated results were communicated at SABCS in 2007.

Efficacy results

DFS was significantly improved by one third (33 percent) in the TCH treatment arm (HR=0.67, 95% CI [0.54-0.83], p=0.0003) and 39 percent (HR=0.61, 95% CI [0.49-0.77], p<0.0001) in the AC-TH arm, compared to the AC-T control arm. The DFS benefit of TCH and AC-TH was present regardless of a patient's age, the tumor responsiveness to hormones (hormone receptor status), or whether or not the cancer had spread to lymph nodes (nodal status). There was no statistically significant difference in DFS between the two experimental arms (TCH and AC-TH).

OS was also significantly improved with the TCH regimen with 34% reduction in the risk of death (HR=0.66, 95% CI [0.47-0.93], p=0.0182) compared to the AC-T control arm. Similarly, AC-TH was associated with a 42% reduction in the risk of death (HR=0.58, 95% CI [0.40-0.83], p=0.0024) compared to the AC-T control arm. There was no statistically significant difference in OS between the two experimental arms (TCH and AC-TH).

Tolerance

The most common adverse event was grade 3-4 febrile neutropenia (AC-T: 9.1%, AC-TH: 11.0%, TCH: 9.8%). Other common grade 3-4 adverse events included diarrhea (3.0% in the AC-T arm, 5.1% in the AC-TH arm, and 4.9% in the TCH arm) and infection without neutropenia (7.0% in the AC-T arm, 5.5% in the AC-TH arm, and 3.6% in the TCH arm).

The 3 year cumulative incidence of symptomatic cardiac events and congestive heart failure (0.3%, 1.9%, and 0.4% for AC-T, AC-TH, and TCH, respectively) was lower in the TCH arm compared to the AC-TH arm.

About the Cancer International Research Group (CIRG) and Translational Research in Oncology (TRIO)

CIRG is a not-for-profit research organization with offices based in Paris, France and Alberta, Canada. With an international network of 2000 investigators and 450 cancer centers in over 45 different countries, CIRG has conducted a number of new and innovative global studies evaluating systemic therapy for cancer. Recently, CIRG has partnered with the UCLA-based investigator network of Translational Oncology Research International, to form TRIO (Translational Research in Oncology). In addition to a network of dedicated investigators and clinical trial services, TRIO also includes the Slamon/TRIO laboratories at UCLA. Slamon and fellow scientists have developed and adapted preclinical models which allow for the validation of molecular markers, the preclinical assessment of new biologic agents and the characterization of an agent's mechanisms of action. This preclinical work, in turn, generates the clinical hypotheses for the group's future cancer trials in patients. This translational approach was the one used in the BCIRG 006.

TRIO is dedicated to advancing translational cancer research by bringing innovative and targeted therapeutics to clinical practice.

Additional information is available on the Internet at http://www.trioncology.org


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SOURCE Cancer International Research Group
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