December 7, 2011 (San Antonio, Texas) — The combination of trastuzumab (Herceptin, Roche/Genentech) and the experimental agent pertuzumab (Roche/Genentech) significantly prolonged progression-free survival (PFS) by 6 months compared with trastuzumab alone, according to a new study of HER2-positive metastatic breast cancer in the first-line setting.
All 808 women in the phase 3 study also received docetaxel.
The further good news from the study, which is known as CLEOPATRA (CLinical Evaluation Of PertuzumAb and TRAstuzumab), is that the combination of the 2 targeted therapies did not increase cardiac toxicity, according to the study authors who were led by José Baselga, MD, PhD, professor of medicine at Harvard Medical School and associate director of the Massachusetts General Hospital Cancer Center in Boston.
The results are published online December 7 in the New England Journal of Medicine and will be presented here at the 34th Annual San Antonio Breast Cancer Symposium.
The median PFS was 18.5 months in the pertuzumab group compared with 12.4 months in the control group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 - 0.75; P < .001).
The interim analysis of overall survival also showed a strong trend in favor of pertuzumab group, said Dr. Baselga and an international team of colleagues.
"This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS," said Dr. Baselga in a press statement.
"This combination is likely to become a standard of care in this setting," said Harold Burstein, MD, from Dana-Farber Cancer Institute in Boston, Massachusetts, adding the caveat that the agent still needs regulatory approval.
He spoke with Medscape Medical News at the breast cancer meeting.
"The results are better than imagined. This is a fairly robust improvement. I think there will be tremendous interest [in the combination]," he added.
Dr. Burstein also pointed out that the control group of the study, the trastuzumab plus docetaxel group, had an above-average PFS; the average PFS in this setting is 8 to 10 months. Thus, the superiority in PFS found with the addition of pertuzumab was not because the control group performed poorly, he said.
Need for New Treatments
The safety profile was generally similar in the 2 groups, with no increase in left ventricular systolic dysfunction, said the authors. The rates of febrile neutropenia and diarrhea of grade 3 or greater were higher in the pertuzumab group (48.9% and 7.9%, respectively) than in the control group (45.8% and 5%), the authors highlighted.
New therapies for metastatic HER2-positive disease are needed, pointed out William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago, Illinois.
"Despite the practice-changing impact of trastuzumab and the substantial improvement in outcomes, patients with HER2-positive metastatic breast cancer ultimately die from the disease," he writes in an editorial that accompanies the new study.
Like trastuzumab, pertuzumab is a humanized monoclonal antibody and stimulates antibody-dependent, cell-mediated cytotoxicity. However, pertuzumab binds HER2 at a different epitope than that at which trastuzumab binds, explain the study authors.
As a single agent, pertuzumab has only "modest antitumor activity," said Dr. Gradishar. However, preclinical studies showed that the 2 agents had a "synergy," he added.
Dr. Baselga and his colleagues explain that synergy. Because pertuzumab and trastuzumab have complementary mechanisms of action and bind at different epitopes, the combination of the 2 agents provide a "more comprehensive blockade of HER2 signaling and result in greater antitumor activity than either agent alone," they write, referring to HER2-positive tumor model studies.
Study Details
The double-blind trial involved patients with HER2-positive metastatic breast cancer who had not received chemotherapy or biologic therapy for their metastatic disease. The primary end point in the study was progression-free survival, as determined by an independent review facility.
Patients received a loading dose of 8 mg of trastuzumab per kg of body weight, followed by a maintenance dose of 6 mg per kg every 3 weeks until disease progression or the development of unmanageable toxicity. Docetaxel was administered every 3 weeks at a starting dose of 75 mg/m2, which could be increased to 100 mg/m2 if tolerated or could be adjusted downward if needed. The recommended number of cycles was 6.
Pertuzumab or placebo was given at a fixed loading dose of 840 mg, followed by 420 mg every 3 weeks until disease progression or the development of unmanageable toxicity.
Adding pertuzumab to the trastuzumab plus docetaxel combination therapy resulted in an objective response rate (tumor shrinkage of at least 30%) of 80.2% compared with 69.3% for the combination therapy alone.
Although survival outcomes are not mature, Dr. Baselga and colleagues reported 69 deaths among the 402 patients treated with the 3-drug combination and 96 deaths among the 406 patients who received 2 drugs in the control group.
The 3-drug combination is "remarkably safe and well tolerated. Only minimal side effects were seen with the addition of pertuzumab," said Dr. Baselga in a press statement. Left ventricular systolic dysfunction of grade 3 or higher was reported in 2.8% of the patients in the 2-drug control group and in 1.2% of the patients in the 3-drug pertuzumab group.
Enrollment is underway in a new double-blind, randomized clinical trial to test the use of pertuzumab as adjuvant treatment for early-stage HER2-positive breast cancer.
The study was funded by Roche/Genentech. Dr. Baselga, Dr. Burstein, and Dr. Gradishar have disclosed no relevant financial relationships.
34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-5. Presented December 9, 2011.
All 808 women in the phase 3 study also received docetaxel.
The further good news from the study, which is known as CLEOPATRA (CLinical Evaluation Of PertuzumAb and TRAstuzumab), is that the combination of the 2 targeted therapies did not increase cardiac toxicity, according to the study authors who were led by José Baselga, MD, PhD, professor of medicine at Harvard Medical School and associate director of the Massachusetts General Hospital Cancer Center in Boston.
The results are published online December 7 in the New England Journal of Medicine and will be presented here at the 34th Annual San Antonio Breast Cancer Symposium.
The median PFS was 18.5 months in the pertuzumab group compared with 12.4 months in the control group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 - 0.75; P < .001).
The interim analysis of overall survival also showed a strong trend in favor of pertuzumab group, said Dr. Baselga and an international team of colleagues.
"This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS," said Dr. Baselga in a press statement.
"This combination is likely to become a standard of care in this setting," said Harold Burstein, MD, from Dana-Farber Cancer Institute in Boston, Massachusetts, adding the caveat that the agent still needs regulatory approval.
He spoke with Medscape Medical News at the breast cancer meeting.
"The results are better than imagined. This is a fairly robust improvement. I think there will be tremendous interest [in the combination]," he added.
Dr. Burstein also pointed out that the control group of the study, the trastuzumab plus docetaxel group, had an above-average PFS; the average PFS in this setting is 8 to 10 months. Thus, the superiority in PFS found with the addition of pertuzumab was not because the control group performed poorly, he said.
Need for New Treatments
The safety profile was generally similar in the 2 groups, with no increase in left ventricular systolic dysfunction, said the authors. The rates of febrile neutropenia and diarrhea of grade 3 or greater were higher in the pertuzumab group (48.9% and 7.9%, respectively) than in the control group (45.8% and 5%), the authors highlighted.
New therapies for metastatic HER2-positive disease are needed, pointed out William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago, Illinois.
"Despite the practice-changing impact of trastuzumab and the substantial improvement in outcomes, patients with HER2-positive metastatic breast cancer ultimately die from the disease," he writes in an editorial that accompanies the new study.
Like trastuzumab, pertuzumab is a humanized monoclonal antibody and stimulates antibody-dependent, cell-mediated cytotoxicity. However, pertuzumab binds HER2 at a different epitope than that at which trastuzumab binds, explain the study authors.
As a single agent, pertuzumab has only "modest antitumor activity," said Dr. Gradishar. However, preclinical studies showed that the 2 agents had a "synergy," he added.
Dr. Baselga and his colleagues explain that synergy. Because pertuzumab and trastuzumab have complementary mechanisms of action and bind at different epitopes, the combination of the 2 agents provide a "more comprehensive blockade of HER2 signaling and result in greater antitumor activity than either agent alone," they write, referring to HER2-positive tumor model studies.
Study Details
The double-blind trial involved patients with HER2-positive metastatic breast cancer who had not received chemotherapy or biologic therapy for their metastatic disease. The primary end point in the study was progression-free survival, as determined by an independent review facility.
Patients received a loading dose of 8 mg of trastuzumab per kg of body weight, followed by a maintenance dose of 6 mg per kg every 3 weeks until disease progression or the development of unmanageable toxicity. Docetaxel was administered every 3 weeks at a starting dose of 75 mg/m2, which could be increased to 100 mg/m2 if tolerated or could be adjusted downward if needed. The recommended number of cycles was 6.
Pertuzumab or placebo was given at a fixed loading dose of 840 mg, followed by 420 mg every 3 weeks until disease progression or the development of unmanageable toxicity.
Adding pertuzumab to the trastuzumab plus docetaxel combination therapy resulted in an objective response rate (tumor shrinkage of at least 30%) of 80.2% compared with 69.3% for the combination therapy alone.
Although survival outcomes are not mature, Dr. Baselga and colleagues reported 69 deaths among the 402 patients treated with the 3-drug combination and 96 deaths among the 406 patients who received 2 drugs in the control group.
The 3-drug combination is "remarkably safe and well tolerated. Only minimal side effects were seen with the addition of pertuzumab," said Dr. Baselga in a press statement. Left ventricular systolic dysfunction of grade 3 or higher was reported in 2.8% of the patients in the 2-drug control group and in 1.2% of the patients in the 3-drug pertuzumab group.
Enrollment is underway in a new double-blind, randomized clinical trial to test the use of pertuzumab as adjuvant treatment for early-stage HER2-positive breast cancer.
The study was funded by Roche/Genentech. Dr. Baselga, Dr. Burstein, and Dr. Gradishar have disclosed no relevant financial relationships.
34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-5. Presented December 9, 2011.
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