Dual HER2 Blockade Significantly Extends Progression-Free Survival

Main Category: Breast Cancer
Also Included In: Biology / Biochemistry;  Clinical Trials / Drug Trials
Article Date: 08 Dec 2011 - 2:00 PST

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Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy extended progression-free survival by a median of 6.1 months in patients with metastatic HER2-positive breast cancer compared with patients who received the combination therapy with placebo.

Researchers conducted an international phase 3, double-blind, randomized trial, known as CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab), in which they randomly assigned 808 patients to receive trastuzumab and docetaxel chemotherapy with pertuzumab or placebo. Progression-free survival (PFS) was 18.5 months for patients who received pertuzumab compared with 12.4 months for patients who received placebo a 38 percent reduction in risk for progression.

The findings, reported at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 6-10, 2011, represent a significant advance in the treatment of this advanced breast cancer, said senior researcher José Baselga, M.D., Ph.D., professor in the department of medicine at Harvard Medical School, associate director of the Massachusetts General Hospital Cancer Center and chief of hematology/oncology at Massachusetts General Hospital.

"This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS," said Baselga. "Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting. With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

The results were published in the New England Journal of Medicine.

Pertuzumab is designed to work in combination with trastuzumab as a dual blockade of the HER2 growth factor, which fuels about one third of all breast tumors. Both drugs are monoclonal antibodies that bind to the HER2 receptor protein in different locations. Pertuzumab's role is to prevent the receptor from linking to HER3 and therefore forming a "dimer" that further signals tumor growth making pertuzumab the first in a new class of drugs called "dimerization inhibitors," Baselga said. "These two agents offer a dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling."

Adding pertuzumab to the combination therapy resulted in an objective response rate (tumor shrinkage of at least 30 percent) of 80.2 percent compared with 69.3 percent for the combination therapy alone.

Although survival outcomes are not mature, meaning not enough time has passed for a valid statistical analysis, Baselga reported 69 deaths among the 402 patients treated with the three-drug combination and 96 deaths among the 406 patients who received two drugs.

He added that the three-drug combination is "remarkably safe and well tolerated. Only minimal side effects were seen with the addition of pertuzumab." Some of those effects were grades 1 and 2 diarrhea and neutropenia, but no additional cardiac toxicity was seen, he said.

Enrollment is already underway in a new double-blind, randomized clinical trial, APHINITY, to test the use of pertuzumab as adjuvant treatment for early-stage HER2-positive breast cancer. "It is in that setting that you can really cure patients," Baselga said.

Article adapted by Medical News Today from original press release. Source: American Association for Cancer Research
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Combination Of Everolimus And Exemestane Improves Progression-Free Survival For Women With Metastatic Breast Cancer

Main Category: Breast Cancer
Article Date: 08 Dec 2011 - 2:00 PST

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In an international Phase III randomized study, everolimus, when combined with the hormonal therapy exemestane, has been shown to dramatically improve progression-free survival, according to research from The University of Texas MD Anderson Cancer Center.

The study, known as Breast Cancer Trials of Oral Everolimus (BOLERO-2), was presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium by Gabriel Hortobagyi, M.D., professor and chair of MD Anderson's Department of Breast Medical Oncology. Earlier findings were simultaneously reported in the New England Journal of Medicine.

Everolimus, an immunosuppressant agent first used to prevent rejection of organ transplants, also has anti-angiogenic properties. It inhibits the mammalian target of rapamycin (mTOR) protein, a central regulator of tumor cell division and blood vessel growth in cancer cells; the mTOR pathway is activated in hormone-resistant breast cancer, explained Hortobagyi. Currently, the oral agent is approved for both the treatment of kidney cancer and pancreatic neuro-endocrine tumors, with MD Anderson's research leading the way for the latter's usage approval by the FDA.

Preliminary BOLERO-2 data were first presented at ESMO and showed a significant progression-free survival benefit; these updated findings represent six additional months of patient follow-up, Hortobagyi explained.

"This study is based on the concept that we now know more about the resistance mechanisms to endocrine therapy and the experimental arm of BOLERO-2 uses a dual-attack on treatment refractory hormone receptor-positive breast cancer: it simultaneously inhibits the estrogen-signaling pathway with the aromatase inhibitor, exemestane, and the PI3-kinase/AKT/mTOR pathway with the use of everolimus," Hortobagyi said. "For the first time in a large Phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy."

The international Phase III trial enrolled 724 metastatic breast cancer patients, all of whom were post-menopausal, had hormone receptor-positive disease and evidence of progressive disease. In a two-to-one ratio, 485 women were randomized to receive the combination of everolimus (10 mg daily), and exemestane, an aromatase inhibitor, and compared to 239 women who received exemestane and placebo. All were previously treated with and progressed on letrozole and anastrozole, with the majority of women extensively treated with prior therapies. The median age of the women enrolled was 62 years; the study's primary endpoint was progression-free survival.

In patients receiving the everolimus combination, researchers found a progression-free survival of 7.4 months, compared to 3.2 months in those who took exemestane alone, a finding Hortobagyi describes as "highly significant." The clinical benefit rate complete responses, partial responses and stability exceeding six months was 50.5 percent in those in the combination arm, compared to 25.5 percent in those who received the hormonal therapy alone. Adverse effects, such as shortness of breath, hyperglycemia, mouth sores and fatigue, were all higher in the combination group, but were manageable and did not disrupt patients' quality of life, the researchers found. Survival data are still being analyzed.

Because aromatase inhibitors are associated with bone loss and fractures, as a safety measure, Hortobagyi and the researchers assessed patients for bone-turnover markers. The addition of everolimus was found to significantly reduce the level of such markers an interesting area for future study, noted Hortobagyi.

"Over the years, our treatment approach for such women with metastatic breast cancer has been sequential use of as many hormone therapies as possible, keeping metastatic disease under control for as long as possible. These findings may allow us to change our approach. In this group of heavily pre-treated patients, all of whom progressed on prior endocrine therapy, the addition of this mTOR inhibitor resulted in significant prolongation of progression-free survival and an improved response rate, with only a modest addition of toxicity," said Hortobagyi.

Hortobagyi believes that these findings may be practice-changing for women who meet the criteria for BOLERO-2. Additional studies are planned with everolimus in breast cancer, including in combination with an aromatase inhibitor in the adjuvant setting, as well as additional clinical trials in the metastatic setting.

In addition to Hortobagyi, authors on the international study include: Jorge Baselga, M.D., Massachusetts General Hospital Cancer Center and Harvard Medical School, and the NEJM study's corresponding author; Martine Piccart, M.D., Jules Bordet Institute; Hope S. Rugo, M.D., University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Howard Burris, M.D., Sarah Cannon Research Institute; Mario Campone, M.D., Institut de Cancérologie de l'Ouest; Shinzaburo Noguchi, M.D., Osaka University; Michael Gnant, M.D., Comprehensive Cancer Center, Medical University of Vienna; Kathleen Pritchard, M.D., Sunnybrook Odette Cancer Centre; Luc Vittori, Zhiying Xu, Ph.D., Pabak Mukhopadhyay, Ph.D., Tarek Sahmoud, M.D., Ph.D. and David Lebwohl, M.D., the last five of Novartis Pharmaceuticals.

The trial was funded, in part, by Novartis. Hortobagyi reports receiving research funds from, as well as having served as a consultant for, Novartis.

Article adapted by Medical News Today from original press release. Source: University of Texas M. D. Anderson Cancer Center
Visit our breast cancer section for the latest news on this subject. University of Texas M. D. Anderson Cancer Center Please use one of the following formats to cite this article in your essay, paper or report:

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University of Texas M. D. Anderson Cancer Center. "Combination Of Everolimus And Exemestane Improves Progression-Free Survival For Women With Metastatic Breast Cancer." Medical News Today. MediLexicon, Intl., 8 Dec. 2011. Web.
8 Dec. 2011. APA
University of Texas M. D. Anderson Cancer Center. (2011, December 8). "Combination Of Everolimus And Exemestane Improves Progression-Free Survival For Women With Metastatic Breast Cancer." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/238840.php.

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