http://www.curetoday.com/publications/cure/2011/winter2011/research-updates
Research Updates

Elizabeth Whittington

Afinitor Impresses in Advanced Breast Cancer 

One of the most anticipated presentations at SABCS was on a phase 3 study of Afinitor (everolimus) plus Aromasin (exemestane) for treating postmenopausal women with advanced estrogen-positive breast cancer.

The study followed 724 patients with progressing hormone-positive metastatic breast cancer. All women in the trial were receiving either anastrozole or letrozole, both aromatase inhibitors. 

The trial was halted in February when it became apparent the Afinitor combination was better than Aromasin alone. Preliminary data showed that with the addition of Afinitor, progression-free survival (PFS) improved from 2.8 months to 6.9. After a year follow-up, PFS had improved from 3.2 months in the Aromasin arm to 7.4 months in the Aromasin and Afinitor arm, an improvement of about 57 percent. Response rates also doubled from 25.5 to 50.5 percent, which included complete and partial responses, as well as stable disease lasting at least six months.

“These results establish a new standard of care for this group of patients,” says Gabriel N. Hortobagyi, MD, director of the Breast Cancer Research Program at the M.D. Anderson Cancer Center in Houston. 

Novel Hormone Therapy Combination Shown to Prolong Survival

A phase 3 randomized trial of two hormone therapies, anastrozole and Faslodex (fulvestrant), showed that in some postmenopausal women with hormone-positive metastatic breast cancer, the combo improves survival. 

Both are approved for women with hormone-positive metastatic breast cancer. Faslodex is used when the cancer has stopped responding to other hormonal therapies. Anastrozole is an aromatase inhibitor also approved to prevent breast cancer from recurring in women with early-stage disease. 

The trial included 707 women who had not been previously treated for metastatic cancer. The combination improved median survival from 41.3 months to 47.7 months.

New HER2-Targeted Drug Combo Delays Metastatic Breast Cancer

Pertuzumab, an investigational agent that targets the human epidermal growth factor receptor 2 (HER2), improves progression-free survival when added to Herceptin (trastuzumab) and Taxotere (docetaxel). 

The first results of the phase 3 trial found that the addition of pertuzumab improved PFS by 6.1 months, a 38 percent decrease in risk of progression. 

The study assigned 808 previously untreated women with HER2-positive, advanced breast cancer to receive Herceptin and Taxotere with or without pertuzumab. 

“This is huge,” says José Baselga, MD, PhD, associate director of the Massachusetts General Hospital Cancer Center. “It is very uncommon to have a clinical trial show this level of improvement in [progression-free survival].” 

Herceptin was the first HER2-targeted therapy approved for the aggressive disease (about a third of all breast tumors are fueled by this oncogene), but most cancers eventually progress. Researchers are optimistic that pertuzumab could add to the benefit of Herceptin, which is approved for HER2-positive early-stage and advanced breast cancer. Both drugs block the HER protein from binding to its receptors—Herceptin binds to the HER2 receptor on the cell surface, while pertuzumab blocks HER2 from binding with other HER receptors (HER1/EGFR, HER3 and HER4), a process called “dimerization,” that further signals tumor growth. Pertuzumab is the first of a new class of drugs known as “dimerization inhibitors.”

It’s too early to determine a survival benefit, but Baselga notes that more patients have survived in the pertuzumab arm.

Zometa’s Survival Benefit Confirmed

Women receiving a supportive care drug to reduce bone loss caused by breast cancer treatment may actually be getting more than that—improved survival and lower risk of metastatic recurrence. 

A seven-year follow-up confirmed that the bisphosphonate Zometa (zolendronate) improves survival and delays disease progression in postmenopausal women with early-stage breast cancer. Zometa is currently approved for reducing skeletal-related complications in metastatic breast cancer.

Investigators learned that women with early-stage, hormone-positive breast cancer who received anastrozole and Zometa for three years lowered their absolute risk of recurrence by about 4 percent and death by about 2 percent. The benefit appeared to be greatest in women over 40 who were postmenopausal. Side effects were minimal, but no cases of kidney failure or osteonecrosis of the jaw (a rare but serious side effect) were reported.

“It’s reassuring that when we target the microenvironment rather than the tumor cells themselves, we can make a difference, and it lasts long term,” says Michael Gnant, MD, of the Medical University of Vienna in Austria. 

While the results are positive, it is unknown whether U.S. doctors will adopt the new regimen. The women in the trial did not receive adjuvant chemotherapy—a standard of care for women with early-stage breast cancer in the U.S. For women who are treated in this fashion, however, it could represent a new standard. “It’s appropriate therapy for women who fulfill criteria in this study,” says James N. Ingle, a breast specialist at the Mayo Clinic in Rochester, Minn.

Different Dosing Schedule May Revive Withdrawn Drug

A drug removed from the market last year may have a second chance after researchers tweaked the dose for older patients with acute myeloid leukemia (AML). Mylotarg (gemtuzumab ozogamicin), given accelerated approval in 2000 for relapsed AML, was withdrawn by the manufacturer when later confirmation studies showed the drug did not improve survival and also increased the risk of a rare, but deadly liver complication. 

A French group tested the drug in a phase 3 trial using a modified dosing regimen that was easier on patients, reducing side effects and significantly improving event-free and overall survival. Newly diagnosed patients aged 50 to 70 years who received standard chemotherapy with Mylotarg lived longer than patients on chemotherapy alone (19.2 months versus 34 months). “With the lower dose, we have less toxicity and more efficacy,” says Sylvie Castaigne, MD, lead investigator of the study. This study included fewer deaths from liver complications than previous studies, but patients also experienced low but manageable platelet counts. 

Several ongoing trials with Mylotarg may show the drug still has a place in AML treatment. The drug’s maker, Pfizer, is awaiting additional study results before determining whether to resubmit the drug for FDA approval. “At this point, we are trying to better understand the data out there in hopes that they indeed look as good as we would like them to look,” says Mark Shapiro, MD, PhD, a senior director of global medical affairs with the drug company. “Pfizer is definitely interested, the issue is what can we do with this data.”

Because the drug was withdrawn, it typically would be unavailable to patients in the U.S. unless they are participating in a clinical trial.

Recently Approved Lymphoma Drug Adcetris Tested in Newly Diagnosed Patients

With the August approval of Adcetris (brentuximab vedotin) for Hodgkin lymphoma patients who have relapsed after stem cell transplantation or two lines of chemotherapy, researchers are now examining whether the drug will help newly diagnosed patients. Adcetris, an antibody-drug conjugate, combines a chemotherapy agent with an antibody that targets the CD30 receptor found on lymphoma cells. 

Although early, results of a phase 1 study show Adcetris’ potential benefit with standard chemotherapy. The purpose of the trial was to determine the best dosing strategy and toxicity, not efficacy. Yet the first 15 of 44 patients evaluated in the trial had complete remissions. Side effects included neutropenia and anemia. A phase 3 study is in the works.

The annual meetings of the San Antonio Breast Cancer Symposium (SABCS) and the American Society of Hematology (ASH) were held in December, bringing together thousands of cancer researchers, physicians and industry professionals to report on critical issues in cancer treatment, prevention, supportive care and more. For additional coverage, visit curetoday.com/sabcs2011.

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