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BOLERO-1 Reports HER2-Positive Breast Cancer Subset Benefits from Afinitor, Herceptin Regimen

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SAN ANTONIO – The addition of Novartis' mTOR inhibitor Afinitor (everolimus) to chemotherapy and Genentech's Herceptin (trastuzumab) did not improve progression-free survival compared to Herceptin and chemo in advanced HER2-positive patients in the BOLERO-1 trial, researchers reported at the San Antonio Breast Cancer Symposium.

However, the Afinitor-containing regimen did boost median progression-free survival by seven months in a subset of women with hormone receptor (HR)-negative disease, investigators led by Sara Hurvitz, director of the Breast Oncology Program at the University of California, Los Angeles, reported at the meeting.

Investigators in the Phase III BOLERO-1 program wanted to assess the safety and efficacy of adding Afinitor to Genentech's Herceptin and paclitaxel in advanced HER2-positive breast cancer patients who had received no other treatment compared to patients receiving paclitaxel and Herceptin. Previously, the BOLERO-3 trial had reported that adding Afinitor to Herceptin and the chemotherapy vinorelbine significantly improved progression-free survival for patients with metastatic HER2-positive breast cancer who had been treated with taxane-based chemo and had become resistant to Herceptin.

As such, in the BOLERO-1 trial, researchers wanted to see if the addition of Afinitor earlier in metastatic patients, before they were treated for their advanced illness, delayed their resistance to HER2-targeted drugs. Patients receiving Afinitor in BOLERO-1 received a 10 mg dose, while in BOLERO-3 patients received a 5 mg dose.

The BOLERO-1 study involved more than 700 patients with advanced, HER2-positive disease, of which 480 were assigned to receive the Afinitor containing regimen, while approximately 240 were assigned to the Herceptin/chemo arm without Afinitor. Final outcomes were analyzed after 425 patients progressed on treatment in the study and showed that in the unselected population median progression-free survival was 14.95 months in the Afinitor arm and 14.49 months in comparator arm.

Researchers then looked at approximately 300 patients with HR-negative disease. When the PI3K/mTOR pathway is overactive it offers a way for tumors to develop resistance to HER2 targeted drugs. "mTOR inhibitors have been proposed to reverse this resistance," Hurvitz said at SABCS. "Preclinically and Phase I and II trials have shown activity of the mTOR inhibitor [Afinitor] against HER2 positive breast cancer." She further noted that there were hints in the BOLERO-3 study that combining Afinitor with Herceptin/chemo could particularly benefit HR-negative breast cancer patients who had become resistant to HER2-targeted treatment. 

BOLERO-1 confirmed this but just missed the trial's pre-specified statistical significance threshold. Median progression-free survival was 20.27 months in the Afinitor arm versus 13.08 months in the comparator group. Researchers had set a pre-specified p-value of less that 0.0044, but the study yielded a p-value of 0.0049.

Hurvitz explained that the BOLERO-1 study wasn't originally designed to analyze progression-free survival in the HR-negative subset, but after the BOLERO-3 signal was seen in this group, the Phase III protocol was amended before the data were unblinded. If researchers had known about this signal in the HR-negative group earlier, they might have done the study only in the HR-negative population or increased the study size, she said.

In BOLERO-1 there were higher rates of neutropenia and anemia in the Afinitor arm. There were also more deaths among Afinitor-treated patients compared to those who were not treated with the drug, 3.6 percent versus no deaths, respectively. The adverse events that led to the deaths were pulmonary related and Hurvitz noted that investigators had to educate the study sites about aggressively managing toxicities in patients treated with Afinitor. After this education, there was one treatment-related death in the study.

The data from BOLERO-1 "are consistent with the preliminary observation from BOLERO-3 that patients with HR-negative, HER2-positive breast cancer appear to benefit more from [Afinitor] compared to patients with HR-positive, HER2-positive disease," Hurvitz said. She noted that in BOLERO-1 HR-positive patients didn't receive endocrine therapy, which is commonly given to this subset of patients after surgery, radiation, or chemo to lower the risk of recurrence. According to Hurvitz, researchers are working on additional studies investigating the benefit of adding mTOR/PI3K inhibitors to endocrine therapy and HER2 targeted treatment in HR-positive, HER2-driven advanced breast cancer.

Hurvitz also said that researchers are discussing combining patient samples form BOLERO-1 and BOLERO-3 to increase the power of future biomarker analysis. Exploring the response of Afinitor plus Herceptin/chemo in patients with loss of tumor suppressor gene PTEN or PIK3CA mutations, those most likely to respond to an mTOR inhibitor, might be worthwhile, C. Kent Osborne, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, said at SABCS.

"Once you identify a subgroup, it might be that you see a more definitive … result," Osborne said. "I wonder if the ER-negative subset, which does have a higher degree of PTEN loss, may be an explanation."

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