BOLERO-2: Everolimus Plus Exemestane Delays Breast Cancer Progression

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"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," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"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," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"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," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.