BOLERO-3: Everolimus tweaks trastuzumab-resistant metastatic breast cancer

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]