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CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.
The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.
The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.
As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.
"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."
"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.
Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."
"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."
Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."
Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.
Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.
"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."
Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"
Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.
The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.
Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.
A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.
Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).
The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).
The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.
The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.
The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.
BOLERO-3 has landed in a crowded field of trastuzumab-resistant clinical trials. The unique aspect of BOLERO-3 was that it did allow for prior lapatinib use, and patients were allowed to go on to study even in the fourth-line metastatic setting.
Clinically, there was no benefit for the addition of everolimus in terms of the objective response rate or clinical benefit rate. In addition – and I think this is one of the most interesting aspects of this study – there were subgroups of patients who appeared to derive less benefit from the addition of everolimus, including the estrogen receptor–positive subgroup, patients with liver involvement, and probably most intriguing, those patients who had never seen trastuzumab in the adjuvant setting.
Is there a role for mTOR inhibition in HER2-positive metastatic breast cancer? My answer is ... yes, no, maybe so.
Yes, everolimus did improve progression-free survival. The study met its primary endpoint.
No, it had little impact on other clinically meaningful outcomes, some subgroups did not derive significant benefit, and it really is too early to see an overall survival advantage.
And finally, maybe so, because it did appear to have activity in a unique study design in patients having received prior lapatinib and relapsing having had a year of adjuvant trastuzumab, which makes this study unique.
In sum, the BOLERO-3 regimen offers a potential treatment option for patients after pertuzumab and TDM-1 therapy.
Dr. Kimberly L. Blackwell is a professor at the Duke Cancer Institute in Durham, N.C. She was the invited discussant of the study. Dr. Blackwell disclosed that she is a consultant to Genentech, the maker of Perjeta and Kadcyla, and GlaxoSmithKline; she receives research funding from Novartis, the maker of Afinitor, and Roche/Genentech.
BOLERO-3 has landed in a crowded field of trastuzumab-resistant clinical trials. The unique aspect of BOLERO-3 was that it did allow for prior lapatinib use, and patients were allowed to go on to study even in the fourth-line metastatic setting.
Clinically, there was no benefit for the addition of everolimus in terms of the objective response rate or clinical benefit rate. In addition – and I think this is one of the most interesting aspects of this study – there were subgroups of patients who appeared to derive less benefit from the addition of everolimus, including the estrogen receptor–positive subgroup, patients with liver involvement, and probably most intriguing, those patients who had never seen trastuzumab in the adjuvant setting.
Is there a role for mTOR inhibition in HER2-positive metastatic breast cancer? My answer is ... yes, no, maybe so.
Yes, everolimus did improve progression-free survival. The study met its primary endpoint.
No, it had little impact on other clinically meaningful outcomes, some subgroups did not derive significant benefit, and it really is too early to see an overall survival advantage.
And finally, maybe so, because it did appear to have activity in a unique study design in patients having received prior lapatinib and relapsing having had a year of adjuvant trastuzumab, which makes this study unique.
In sum, the BOLERO-3 regimen offers a potential treatment option for patients after pertuzumab and TDM-1 therapy.
Dr. Kimberly L. Blackwell is a professor at the Duke Cancer Institute in Durham, N.C. She was the invited discussant of the study. Dr. Blackwell disclosed that she is a consultant to Genentech, the maker of Perjeta and Kadcyla, and GlaxoSmithKline; she receives research funding from Novartis, the maker of Afinitor, and Roche/Genentech.
BOLERO-3 has landed in a crowded field of trastuzumab-resistant clinical trials. The unique aspect of BOLERO-3 was that it did allow for prior lapatinib use, and patients were allowed to go on to study even in the fourth-line metastatic setting.
Clinically, there was no benefit for the addition of everolimus in terms of the objective response rate or clinical benefit rate. In addition – and I think this is one of the most interesting aspects of this study – there were subgroups of patients who appeared to derive less benefit from the addition of everolimus, including the estrogen receptor–positive subgroup, patients with liver involvement, and probably most intriguing, those patients who had never seen trastuzumab in the adjuvant setting.
Is there a role for mTOR inhibition in HER2-positive metastatic breast cancer? My answer is ... yes, no, maybe so.
Yes, everolimus did improve progression-free survival. The study met its primary endpoint.
No, it had little impact on other clinically meaningful outcomes, some subgroups did not derive significant benefit, and it really is too early to see an overall survival advantage.
And finally, maybe so, because it did appear to have activity in a unique study design in patients having received prior lapatinib and relapsing having had a year of adjuvant trastuzumab, which makes this study unique.
In sum, the BOLERO-3 regimen offers a potential treatment option for patients after pertuzumab and TDM-1 therapy.
Dr. Kimberly L. Blackwell is a professor at the Duke Cancer Institute in Durham, N.C. She was the invited discussant of the study. Dr. Blackwell disclosed that she is a consultant to Genentech, the maker of Perjeta and Kadcyla, and GlaxoSmithKline; she receives research funding from Novartis, the maker of Afinitor, and Roche/Genentech.
CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.
The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.
The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.
As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.
"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."
"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.
Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."
"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."
Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."
Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.
Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.
"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."
Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"
Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.
The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.
Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.
A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.
Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).
The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).
The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.
The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.
The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.
CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.
The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.
The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.
As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.
"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."
"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.
Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."
"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."
Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."
Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.
Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.
"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."
Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"
Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.
The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.
Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.
A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.
Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).
The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).
The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.
The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.
The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.
AT THE ASCO ANNUAL MEETING 2013
Major finding: Compared with placebo, everolimus led to better progression-free survival when added to trastuzumab and vinorelbine (hazard ratio, 0.78).
Data source: A phase III, randomized, double-blind trial among 572 patients with trastuzumab-resistant HER2-positive advanced breast cancer (BOLERO-3 trial)
Disclosures: The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she has ties to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta.