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Can Lapatinib Prevent Brain Metastases from Breast Cancer? Data 'Inconclusive'
VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.
Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.
Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.
Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.
‘No Conclusion Can Be Made...’
In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).
The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.
"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.
Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.
Trial Excluded Asymptomatic Brain Metastases
"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.
"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.
CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.
In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m2/day on days 1-14 every 21 days).
PFS Longer with Trastuzumab and Capecitabine
The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).
This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.
While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.
Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.
Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.
"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."
LANDSCAPE Results Favorable
The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.
Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).
Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.
"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.
The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.
Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.
VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.
Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.
Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.
Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.
‘No Conclusion Can Be Made...’
In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).
The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.
"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.
Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.
Trial Excluded Asymptomatic Brain Metastases
"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.
"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.
CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.
In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m2/day on days 1-14 every 21 days).
PFS Longer with Trastuzumab and Capecitabine
The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).
This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.
While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.
Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.
Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.
"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."
LANDSCAPE Results Favorable
The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.
Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).
Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.
"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.
The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.
Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.
VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.
Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.
Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.
Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.
‘No Conclusion Can Be Made...’
In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).
The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.
"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.
Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.
Trial Excluded Asymptomatic Brain Metastases
"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.
"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.
CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.
In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m2/day on days 1-14 every 21 days).
PFS Longer with Trastuzumab and Capecitabine
The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).
This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.
While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.
Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.
Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.
"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."
LANDSCAPE Results Favorable
The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.
Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).
Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.
"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.
The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.
Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
<p></p><p><b>Major Findings:</b> The primary end point of CNS as first site of relapse was no different comparing lapatinib-capecitabine (3%) vs. trastuzumab-capecitabine (5%) in the CEREBREL trial. The LANDSCAPE study showed a CNS objective response in 66% of patients treated with up-front lapatinib plus capecitabine.</p><p><b>Data Source:</b> CEREBREL was an open-label phase III study, and LANDSCAPE was a phase II study. Both enrolled women with metastatic breast cancer.</p><p><b>Disclosures:</b> Both studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.</p>
One Year of Trastuzumab Remains the Standard in Early Breast Cancer
VIENNA – One year of adjuvant trastuzumab after primary therapy for HER2-positive early breast cancer remains the recommended standard of care, according to the first report of a landmark analysis from the HERA trial and findings from the PHARE study.
The latest data to emerge from the HERA (Herceptin Adjuvant) trial show similar disease-free survival and overall survival for 1 and 2 years of adjuvant trastuzumab (Herceptin), with respective hazard ratios (HRs) of 0.99 (95% confidence interval, 0.85-1.14; P =.86) and 1.05 (95% CI, 0.86-1.28; P = .63).
In the PHARE (Protocol of Herceptin Adjuvant With Reduced Exposure) study, which was designed as a noninferiority trial, disease-free survival at 1, 2, 3, and 4 years was not statistically different for those given 6 months versus 1 year of adjuvant trastuzumab. The respective disease-free survivals at 4 years were 84.9% and 87.8%, with an HR of 1.28 (95% CI 1.05-1.56, P = .29).
"In my opinion, 1 year adjuvant trastuzumab is still considered the standard of care," ASCO president Dr. Barbara Swain commented.
Dr. Swain, who is the director of the Washington Cancer Institute, was the invited discussant for the trials after their presentation, Oct. 1, at the European Society for Medical Oncology Congress.
"It’s very important that the presented data be peer reviewed and certainly longer follow-up for PHARE be obtained before final conclusions can be made," she added.
HERA Now at 8-Years’ Follow-up
To date, HERA has been the only trial to look at whether prolonging trastuzumab for more than 1 year may further increase patient survival. The trial findings, which were originally published in 2005 (N. Engl. J. Med. 2005;353:1659-72), showed that 1 year of treatment after adjuvant chemotherapy significantly improved disease-free survival among women with HER2-positive breast cancer.
Now with a median of 8 years of follow-up, the HERA investigators were able to report on the 2-year versus 1-year comparison, using a landmark analysis that considered 3,105 women who had remained disease free for at least 1 year since being randomized to trastuzumab.
Disease-free survivals for 2 years versus 1 year of trastuzumab were comparable, at 89.1% and 86.7%, respectively, at 1 year; 81.6% and 81.0% at 5 years; and 75.8% and 76.0% at 8 years.
Disease-free survivals according to hormone receptor status were also comparable, although an intriguing finding was that there was a slight difference in disease-free survival favoring 2 years of trastuzumab in HR-negative women at about the 3-year mark.
"This raises hypotheses and illustrates the need to evaluate results by receptor status," Richard Gelber, Ph.D., one of the biostatisticians for the HERA trial, commented at a press briefing.
Looking at safety, secondary cardiac end points and other adverse events were increased in the 2-year trastuzumab arm, with 7.2% of patients having a decreased left ventricular ejection fraction versus 4.1% of those treated for 1 year, and 0.9% of those who were in the observation arm.
"Today, I am happy to report that the overall survival advantage for trastuzumab versus observation is sustained, it’s robust, and it’s long term," said Dr. Gelber, of the Dana-Farber Cancer Institute in Boston.
Rationale for Shorter Treatment
The rationale for investigating the possible benefit of shorter trastuzumab treatment is twofold, explained Dr. Xavier Pivot, of the Université de Franche-Comté in Besançon, who presented the PHARE data. First, the FinHer study suggested that just 9 weeks of trastuzumab could perhaps provide a similar magnitude of benefit as 1 year of therapy (N. Engl. J. Med. 2006;354:809-20). Second, there were cardiotoxicity concerns with trastuzumab, which might be reduced by a shorter duration of treatment.
The PHARE trial was initiated in 2006 and involved 3,380 women who were treated for 6 or 12 months with trastuzumab.
"Results were inconclusive for the noninferiority between 6 months’ duration and 12 months’ duration," Dr. Pivot said.
"Nevertheless, there was a trend favoring the standard 12 months’ treatment." The hazard ratio for overall survival after a median of 3.6 years was 1.47 (95% CI, 1.07-2.02).
A significant difference in cardiac events favored the shorter treatment regimen, however, and a multivariate analysis is due to be presented at the San Antonio Breast Cancer Symposium in December.
Practice Remains Unchanged
"These are extremely important, well-designed, phase III trials on the duration of trastuzumab treatment in the adjuvant setting," Dr. Swain said.
Commenting on the PHARE study results, she said: "The observed hazard ratio was 1.28, so it is inconclusive statistically in terms of noninferiority." The bar for noninferiority was set at an HR of 1.15.
"However, since the lower confidence interval is greater than 1, we can conclude that 12 months at this time with a short follow-up is better than 6 months," Dr. Swain said.
The use of concurrent versus sequential chemotherapy could have influenced the results, she suggested. The HR for concurrent chemotherapy with docetaxel and trastuzumab, which was received by 42% of patients, was 1.17 (95% CI, 0.89-1.54). The HR for sequential chemotherapy was 1.39 (95% CI, 1.05-1.85).
If the study had continued, she added, the HR for 6 months versus 1 year of treatment may have shown that the shorter duration is at least as good as the standard regimen.
There are several ongoing studies still looking at the optimum duration of adjuvant trastuzumab in the early breast cancer setting, Dr. Swain observed, These include the Persephone, Hellenic, Short-Her, and SOLD trials.
Persephone and Hellenic are looking at 6 versus 12 months of trastuzumab, but the former is still accruing patients until the end of next year and won’t report until the middle of 2016 at the earliest.
Results of the Short-Her and SOLD trials, which are looking at 9 weeks versus 12 months of trastuzumab, should appear sooner. Until results are available, there is no practice-changing message, and 1 year of trastuzumab – at least outside the clinical trial setting – should remain the current practice standard.
The HERA trial was run by the Breast International Group with funding from Roche. Dr. Gelber disclosed he had no conflicts of interest. The PHARE trial was funded and conducted by the French National Cancer Institute. Dr. Pivot has received honoraria from and acted as a consultant to Roche and GlaxoSmithKline. Dr. Swain disclosed receiving honoraria from Genentech/Roche.
VIENNA – One year of adjuvant trastuzumab after primary therapy for HER2-positive early breast cancer remains the recommended standard of care, according to the first report of a landmark analysis from the HERA trial and findings from the PHARE study.
The latest data to emerge from the HERA (Herceptin Adjuvant) trial show similar disease-free survival and overall survival for 1 and 2 years of adjuvant trastuzumab (Herceptin), with respective hazard ratios (HRs) of 0.99 (95% confidence interval, 0.85-1.14; P =.86) and 1.05 (95% CI, 0.86-1.28; P = .63).
In the PHARE (Protocol of Herceptin Adjuvant With Reduced Exposure) study, which was designed as a noninferiority trial, disease-free survival at 1, 2, 3, and 4 years was not statistically different for those given 6 months versus 1 year of adjuvant trastuzumab. The respective disease-free survivals at 4 years were 84.9% and 87.8%, with an HR of 1.28 (95% CI 1.05-1.56, P = .29).
"In my opinion, 1 year adjuvant trastuzumab is still considered the standard of care," ASCO president Dr. Barbara Swain commented.
Dr. Swain, who is the director of the Washington Cancer Institute, was the invited discussant for the trials after their presentation, Oct. 1, at the European Society for Medical Oncology Congress.
"It’s very important that the presented data be peer reviewed and certainly longer follow-up for PHARE be obtained before final conclusions can be made," she added.
HERA Now at 8-Years’ Follow-up
To date, HERA has been the only trial to look at whether prolonging trastuzumab for more than 1 year may further increase patient survival. The trial findings, which were originally published in 2005 (N. Engl. J. Med. 2005;353:1659-72), showed that 1 year of treatment after adjuvant chemotherapy significantly improved disease-free survival among women with HER2-positive breast cancer.
Now with a median of 8 years of follow-up, the HERA investigators were able to report on the 2-year versus 1-year comparison, using a landmark analysis that considered 3,105 women who had remained disease free for at least 1 year since being randomized to trastuzumab.
Disease-free survivals for 2 years versus 1 year of trastuzumab were comparable, at 89.1% and 86.7%, respectively, at 1 year; 81.6% and 81.0% at 5 years; and 75.8% and 76.0% at 8 years.
Disease-free survivals according to hormone receptor status were also comparable, although an intriguing finding was that there was a slight difference in disease-free survival favoring 2 years of trastuzumab in HR-negative women at about the 3-year mark.
"This raises hypotheses and illustrates the need to evaluate results by receptor status," Richard Gelber, Ph.D., one of the biostatisticians for the HERA trial, commented at a press briefing.
Looking at safety, secondary cardiac end points and other adverse events were increased in the 2-year trastuzumab arm, with 7.2% of patients having a decreased left ventricular ejection fraction versus 4.1% of those treated for 1 year, and 0.9% of those who were in the observation arm.
"Today, I am happy to report that the overall survival advantage for trastuzumab versus observation is sustained, it’s robust, and it’s long term," said Dr. Gelber, of the Dana-Farber Cancer Institute in Boston.
Rationale for Shorter Treatment
The rationale for investigating the possible benefit of shorter trastuzumab treatment is twofold, explained Dr. Xavier Pivot, of the Université de Franche-Comté in Besançon, who presented the PHARE data. First, the FinHer study suggested that just 9 weeks of trastuzumab could perhaps provide a similar magnitude of benefit as 1 year of therapy (N. Engl. J. Med. 2006;354:809-20). Second, there were cardiotoxicity concerns with trastuzumab, which might be reduced by a shorter duration of treatment.
The PHARE trial was initiated in 2006 and involved 3,380 women who were treated for 6 or 12 months with trastuzumab.
"Results were inconclusive for the noninferiority between 6 months’ duration and 12 months’ duration," Dr. Pivot said.
"Nevertheless, there was a trend favoring the standard 12 months’ treatment." The hazard ratio for overall survival after a median of 3.6 years was 1.47 (95% CI, 1.07-2.02).
A significant difference in cardiac events favored the shorter treatment regimen, however, and a multivariate analysis is due to be presented at the San Antonio Breast Cancer Symposium in December.
Practice Remains Unchanged
"These are extremely important, well-designed, phase III trials on the duration of trastuzumab treatment in the adjuvant setting," Dr. Swain said.
Commenting on the PHARE study results, she said: "The observed hazard ratio was 1.28, so it is inconclusive statistically in terms of noninferiority." The bar for noninferiority was set at an HR of 1.15.
"However, since the lower confidence interval is greater than 1, we can conclude that 12 months at this time with a short follow-up is better than 6 months," Dr. Swain said.
The use of concurrent versus sequential chemotherapy could have influenced the results, she suggested. The HR for concurrent chemotherapy with docetaxel and trastuzumab, which was received by 42% of patients, was 1.17 (95% CI, 0.89-1.54). The HR for sequential chemotherapy was 1.39 (95% CI, 1.05-1.85).
If the study had continued, she added, the HR for 6 months versus 1 year of treatment may have shown that the shorter duration is at least as good as the standard regimen.
There are several ongoing studies still looking at the optimum duration of adjuvant trastuzumab in the early breast cancer setting, Dr. Swain observed, These include the Persephone, Hellenic, Short-Her, and SOLD trials.
Persephone and Hellenic are looking at 6 versus 12 months of trastuzumab, but the former is still accruing patients until the end of next year and won’t report until the middle of 2016 at the earliest.
Results of the Short-Her and SOLD trials, which are looking at 9 weeks versus 12 months of trastuzumab, should appear sooner. Until results are available, there is no practice-changing message, and 1 year of trastuzumab – at least outside the clinical trial setting – should remain the current practice standard.
The HERA trial was run by the Breast International Group with funding from Roche. Dr. Gelber disclosed he had no conflicts of interest. The PHARE trial was funded and conducted by the French National Cancer Institute. Dr. Pivot has received honoraria from and acted as a consultant to Roche and GlaxoSmithKline. Dr. Swain disclosed receiving honoraria from Genentech/Roche.
VIENNA – One year of adjuvant trastuzumab after primary therapy for HER2-positive early breast cancer remains the recommended standard of care, according to the first report of a landmark analysis from the HERA trial and findings from the PHARE study.
The latest data to emerge from the HERA (Herceptin Adjuvant) trial show similar disease-free survival and overall survival for 1 and 2 years of adjuvant trastuzumab (Herceptin), with respective hazard ratios (HRs) of 0.99 (95% confidence interval, 0.85-1.14; P =.86) and 1.05 (95% CI, 0.86-1.28; P = .63).
In the PHARE (Protocol of Herceptin Adjuvant With Reduced Exposure) study, which was designed as a noninferiority trial, disease-free survival at 1, 2, 3, and 4 years was not statistically different for those given 6 months versus 1 year of adjuvant trastuzumab. The respective disease-free survivals at 4 years were 84.9% and 87.8%, with an HR of 1.28 (95% CI 1.05-1.56, P = .29).
"In my opinion, 1 year adjuvant trastuzumab is still considered the standard of care," ASCO president Dr. Barbara Swain commented.
Dr. Swain, who is the director of the Washington Cancer Institute, was the invited discussant for the trials after their presentation, Oct. 1, at the European Society for Medical Oncology Congress.
"It’s very important that the presented data be peer reviewed and certainly longer follow-up for PHARE be obtained before final conclusions can be made," she added.
HERA Now at 8-Years’ Follow-up
To date, HERA has been the only trial to look at whether prolonging trastuzumab for more than 1 year may further increase patient survival. The trial findings, which were originally published in 2005 (N. Engl. J. Med. 2005;353:1659-72), showed that 1 year of treatment after adjuvant chemotherapy significantly improved disease-free survival among women with HER2-positive breast cancer.
Now with a median of 8 years of follow-up, the HERA investigators were able to report on the 2-year versus 1-year comparison, using a landmark analysis that considered 3,105 women who had remained disease free for at least 1 year since being randomized to trastuzumab.
Disease-free survivals for 2 years versus 1 year of trastuzumab were comparable, at 89.1% and 86.7%, respectively, at 1 year; 81.6% and 81.0% at 5 years; and 75.8% and 76.0% at 8 years.
Disease-free survivals according to hormone receptor status were also comparable, although an intriguing finding was that there was a slight difference in disease-free survival favoring 2 years of trastuzumab in HR-negative women at about the 3-year mark.
"This raises hypotheses and illustrates the need to evaluate results by receptor status," Richard Gelber, Ph.D., one of the biostatisticians for the HERA trial, commented at a press briefing.
Looking at safety, secondary cardiac end points and other adverse events were increased in the 2-year trastuzumab arm, with 7.2% of patients having a decreased left ventricular ejection fraction versus 4.1% of those treated for 1 year, and 0.9% of those who were in the observation arm.
"Today, I am happy to report that the overall survival advantage for trastuzumab versus observation is sustained, it’s robust, and it’s long term," said Dr. Gelber, of the Dana-Farber Cancer Institute in Boston.
Rationale for Shorter Treatment
The rationale for investigating the possible benefit of shorter trastuzumab treatment is twofold, explained Dr. Xavier Pivot, of the Université de Franche-Comté in Besançon, who presented the PHARE data. First, the FinHer study suggested that just 9 weeks of trastuzumab could perhaps provide a similar magnitude of benefit as 1 year of therapy (N. Engl. J. Med. 2006;354:809-20). Second, there were cardiotoxicity concerns with trastuzumab, which might be reduced by a shorter duration of treatment.
The PHARE trial was initiated in 2006 and involved 3,380 women who were treated for 6 or 12 months with trastuzumab.
"Results were inconclusive for the noninferiority between 6 months’ duration and 12 months’ duration," Dr. Pivot said.
"Nevertheless, there was a trend favoring the standard 12 months’ treatment." The hazard ratio for overall survival after a median of 3.6 years was 1.47 (95% CI, 1.07-2.02).
A significant difference in cardiac events favored the shorter treatment regimen, however, and a multivariate analysis is due to be presented at the San Antonio Breast Cancer Symposium in December.
Practice Remains Unchanged
"These are extremely important, well-designed, phase III trials on the duration of trastuzumab treatment in the adjuvant setting," Dr. Swain said.
Commenting on the PHARE study results, she said: "The observed hazard ratio was 1.28, so it is inconclusive statistically in terms of noninferiority." The bar for noninferiority was set at an HR of 1.15.
"However, since the lower confidence interval is greater than 1, we can conclude that 12 months at this time with a short follow-up is better than 6 months," Dr. Swain said.
The use of concurrent versus sequential chemotherapy could have influenced the results, she suggested. The HR for concurrent chemotherapy with docetaxel and trastuzumab, which was received by 42% of patients, was 1.17 (95% CI, 0.89-1.54). The HR for sequential chemotherapy was 1.39 (95% CI, 1.05-1.85).
If the study had continued, she added, the HR for 6 months versus 1 year of treatment may have shown that the shorter duration is at least as good as the standard regimen.
There are several ongoing studies still looking at the optimum duration of adjuvant trastuzumab in the early breast cancer setting, Dr. Swain observed, These include the Persephone, Hellenic, Short-Her, and SOLD trials.
Persephone and Hellenic are looking at 6 versus 12 months of trastuzumab, but the former is still accruing patients until the end of next year and won’t report until the middle of 2016 at the earliest.
Results of the Short-Her and SOLD trials, which are looking at 9 weeks versus 12 months of trastuzumab, should appear sooner. Until results are available, there is no practice-changing message, and 1 year of trastuzumab – at least outside the clinical trial setting – should remain the current practice standard.
The HERA trial was run by the Breast International Group with funding from Roche. Dr. Gelber disclosed he had no conflicts of interest. The PHARE trial was funded and conducted by the French National Cancer Institute. Dr. Pivot has received honoraria from and acted as a consultant to Roche and GlaxoSmithKline. Dr. Swain disclosed receiving honoraria from Genentech/Roche.
AT THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY CONGRESS
<p></p><p><b>Major Findings:</b> The hazard ratios for disease-free and overall survival comparing 1 year and 2 years of adjuvant trastuzumab in the HERA trial were 0.99 (<i>P </i>= .86<i>)</i> and 1.05 (<i>P </i>= .63), respectively.<i> </i>The respective disease-free survival rates at 4 years in the PHARE trial were 84.9% and 87.8%, with an HR of 1.28 (<i>P</i> = .29).</p><p><b>Data Sources:</b> Findings were analyzed from the phase III HERA trial involving 5,102 women with HER2-positive breast cancer who received 1 or 2 years of adjuvant trastuzumab. The PHARE noninferiority trial included 3,380 women who were treated with 6 or 12 months of adjuvant trastuzumab.</p><p><b>Disclosures:</b> The HERA trial was run by the Breast International Group with funding from Roche. Dr. Gelber disclosed he had no conflicts of interest. The PHARE trial was funded and conducted by the French National Cancer Institute. Dr. Pivot has received honoraria and acted as a consultant to Roche and GlaxoSmithKline. Dr. Swain disclosed receiving honoraria from Genentech/Roche.</p>
