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by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.
After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.
The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.
Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.
“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”
Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.
This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.
SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.
The findings by Wildiers et al. regarding the benefits of adding oral cyclophosphamide to dual HER2 blockade should be evaluated further, according to Charles E. Geyer Jr., MD, who applauded the investigators’ demonstration of a framework for much-needed clinical trials in frail elderly patients with breast cancer.
In an editorial, Dr. Geyer wrote that the trial results provide sufficient evidence for consideration of trastuzumab and pertuzumab plus oral cyclophosphamide in frail elderly patients at increased risk of adverse events from taxane-based therapies, but he also encouraged additional study (Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30084-6).
An important consideration in future studies will be the choice of a comparator group; he suggested a version of the CLEOPATRA study to look at trastuzumab plus metronomic oral cyclophosphamide with and without pertuzumab. A prior small study suggested that the problematic risk of diarrhea seen in patients in the current study did not occur in patients pretreated with trastuzumab who showed activity with trastuzumab and metronomic oral cyclophosphamide chemotherapy, he noted.
Dr. Geyer is with the Massey Cancer Center at Virginia Commonwealth University, Richmond. He reported receiving personal fees from Myriad and Heron Therapeutics for advisory board participation, and travel support from AstraZeneca, Genentech, and Macrogenics, outside the submitted work.
The findings by Wildiers et al. regarding the benefits of adding oral cyclophosphamide to dual HER2 blockade should be evaluated further, according to Charles E. Geyer Jr., MD, who applauded the investigators’ demonstration of a framework for much-needed clinical trials in frail elderly patients with breast cancer.
In an editorial, Dr. Geyer wrote that the trial results provide sufficient evidence for consideration of trastuzumab and pertuzumab plus oral cyclophosphamide in frail elderly patients at increased risk of adverse events from taxane-based therapies, but he also encouraged additional study (Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30084-6).
An important consideration in future studies will be the choice of a comparator group; he suggested a version of the CLEOPATRA study to look at trastuzumab plus metronomic oral cyclophosphamide with and without pertuzumab. A prior small study suggested that the problematic risk of diarrhea seen in patients in the current study did not occur in patients pretreated with trastuzumab who showed activity with trastuzumab and metronomic oral cyclophosphamide chemotherapy, he noted.
Dr. Geyer is with the Massey Cancer Center at Virginia Commonwealth University, Richmond. He reported receiving personal fees from Myriad and Heron Therapeutics for advisory board participation, and travel support from AstraZeneca, Genentech, and Macrogenics, outside the submitted work.
The findings by Wildiers et al. regarding the benefits of adding oral cyclophosphamide to dual HER2 blockade should be evaluated further, according to Charles E. Geyer Jr., MD, who applauded the investigators’ demonstration of a framework for much-needed clinical trials in frail elderly patients with breast cancer.
In an editorial, Dr. Geyer wrote that the trial results provide sufficient evidence for consideration of trastuzumab and pertuzumab plus oral cyclophosphamide in frail elderly patients at increased risk of adverse events from taxane-based therapies, but he also encouraged additional study (Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30084-6).
An important consideration in future studies will be the choice of a comparator group; he suggested a version of the CLEOPATRA study to look at trastuzumab plus metronomic oral cyclophosphamide with and without pertuzumab. A prior small study suggested that the problematic risk of diarrhea seen in patients in the current study did not occur in patients pretreated with trastuzumab who showed activity with trastuzumab and metronomic oral cyclophosphamide chemotherapy, he noted.
Dr. Geyer is with the Massey Cancer Center at Virginia Commonwealth University, Richmond. He reported receiving personal fees from Myriad and Heron Therapeutics for advisory board participation, and travel support from AstraZeneca, Genentech, and Macrogenics, outside the submitted work.
by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.
After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.
The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.
Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.
“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”
Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.
This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.
SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.
by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.
After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.
The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.
Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.
“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”
Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.
This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.
SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.
FROM THE LANCET ONCOLOGY
Key clinical point: Adding oral cyclophosphamide to trastuzumab and pertuzumab benefits frail elderly breast cancer patients.
Major finding: PFS was 12.7 months vs. 5.6 months with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide vs. trastuzumab and pertuzumab alone.
Study details: A randomized phase 2 trial in 80 patients.
Disclosures: This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, MacroGenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.
Source: Wildiers Hans et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.