- Email: [email protected]
Bevacizumab: no comeback in early breast cancer?
Comment
Despite a sound biological rational, the history of anti-angiogenic therapy in breast cancer has been controversial; bevacizumab, a monoclonal humanised antibody targeting VEGF-A, is regarded as the only efficacious drug in this field so far. In the pivotal study E2100,1 conducted in metastatic disease, addition of bevacizumab to chemotherapy improved progression-free survival and the proportion of patients achieving a response compared to those who received chemotherapy alone. Still, a marginal progression-free survival benefit in the subsequent AVADO trial,2 absence of any overall survival benefit, predictive markers and issues with toxicity eventually lead the US Food and Drug Administration to withdraw their preliminary approval of bevacizumab in metastatic breast cancer. Approval for its use in Europe, however, was retained based on results from E2100 and RIBBON-1, in which the relatively largest additive effect of anti-angiogenic therapy was reported.1,3 Although this debate is currently ongoing, the role of bevacizumab in early stage disease remains entirely elusive, with contradictory evidence from the neoadjuvant setting and three essentially negative adjuvant trials.4–6 In The Lancet Oncology, the overall survival data of NSBAP B-40 trial reported by Harry Bear and colleagues7 allow for a critical reappraisal of the subject. The randomised phase 3 trial NSABP B-40 investigated the addition of capecitabine or gemcitabine to standard neoadjuvant chemotherapy with or without bevacizumab in 1206 patients with early breast cancer. Effect on the proportion of patients achieving a pathological complete response in the breast was the primary study endpoint and it was previously reported that neither capecitabine nor gemcitabine improved outcomes, whereas additional anti-angiogenic therapy with bevacizumab yielded a significantly higher proportion of patients achieving a pathological complete response (28·2% vs 34·5%; p=0·02).8 Interestingly, this effect was most pronounced in hormone-receptor positive (HR-positive) patients, somewhat contradicting other studies such as GBG-44 and ARTemis, in which activity of bevacizumab was restricted to patients with triple-negative or oestrogenreceptor-poor tumours.9,10 ABCSG-32, again, suggested a potential role for neoadjuvant bevacizumab in
HER2-positive diseases.11 By contrast with those studies, however, NSBAP B-40 featured a unique design because bevacizumab was continued in the postoperative setting. In this publication, Bear and colleagues7 report disease-free survival, distant-disease-free interval, and overall survival results of NSABP B-40 at a median follow-up of 4·7 (IQR 4·0–5·2) years. Of note, only disease-free survival was a prespecified secondary endpoint; still, exploratory overall survival data for survival were collected prospectively as well. As might be expected in a sample containing 40% HR-negative tumours, pathological complete response correlated with improved outcome; no disease-free survival or overall survival differences were noted between the three chemotherapy groups. By contrast, addition of bevacizumab resulted in significant overall survival improvement (hazard rate [HR] 0·65 [95% CI 0·49–0·88]; p=0·004), probably driven by a reduction of distant recurrence events (HR 0·70 [0·54–0·92]; p=0·01); the latter, however, was a posthoc analysis. Again, these effects were more pronounced in HR-positive patients although formal tests for interaction between HR status and bevacizumab effect were not significant. The formal secondary endpoint of disease-free survival was not significantly different between treatment groups (HR 0·80 [95% CI 0·63–1·01]; p=0·06). With respect to toxicity and tolerability, treatment was clinically feasible; 80% of patients assigned to the bevacizumab groups completed their preoperative treatment as planned. Still, only half of all patients completed postoperative bevacizumab as well, a proportion much lower compared with other adjuvant studies—eg, with trastuzumab—suggesting that toxicity issues remain (or perhaps that physicians lost trust in the drug as the trial continued?). Thus, is the positive overall survival data for NSABP B-40 sufficient to change current clinical practice? Apparently not, as the authors themselves conclude. Although distant recurrence-free interval and overall survival outcomes in B-40 point towards a beneficial role of bevacizumab, these data could not be replicated in GBG-44 (in which bevacizumab was given as neoadjuvant therapy only). Also, all trials evaluating bevacizumab in the postoperative setting yielded
www.thelancet.com/oncology Published online August 11, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00124-2
Steve Gschmeissner/Science Photo Library
Bevacizumab: no comeback in early breast cancer?
Lancet Oncol 2015 Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00124-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00041-8
1
Comment
negative results henceforth,9–11 casting doubts on the hypothesis that postoperative continuation of bevacizumab might have added to positive results. Therefore, although intriguing, the disease-free survival, distant recurrence-free interval, and overall survival data of NSABP B-40 are hypothesis-generating only, and spurious results cannot be ruled out. In summary, we do believe that there is a role for bevacizumab in breast cancer therapy, but the quest to define its exact place goes on. Still, NSABP B-40 is important, because this is the first study to report any overall survival improvement with the addition of bevacizumab to standard chemotherapy. Indeed, one may hope that correlative science studies with tumour tissue and blood samples from NSABP B-40 will eventually shed new light on the important albeit controversial issue of antiangiogenic therapy in breast cancer.
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*Rupert Bartsch, Michael Gnant, Guenther G Steger
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Departments of Internal Medicine I (RB, GGS) and Surgery (MG), Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria [email protected]
10
RB reports grants and personal fees from Roche Austria and Novartis Austria and personal fees from GlaxoSmithKline, Astra Zeneca, and Celgene outside of the submitted work. MG reports grants from Sanofi-Aventis, grants and personal fees from Roche, Novartis, GlaxoSmithKline, and Pfizer; grants from Smiths Medical; and personal fees from Accelsiors, AstraZeneca, and Nanostring Technologies outside of the submitted work.
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Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–76. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28: 3239–47. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–60. Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumabcontaining therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14: 933–42. Slamon DJ, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res 2013; 73: S1–03. Miller K, O’Neill AM, Dang CT, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol 2014; 32: 500. Bear HD, Tang G, Rastogi P, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 2015; published online Aug 11. http://dx.doi.org/10.1016/S1470-2045(15)00041-8. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012; 366: 310–20. von Minckwitz G, Loibl S, Untch M, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44 - GeparQuinto). Ann Oncol 2014; 25: 2363–72. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol 2015; 16: 656–66. Steger GG, Greil R, Hubalek M, et al. Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: final results of ABCSG-32, a prospective, randomized phase II-study. Cancer Res 2015; 75: P3-11-06.
www.thelancet.com/oncology Published online August 11, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00124-2
Despite a sound biological rational, the history of anti-angiogenic therapy in breast cancer has been controversial; bevacizumab, a monoclonal humanised antibody targeting VEGF-A, is regarded as the only efficacious drug in this field so far. In the pivotal study E2100,1 conducted in metastatic disease, addition of bevacizumab to chemotherapy improved progression-free survival and the proportion of patients achieving a response compared to those who received chemotherapy alone. Still, a marginal progression-free survival benefit in the subsequent AVADO trial,2 absence of any overall survival benefit, predictive markers and issues with toxicity eventually lead the US Food and Drug Administration to withdraw their preliminary approval of bevacizumab in metastatic breast cancer. Approval for its use in Europe, however, was retained based on results from E2100 and RIBBON-1, in which the relatively largest additive effect of anti-angiogenic therapy was reported.1,3 Although this debate is currently ongoing, the role of bevacizumab in early stage disease remains entirely elusive, with contradictory evidence from the neoadjuvant setting and three essentially negative adjuvant trials.4–6 In The Lancet Oncology, the overall survival data of NSBAP B-40 trial reported by Harry Bear and colleagues7 allow for a critical reappraisal of the subject. The randomised phase 3 trial NSABP B-40 investigated the addition of capecitabine or gemcitabine to standard neoadjuvant chemotherapy with or without bevacizumab in 1206 patients with early breast cancer. Effect on the proportion of patients achieving a pathological complete response in the breast was the primary study endpoint and it was previously reported that neither capecitabine nor gemcitabine improved outcomes, whereas additional anti-angiogenic therapy with bevacizumab yielded a significantly higher proportion of patients achieving a pathological complete response (28·2% vs 34·5%; p=0·02).8 Interestingly, this effect was most pronounced in hormone-receptor positive (HR-positive) patients, somewhat contradicting other studies such as GBG-44 and ARTemis, in which activity of bevacizumab was restricted to patients with triple-negative or oestrogenreceptor-poor tumours.9,10 ABCSG-32, again, suggested a potential role for neoadjuvant bevacizumab in
HER2-positive diseases.11 By contrast with those studies, however, NSBAP B-40 featured a unique design because bevacizumab was continued in the postoperative setting. In this publication, Bear and colleagues7 report disease-free survival, distant-disease-free interval, and overall survival results of NSABP B-40 at a median follow-up of 4·7 (IQR 4·0–5·2) years. Of note, only disease-free survival was a prespecified secondary endpoint; still, exploratory overall survival data for survival were collected prospectively as well. As might be expected in a sample containing 40% HR-negative tumours, pathological complete response correlated with improved outcome; no disease-free survival or overall survival differences were noted between the three chemotherapy groups. By contrast, addition of bevacizumab resulted in significant overall survival improvement (hazard rate [HR] 0·65 [95% CI 0·49–0·88]; p=0·004), probably driven by a reduction of distant recurrence events (HR 0·70 [0·54–0·92]; p=0·01); the latter, however, was a posthoc analysis. Again, these effects were more pronounced in HR-positive patients although formal tests for interaction between HR status and bevacizumab effect were not significant. The formal secondary endpoint of disease-free survival was not significantly different between treatment groups (HR 0·80 [95% CI 0·63–1·01]; p=0·06). With respect to toxicity and tolerability, treatment was clinically feasible; 80% of patients assigned to the bevacizumab groups completed their preoperative treatment as planned. Still, only half of all patients completed postoperative bevacizumab as well, a proportion much lower compared with other adjuvant studies—eg, with trastuzumab—suggesting that toxicity issues remain (or perhaps that physicians lost trust in the drug as the trial continued?). Thus, is the positive overall survival data for NSABP B-40 sufficient to change current clinical practice? Apparently not, as the authors themselves conclude. Although distant recurrence-free interval and overall survival outcomes in B-40 point towards a beneficial role of bevacizumab, these data could not be replicated in GBG-44 (in which bevacizumab was given as neoadjuvant therapy only). Also, all trials evaluating bevacizumab in the postoperative setting yielded
www.thelancet.com/oncology Published online August 11, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00124-2
Steve Gschmeissner/Science Photo Library
Bevacizumab: no comeback in early breast cancer?
Lancet Oncol 2015 Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00124-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00041-8
1
Comment
negative results henceforth,9–11 casting doubts on the hypothesis that postoperative continuation of bevacizumab might have added to positive results. Therefore, although intriguing, the disease-free survival, distant recurrence-free interval, and overall survival data of NSABP B-40 are hypothesis-generating only, and spurious results cannot be ruled out. In summary, we do believe that there is a role for bevacizumab in breast cancer therapy, but the quest to define its exact place goes on. Still, NSABP B-40 is important, because this is the first study to report any overall survival improvement with the addition of bevacizumab to standard chemotherapy. Indeed, one may hope that correlative science studies with tumour tissue and blood samples from NSABP B-40 will eventually shed new light on the important albeit controversial issue of antiangiogenic therapy in breast cancer.
2
3
4
5
6
7
8
*Rupert Bartsch, Michael Gnant, Guenther G Steger
9
Departments of Internal Medicine I (RB, GGS) and Surgery (MG), Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria [email protected]
10
RB reports grants and personal fees from Roche Austria and Novartis Austria and personal fees from GlaxoSmithKline, Astra Zeneca, and Celgene outside of the submitted work. MG reports grants from Sanofi-Aventis, grants and personal fees from Roche, Novartis, GlaxoSmithKline, and Pfizer; grants from Smiths Medical; and personal fees from Accelsiors, AstraZeneca, and Nanostring Technologies outside of the submitted work.
2
1
11
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–76. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28: 3239–47. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–60. Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumabcontaining therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14: 933–42. Slamon DJ, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res 2013; 73: S1–03. Miller K, O’Neill AM, Dang CT, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol 2014; 32: 500. Bear HD, Tang G, Rastogi P, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 2015; published online Aug 11. http://dx.doi.org/10.1016/S1470-2045(15)00041-8. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012; 366: 310–20. von Minckwitz G, Loibl S, Untch M, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44 - GeparQuinto). Ann Oncol 2014; 25: 2363–72. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol 2015; 16: 656–66. Steger GG, Greil R, Hubalek M, et al. Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: final results of ABCSG-32, a prospective, randomized phase II-study. Cancer Res 2015; 75: P3-11-06.
www.thelancet.com/oncology Published online August 11, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00124-2