- Email: [email protected]
Real-world experience with abiraterone
Comment
since additional treatment would only create toxicity rather than offer any improvement to a patient’s clinical outcome. Moreover, since maintenance treatment has been tested and has shown its efficacy after, mainly, four cycles of first-line chemotherapy, treatment discontinuation at that point enables the patients to continue with only one active non-platinum agent or to switch to another drug. In conclusion, Rossi and colleagues’ meta-analysis strengthens the view that the duration of chemotherapy should be personalised for every individual patient. Patients who discontinue treatment after three or four cycles of chemotherapy would not be necessarily be deprived of a treatment that will substantially affect their clinical outcome. Instead, they might have a greater benefit from such an approach in terms of their quality of life. The identification and selection of those patients who might benefit more from less chemotherapy should include biological and genomic factors that probably affect the disease course. Therefore, to undertake randomised trials with novel active chemotherapy regimens in more homogeneous non-small-cell lung cancer populations, selected on the basis of their molecular tumour characteristics, emerges as imperative for the identification of those patients who are likely to benefit more from prolongation of front-line chemotherapy treatment.
Athanasios Kotsakis, Vassilis Georgoulias* Department of Medical Oncology, University General Hospital of Heraklion, Voutes, PO Box 1352, 711 10 Heraklion, Crete, Greece [email protected] We declare no competing interests. 1
2
3
4
5
6
7
8 9
Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009; 27: 3277–83. Rossi A, Chiodini P, Sun J-M, et al. Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2014; published online Sept 15. http://dx.doi.org/10.1016/ S1470-2045(14)70402-4. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinumbased chemotherapy in non small-cell lung cancer. J Clin Oncol 2007; 25: 5233–39. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9: 154–62. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in nonsmall-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PloS One 2009; 4: e5133. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010; 11: 521–29. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–40. Reckamp KL. Is benefit of maintenance therapy for NSCLC best defined by progression-free survival? Lancet Oncol 2012; 13: 435–36. Azzoli CG, Temin S, Aliff T, et al. 2011 Focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2011; 29: 3825–31.
Nina Lampen/Science Photo Library
Real-world experience with abiraterone
Published Online September 19, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70463-2 See Articles page 1263
1188
In The Lancet Oncology, Cora Sternberg and colleagues1 present results of an early-access protocol trial of abiraterone acetate for treatment of patients with metastatic castration-resistant prostate cancer who had progressed after taxane chemotherapy and possibly one additional regimen.They provide realworld data for abiraterone in a broad global population, including countries that were not part of the initial registration trial that led to regulatory approval for abiraterone (COU-AA-301). In the initial analysis of COU-AA-301,2 in patients with metastatic castrationresistant prostate cancer who had progressed on a taxane, overall survival was increased significantly after treatment with abiraterone and prednisone, compared with prednisone alone (14·8 months vs 10·9 months; hazard ratio 0·65, 95% CI 0·54–0·77). Furthermore,
abiraterone delayed progression of disease in patients with chemotherapy-naive metastatic castrationresistant prostate cancer, and abiraterone has also been approved in this population.3 Sternberg and colleagues noted no new safety signals in the early-access protocol trial; grade 3–4 treatmentrelated adverse events were reported in 952 (41%) of 2314 patients, whereas grade 3–4 events were recorded in 431 (54%) of 791 patients in COU-AA-301. Grade 3–4 serious adverse events were recorded in 585 (25%) patients in the early-access protocol trial and 297 (38%) in COU-AA-301. Furthermore, the proportion of patients discontinuing treatment because of toxic effects was similar between studies (172 [7%] in the early-access protocol trial and 105 [13%] in COU-AA-301), as was the proportion of treatmentwww.thelancet.com/oncology Vol 15 October 2014
Comment
related deaths (171 [7%] and 21 [3%], respectively). Median time to prostate-specific antigen (PSA) progression was 8·5 months in both the early-access protocol trial and COU-AA-301, and median time to clinical progression was 12·7 months in the early-access protocol trial (data not reported in COU-AA-301). Implementation of an early-access protocol trial and subsequent comparison of data with those from the registration study is challenging, with inherent limitations. The early-access protocol trial did not have the strict regimentation and structure of COU-AA-301, and assessments were clinically based. Only serious adverse events as judged by the investigator were recorded, which Sternberg and colleagues acknowledge. In addition to safety, response assessment was confounded because PSA testing was only required at 3-month intervals, and follow-up imaging was done at the discretion of the treating clinician. Although such variations from the registration trial are anticipated, taken together they are important and likely to lead to under-reporting of toxic effects and perhaps overestimation of time to progression. The median duration of abiraterone treatment was shorter in the early-access protocol trial than in COU-AA-301 (4·9 months vs 7·4 months). Combined with the probable under-reporting of toxic effects, this difference between studies raises further concerns about underestimation of adverse events in the early-access protocol trial, particularly for grade 3 and 4 hepatotoxic events (188 [8%] vs 30 [4%]) and hypertension (99 [4%] vs ten [1%]). Perhaps analysis of patients’ characteristics, comorbidities, and concomitant drugs could augment safety data for abiraterone. As additional safety data for abiraterone emerge, limitations on clinical use of the drug are becoming apparent. Findings from randomised trials of the androgen-receptor antagonist enzalutamide showed increased survival in patients with metastatic castrationresistant prostate cancer both before and after chemotherapy, which led to its approval by the US Food and Drug Administration (FDA) for this population.4,5 Clinicians might favour enzalutamide as a first option over abiraterone because it does not need coadministration of corticosteroids and, thus, might have fewer toxic effects. Furthermore, clinical data suggest that the response to enzalutamide or abiraterone is diminished when either drug is used after the other.6,7 www.thelancet.com/oncology Vol 15 October 2014
This primary or acquired resistance to both agents can be explained partly by the presence of androgen receptor splice variant 7, although several other mechanisms— some of which are drug-specific—have been identified.8 Moreover, use of these agents might have an effect on subsequent docetaxel activity, highlighting the importance of androgen receptor signaling, even in chemotherapy.9 We need a much better understanding of how to select patients who should initially receive either enzalutamide or abiraterone, or even docetaxel, and the individuals who are likely to benefit from sequential treatment. In general, however, Sternberg and colleagues should be commended for rapid acquisition of substantial clinical data for abiraterone in a population that is probably less pristine then COU-AA-301. Even allowing for substantial differences between clinical assessment and data collection in the two studies, the absence of any major toxic effects is reassuring, and clear clinical activity was recorded. Moreover, the depth of these data becomes crucial as CYP17A1 inhibitors with lyase selectivity—eg, VT-464—enter the clinic, easing the ability to note clinical differences in pathway-selective agents.10 In practice, abiraterone will probably be used much earlier in the clinical course than in the population studied by Sternberg and colleagues and in COU-AA-301. However, although these findings greatly increase confidence with respect to the safety of abiraterone, the burden is now on individual practitioners to report unusual toxic effects through the Medwatch system. *William L Dahut, Ravi A Madan Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA [email protected] We declare no competing interests. 1
2
3
4 5
Sternberg CN, Castellano D, Daugaard G, et al, for the Abiraterone Global EAP Investigators. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/ S1470-2045(14)70417-6. de Bono JS, Logothetis CJ, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–48. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–97. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33.
1189
Comment
6
7
8
Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014; 120: 968–75. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802–07. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38.
9
10
Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943–47. Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. Bioorg Med Chem Lett 2014; 24: 2444–47.
Nancy Kedersha/Science Photo Library
Bevacizumab beyond progression in breast cancer
Published Online September 28, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70454-1 See Articles page 1269
1190
Angiogenesis is the sprouting of new blood vessels from pre-existing ones, and is considered to be a prerequisite for the growth of both primary tumours and metastases. VEGF is a crucial factor involved in angiogenesis. Suppression of VEGF signalling in preclinical models results in suppression of tumour growth. These findings led to the clinical development of VEGF-targeted therapies, such as the VEGF-neutralising antibody bevacizumab. However, despite showing efficacy in other cancer types, VEGF-targeted therapies have done less well in advanced breast cancer.1,2 The combination of bevacizumab with cytotoxic chemotherapy for advanced breast cancer has been examined as first-line therapy in three phase 3 trials (E2100, AVADO, RIBBON-1) and as second-line therapy in two phase 3 trials (AVF2119, RIBBON-2). Across these studies, the addition of bevacizumab invariably increased the proportion of patients achieving a response, and a statistically significant improvement in progression-free survival was noted in four studies (E2100, AVADO, RIBBON-1, and RIBBON-2).3 However, no study published in this setting so far has shown an improvement in overall survival. This absence of substantial effect on overall survival has made the use of bevacizumab in advanced breast cancer controversial. One potential explanation for the absence of effect on survival is that bevacizumab was not given for long enough to patients with breast cancer for a survival benefit to manifest. Preclinical data show that tumour vessels can regrow on cessation of VEGF-targeted therapy4 or that disease can rebound during treatment cessation2 suggesting that prolonged administration of these cytostatic drugs might be necessary. In support of this, administration of bevacizumab with chemotherapy beyond progression has been shown to prolong overall survival in patients with advanced colorectal
cancer compared with chemotherapy alone beyond progression.5 But, could the same hold true for advanced breast cancer? In this issue of The Lancet Oncology, Gunter von Minckwitz and colleagues6 report the results of the phase 3 TANIA study. This study enrolled patients with HER2-negative locally recurrent or metastatic breast cancer who had received first-line bevacizumab and chemotherapy, and progressed after at least 12 weeks of disease control. Patients were randomly assigned to receive either bevacizumab and chemotherapy, or to receive chemotherapy alone. After a median follow-up of about 16 months, the second-line median progressionfree survival was 4·2 months for chemotherapy alone versus 6·3 months in the bevacizumab containing group (HR 0·75, [95% CI 0·61–0·93]; p=0·0068). The authors can be congratulated for showing that continued treatment with bevacizumab, after previous progression on bevacizumab, is beneficial in terms of delaying disease progression in patients with advanced breast cancer. In this selected population of patients, most have relatively chemosensitive disease, in that they achieve a long period of first-line disease control: for more than two-thirds of patients, bevacizumab, with its long half-life, was effectively never interrupted. However, the difference in progression-free survival was not paralled by a significant increase in the number of patients achieving a response, and the overall survival data are immature at the time of this analysis, although no new safety signals were reported. In a study of similar design, patients with advanced breast cancer progressing during or after a bevacizumab containing regimen were randomly assigned to one of two types of chemotherapy combined with either placebo or sorafenib, another inhibitor of multiple tyrosine kinases including the VEGF receptor. This study www.thelancet.com/oncology Vol 15 October 2014
since additional treatment would only create toxicity rather than offer any improvement to a patient’s clinical outcome. Moreover, since maintenance treatment has been tested and has shown its efficacy after, mainly, four cycles of first-line chemotherapy, treatment discontinuation at that point enables the patients to continue with only one active non-platinum agent or to switch to another drug. In conclusion, Rossi and colleagues’ meta-analysis strengthens the view that the duration of chemotherapy should be personalised for every individual patient. Patients who discontinue treatment after three or four cycles of chemotherapy would not be necessarily be deprived of a treatment that will substantially affect their clinical outcome. Instead, they might have a greater benefit from such an approach in terms of their quality of life. The identification and selection of those patients who might benefit more from less chemotherapy should include biological and genomic factors that probably affect the disease course. Therefore, to undertake randomised trials with novel active chemotherapy regimens in more homogeneous non-small-cell lung cancer populations, selected on the basis of their molecular tumour characteristics, emerges as imperative for the identification of those patients who are likely to benefit more from prolongation of front-line chemotherapy treatment.
Athanasios Kotsakis, Vassilis Georgoulias* Department of Medical Oncology, University General Hospital of Heraklion, Voutes, PO Box 1352, 711 10 Heraklion, Crete, Greece [email protected] We declare no competing interests. 1
2
3
4
5
6
7
8 9
Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009; 27: 3277–83. Rossi A, Chiodini P, Sun J-M, et al. Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2014; published online Sept 15. http://dx.doi.org/10.1016/ S1470-2045(14)70402-4. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinumbased chemotherapy in non small-cell lung cancer. J Clin Oncol 2007; 25: 5233–39. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9: 154–62. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in nonsmall-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PloS One 2009; 4: e5133. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010; 11: 521–29. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–40. Reckamp KL. Is benefit of maintenance therapy for NSCLC best defined by progression-free survival? Lancet Oncol 2012; 13: 435–36. Azzoli CG, Temin S, Aliff T, et al. 2011 Focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2011; 29: 3825–31.
Nina Lampen/Science Photo Library
Real-world experience with abiraterone
Published Online September 19, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70463-2 See Articles page 1263
1188
In The Lancet Oncology, Cora Sternberg and colleagues1 present results of an early-access protocol trial of abiraterone acetate for treatment of patients with metastatic castration-resistant prostate cancer who had progressed after taxane chemotherapy and possibly one additional regimen.They provide realworld data for abiraterone in a broad global population, including countries that were not part of the initial registration trial that led to regulatory approval for abiraterone (COU-AA-301). In the initial analysis of COU-AA-301,2 in patients with metastatic castrationresistant prostate cancer who had progressed on a taxane, overall survival was increased significantly after treatment with abiraterone and prednisone, compared with prednisone alone (14·8 months vs 10·9 months; hazard ratio 0·65, 95% CI 0·54–0·77). Furthermore,
abiraterone delayed progression of disease in patients with chemotherapy-naive metastatic castrationresistant prostate cancer, and abiraterone has also been approved in this population.3 Sternberg and colleagues noted no new safety signals in the early-access protocol trial; grade 3–4 treatmentrelated adverse events were reported in 952 (41%) of 2314 patients, whereas grade 3–4 events were recorded in 431 (54%) of 791 patients in COU-AA-301. Grade 3–4 serious adverse events were recorded in 585 (25%) patients in the early-access protocol trial and 297 (38%) in COU-AA-301. Furthermore, the proportion of patients discontinuing treatment because of toxic effects was similar between studies (172 [7%] in the early-access protocol trial and 105 [13%] in COU-AA-301), as was the proportion of treatmentwww.thelancet.com/oncology Vol 15 October 2014
Comment
related deaths (171 [7%] and 21 [3%], respectively). Median time to prostate-specific antigen (PSA) progression was 8·5 months in both the early-access protocol trial and COU-AA-301, and median time to clinical progression was 12·7 months in the early-access protocol trial (data not reported in COU-AA-301). Implementation of an early-access protocol trial and subsequent comparison of data with those from the registration study is challenging, with inherent limitations. The early-access protocol trial did not have the strict regimentation and structure of COU-AA-301, and assessments were clinically based. Only serious adverse events as judged by the investigator were recorded, which Sternberg and colleagues acknowledge. In addition to safety, response assessment was confounded because PSA testing was only required at 3-month intervals, and follow-up imaging was done at the discretion of the treating clinician. Although such variations from the registration trial are anticipated, taken together they are important and likely to lead to under-reporting of toxic effects and perhaps overestimation of time to progression. The median duration of abiraterone treatment was shorter in the early-access protocol trial than in COU-AA-301 (4·9 months vs 7·4 months). Combined with the probable under-reporting of toxic effects, this difference between studies raises further concerns about underestimation of adverse events in the early-access protocol trial, particularly for grade 3 and 4 hepatotoxic events (188 [8%] vs 30 [4%]) and hypertension (99 [4%] vs ten [1%]). Perhaps analysis of patients’ characteristics, comorbidities, and concomitant drugs could augment safety data for abiraterone. As additional safety data for abiraterone emerge, limitations on clinical use of the drug are becoming apparent. Findings from randomised trials of the androgen-receptor antagonist enzalutamide showed increased survival in patients with metastatic castrationresistant prostate cancer both before and after chemotherapy, which led to its approval by the US Food and Drug Administration (FDA) for this population.4,5 Clinicians might favour enzalutamide as a first option over abiraterone because it does not need coadministration of corticosteroids and, thus, might have fewer toxic effects. Furthermore, clinical data suggest that the response to enzalutamide or abiraterone is diminished when either drug is used after the other.6,7 www.thelancet.com/oncology Vol 15 October 2014
This primary or acquired resistance to both agents can be explained partly by the presence of androgen receptor splice variant 7, although several other mechanisms— some of which are drug-specific—have been identified.8 Moreover, use of these agents might have an effect on subsequent docetaxel activity, highlighting the importance of androgen receptor signaling, even in chemotherapy.9 We need a much better understanding of how to select patients who should initially receive either enzalutamide or abiraterone, or even docetaxel, and the individuals who are likely to benefit from sequential treatment. In general, however, Sternberg and colleagues should be commended for rapid acquisition of substantial clinical data for abiraterone in a population that is probably less pristine then COU-AA-301. Even allowing for substantial differences between clinical assessment and data collection in the two studies, the absence of any major toxic effects is reassuring, and clear clinical activity was recorded. Moreover, the depth of these data becomes crucial as CYP17A1 inhibitors with lyase selectivity—eg, VT-464—enter the clinic, easing the ability to note clinical differences in pathway-selective agents.10 In practice, abiraterone will probably be used much earlier in the clinical course than in the population studied by Sternberg and colleagues and in COU-AA-301. However, although these findings greatly increase confidence with respect to the safety of abiraterone, the burden is now on individual practitioners to report unusual toxic effects through the Medwatch system. *William L Dahut, Ravi A Madan Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA [email protected] We declare no competing interests. 1
2
3
4 5
Sternberg CN, Castellano D, Daugaard G, et al, for the Abiraterone Global EAP Investigators. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/ S1470-2045(14)70417-6. de Bono JS, Logothetis CJ, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–48. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–97. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33.
1189
Comment
6
7
8
Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014; 120: 968–75. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802–07. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38.
9
10
Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943–47. Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. Bioorg Med Chem Lett 2014; 24: 2444–47.
Nancy Kedersha/Science Photo Library
Bevacizumab beyond progression in breast cancer
Published Online September 28, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70454-1 See Articles page 1269
1190
Angiogenesis is the sprouting of new blood vessels from pre-existing ones, and is considered to be a prerequisite for the growth of both primary tumours and metastases. VEGF is a crucial factor involved in angiogenesis. Suppression of VEGF signalling in preclinical models results in suppression of tumour growth. These findings led to the clinical development of VEGF-targeted therapies, such as the VEGF-neutralising antibody bevacizumab. However, despite showing efficacy in other cancer types, VEGF-targeted therapies have done less well in advanced breast cancer.1,2 The combination of bevacizumab with cytotoxic chemotherapy for advanced breast cancer has been examined as first-line therapy in three phase 3 trials (E2100, AVADO, RIBBON-1) and as second-line therapy in two phase 3 trials (AVF2119, RIBBON-2). Across these studies, the addition of bevacizumab invariably increased the proportion of patients achieving a response, and a statistically significant improvement in progression-free survival was noted in four studies (E2100, AVADO, RIBBON-1, and RIBBON-2).3 However, no study published in this setting so far has shown an improvement in overall survival. This absence of substantial effect on overall survival has made the use of bevacizumab in advanced breast cancer controversial. One potential explanation for the absence of effect on survival is that bevacizumab was not given for long enough to patients with breast cancer for a survival benefit to manifest. Preclinical data show that tumour vessels can regrow on cessation of VEGF-targeted therapy4 or that disease can rebound during treatment cessation2 suggesting that prolonged administration of these cytostatic drugs might be necessary. In support of this, administration of bevacizumab with chemotherapy beyond progression has been shown to prolong overall survival in patients with advanced colorectal
cancer compared with chemotherapy alone beyond progression.5 But, could the same hold true for advanced breast cancer? In this issue of The Lancet Oncology, Gunter von Minckwitz and colleagues6 report the results of the phase 3 TANIA study. This study enrolled patients with HER2-negative locally recurrent or metastatic breast cancer who had received first-line bevacizumab and chemotherapy, and progressed after at least 12 weeks of disease control. Patients were randomly assigned to receive either bevacizumab and chemotherapy, or to receive chemotherapy alone. After a median follow-up of about 16 months, the second-line median progressionfree survival was 4·2 months for chemotherapy alone versus 6·3 months in the bevacizumab containing group (HR 0·75, [95% CI 0·61–0·93]; p=0·0068). The authors can be congratulated for showing that continued treatment with bevacizumab, after previous progression on bevacizumab, is beneficial in terms of delaying disease progression in patients with advanced breast cancer. In this selected population of patients, most have relatively chemosensitive disease, in that they achieve a long period of first-line disease control: for more than two-thirds of patients, bevacizumab, with its long half-life, was effectively never interrupted. However, the difference in progression-free survival was not paralled by a significant increase in the number of patients achieving a response, and the overall survival data are immature at the time of this analysis, although no new safety signals were reported. In a study of similar design, patients with advanced breast cancer progressing during or after a bevacizumab containing regimen were randomly assigned to one of two types of chemotherapy combined with either placebo or sorafenib, another inhibitor of multiple tyrosine kinases including the VEGF receptor. This study www.thelancet.com/oncology Vol 15 October 2014