VOLUME
32
䡠
NUMBER
8
䡠
MARCH
10
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Maturing of Renal Cancer Therapeutics Walter M. Stadler, University of Chicago, Chicago, IL See accompanying articles on pages 752 and 760
Until recently, options for treatment of metastatic renal cancer were limited. High-dose interleukin-2 leads to sustained nearcomplete responses in a minority of patients, but is too toxic for most. Interferon leads to occasional responses and was the historical treatment reference,1 but the benefit is modest, and the quality of life impact significant. It is in this context that the current vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) – directed agents were developed. The phase II studies of the VEGF pathway inhibitors bevacizumab, sorafenib, and sunitinib and the mTOR inhibitor temsirolimus for treatment of renal cancer were all conducted within the same time frame; however, their sponsors elected different pathways for regulatory approval. Temsirolimus was compared with interferon in the front-line setting, with inclusion of a third combination arm, and with a survival end point in patients with poor prognostic features.2 By limiting the study to poor-risk patients, the sponsors had hoped that the end point would be reached more rapidly in the competitive marketplace of multiple agents undergoing phase III evaluation. Unfortunately, this restriction also led to much slower accrual, and the final results were delayed until after sunitinib and sorafenib were already established in practice. The definitive sorafenib trial was placebo controlled and conducted in the second-line setting after interferon or interleukin-2.3 The sponsors for sunitinib were a bit more confident and elected to conduct their definitive trial in the first-line setting versus interferon.4 Because both studies were positive, the level 1 data strongly suggested that the preferred first-line agent be sunitinib. Bevacizumab took a more circuitous route to regulatory approval, largely because the sponsor was reluctant to conduct confirmatory phase III studies in renal cancer before approval of their drug in other diseases. I had the honor of serving on the cooperative group committee that designed the initial trial, and there were debates whether it should be a two-arm trial of interferon with or without bevacizumab or whether a third arm of bevacizumab alone should be added. There were significant concerns about whether participants could successfully be recruited for the larger threearm trial, and it was thus elected to proceed with a two-arm trial. The combination of toxic interferon with intravenous bevacizumab, along with the availability of alternatives, led to limited adoption of the regimen by the community. The two phase III renal cancer trials that accompany this editorial further define treatment options for metastatic renal cancer. The first is a randomized phase III trial of temsirolimus and 722
© 2014 by American Society of Clinical Oncology
bevacizumab versus interferon alfa and bevacizumab,5 and the second is a phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib.6 Notably, at the time these trials were designed the original temsirolimus sponsor, Wyeth, was sold to Pfizer. Because Pfizer already sponsored sunitinib, there was interest in solidifying a market leadership position in renal cancer, without competing against its own product. This was an important driver for the decision to conduct a first-line trial versus the least commonly used regimen, namely, bevacizumab and interferon. There was also a preclinical rationale for combining an mTOR and VEGF pathway inhibitor inasmuch as mTOR inhibition leads to decreased translation of the hypoxia-inducible transcription factor, and thus the combination could lead to a “double hit” on the downstream VEGF angiogenic pathway. Nevertheless, it is notable that the trial was initiated with essentially no clinical data on combination mTOR and VEGF pathway inhibition in renal cancer. The second-line trial of temsirolimus versus sorafenib was also initiated with limited preliminary clinical data. In fact, the preliminary data consisted essentially of the phase III results from the alternative mTOR inhibitor everolimus, which demonstrated a modest improvement in progression-free survival versus placebo in this disease setting. The obvious presumption was that progression of disease in the context of a VEGFR inhibitor would predict poor response to a second agent with the same mechanism, especially if it was biochemically less potent. Given this background, it is perhaps not surprising that neither trial was able to demonstrate an advantage in progression-free or overall survival over the respective control. Several important lessons can be learned. First and foremost is the need for robust preliminary data before embarking on a large and expensive phase III trial. The amount of data necessary is debatable and has been the subject of multiple editorials; nevertheless, there is increasing recognition that the failure rate for oncology phase III trials is too high.7 A recent review showed that 62% of published oncology phase III trials were negative.8 Given known publication biases, the reality is likely even worse. Along these lines, several phase II trials have been presented that clearly question the principal hypotheses under which these phase III studies were initiated. As Rini et al5 note, two randomized phase II trials initiated before his study suggested that the temsirolimus combination was unlikely to provide a significant benefit over standard of care and may be more toxic.9,10 In addition, a number of observational studies reported measurable objective Journal of Clinical Oncology, Vol 32, No 8 (March 10), 2014: pp 722-724
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
Editorial
response rates and impressive progression-free survival rates in uncontrolled trials of second- and even third-line VEGFR-directed agents.11 In retrospect, waiting for the phase II and retrospective data would have been wise. The clinical activity with second- and third-line VEGFR inhibitors is unlike that of other kinase inhibitors such as those that target EGFR or BCR-ABL. In these cases, one commonly finds additional mutations of the receptor in resistant tumors, and additional tyrosine kinase inhibitors are effective only if they inhibit these new mutations. However, in these cases the alterations exist in mutable cancer cells, whereas the VEGFR receptor is expressed principally in genetically stable blood vessels. Although mechanisms for resistance to VEGF pathway inhibitors are still being identified, mutations are not common, and adaptive phenomena, including upregulation of other angiogenic mediators, are most relevant.12-14 In preclinical models, the system appears to “reset” after a break such that retreatment with the same drug after a drug-free interval is once again effective.12 That this is relevant in patients is supported by the aforementioned responses to second-line inhibitors, as well as the observation that intermittent sunitinib therapy on the standard schedule may have a progression-free survival advantage over lower dose continuous therapy.15 Thus, the result that second-line sorafenib may provide a survival benefit over temsirolimus may not be so surprising, and in fact raises the hypothesis that long-term VEGF pathway inhibition may be critical for treatment of this cancer. Further support for this concept comes from a separate trial of tivozanib versus sorafenib in the first-line setting in which a potential survival advantage in the sorafenib arm was also noted.16 This trial was conducted mainly in countries with limited access to newer agents and had a specified cross-over design. Thus, on a practical level, this was a study of one VEGF pathway inhibitor versus a more prolonged course of treatment with two VEGF pathway– directed therapies. Treatment with these drugs beyond arbitrarily defined progression metrics may be useful and should be formally studied. Finally, the primary end point for both studies was progression-free survival. This is a pragmatic decision based on the multiple agents now available for renal cancer, and on concerns that postprogression therapy might affect outcome, as in the aforementioned tivozanib trial. However, progression-free survival has not been demonstrated to be a surrogate end point for renal cancer trials, and in fact, the correlation of progression-free with overall survival is modest at best.17 This strongly suggests that additional end points that meet surrogate end point criteria, or that provide objective measures of clinically significant patient outcomes, are needed. In conclusion, Rini et al5 and Hutson et al6 have provided two studies defining treatment of metastatic renal cancer. Combination therapies with mTOR and VEGF pathway– directed agents cannot be considered standard and are unlikely to be useful with any set of drugs, and more prolonged and sustained treatment with VEGF pathway inhibitors may be important. Where and how mTOR inhibitors should fit into the treatment of renal cancer, mechanisms of resistance to VEGF pathway– directed agents, and the optimal duration of VEGF pathway– directed therapy all remain to be determined. It should also be noted that these concluwww.jco.org
sions and discussions are relevant for clear-cell tumors, but may or may not be relevant for the multiple subsets of non– clear-cell renal cancer, which were excluded from the Rini trial and made up only a small proportion of patients on the Hutson trial. Finally, for an investigator whose career began developing renal cancer therapeutics when there were essentially no active treatments, the maturing of the field such that combination, sequencing, and specific drug questions can be raised is an extremely gratifying development. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Walter M. Stadler, Novartis (C), Genentech (C), Caremark (C) Stock Ownership: None Honoraria: None Research Funding: Walter M. Stadler, Pfizer, Genentech, Novartis, GlaxoSmithKline Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002 2. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271-2281, 2007 3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 4. Motzer RJ, Hutson TE, Tomczak P, et al: Phase III randomized trial of sunitinib malate versus interferon-alfa (IFN-␣) as first-line systemic therapy for patients with metastatic renal cell carcinoma. J Clin Oncol 24, 2006 (suppl; abstr LBA3) 5. Rini BI, Bellmunt J, Clancy J, et al: Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 32:752-759, 2014 6. Hutson TE, Escudier B, Esteban E, et al: Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32:760-767, 2014 7. Booth B, Glassman R, Ma P: Oncology’s trials. Nat Rev Drug Discov 2:609-610, 2003 8. Gan HK, You B, Pond GR, et al: Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer. J Natl Cancer Inst 104:590-598, 2012 9. Ne´grier S, Gravis G, Perol D, et al: Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): A randomised phase 2 trial. Lancet Oncol 12:673-680, 2011 10. McDermott DF, Manola J, Pins M, et al: The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC). J Clin Oncol 31, 2013 (suppl; abstr 345) 11. Sablin MP, Negrier S, Ravaud A, et al: Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 182:29-34; discussion 34, 2009 12. Zhang L, Bhasin M, Schor-Bardach R, et al: Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression. PLoS One 6:e19144, 2011 13. Hammers HJ, Verheul HM, Salumbides B, et al: Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
723
Editorial
renal cell carcinoma: Evidence from a xenograft study. Mol Cancer Ther 9:1525-1535, 2010 14. Huang D, Ding Y, Zhou M, et al: Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70:10631071, 2010 15. Motzer RJ, Hutson TE, Olsen MR, et al: Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as firstline therapy for advanced renal cell carcinoma. J Clin Oncol 30:1371-1377, 2012
16. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J Clin Oncol 31:3791-3799, 2013 17. Halabi S, Rini B, Escudier B, et al: Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma. Cancer [epub ahead of print on October 8, 2013]
DOI: 10.1200/JCO.2013.54.1748; published online ahead of print at www.jco.org on February 10, 2014
■ ■ ■
Not an ASCO Member? Subscribe to Journal of Oncology Practice Journal of Oncology Practice (JOP) is ASCO’s bimonthly forum for providing its subscribers with information, news, and tools to enhance practice efficiency and promote a high standard of quality for patient care. Every issue of JOP includes important features on cancer policy issues and their practical effect on cancer care, methods for enhancing the quality of patient care, and tools for improving practice management. Whether practitioners are in an office or hospital setting, a community or academic environment, JOP provides practical information and advice that oncologists and other oncology professionals can apply immediately to their practices. Key features include: ● Articles for all members of the practice—physicians, nurses, and administrators ● Timely and relevant information to help practices succeed ● Focus on improving practice efficiency and quality of care ● Coverage of legal, financial, technology, and personnel issues Subscribe today at jop.ascopubs.org.
724
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
32
䡠
NUMBER
8
䡠
MARCH
10
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Maturing of Renal Cancer Therapeutics Walter M. Stadler, University of Chicago, Chicago, IL See accompanying articles on pages 752 and 760
Until recently, options for treatment of metastatic renal cancer were limited. High-dose interleukin-2 leads to sustained nearcomplete responses in a minority of patients, but is too toxic for most. Interferon leads to occasional responses and was the historical treatment reference,1 but the benefit is modest, and the quality of life impact significant. It is in this context that the current vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) – directed agents were developed. The phase II studies of the VEGF pathway inhibitors bevacizumab, sorafenib, and sunitinib and the mTOR inhibitor temsirolimus for treatment of renal cancer were all conducted within the same time frame; however, their sponsors elected different pathways for regulatory approval. Temsirolimus was compared with interferon in the front-line setting, with inclusion of a third combination arm, and with a survival end point in patients with poor prognostic features.2 By limiting the study to poor-risk patients, the sponsors had hoped that the end point would be reached more rapidly in the competitive marketplace of multiple agents undergoing phase III evaluation. Unfortunately, this restriction also led to much slower accrual, and the final results were delayed until after sunitinib and sorafenib were already established in practice. The definitive sorafenib trial was placebo controlled and conducted in the second-line setting after interferon or interleukin-2.3 The sponsors for sunitinib were a bit more confident and elected to conduct their definitive trial in the first-line setting versus interferon.4 Because both studies were positive, the level 1 data strongly suggested that the preferred first-line agent be sunitinib. Bevacizumab took a more circuitous route to regulatory approval, largely because the sponsor was reluctant to conduct confirmatory phase III studies in renal cancer before approval of their drug in other diseases. I had the honor of serving on the cooperative group committee that designed the initial trial, and there were debates whether it should be a two-arm trial of interferon with or without bevacizumab or whether a third arm of bevacizumab alone should be added. There were significant concerns about whether participants could successfully be recruited for the larger threearm trial, and it was thus elected to proceed with a two-arm trial. The combination of toxic interferon with intravenous bevacizumab, along with the availability of alternatives, led to limited adoption of the regimen by the community. The two phase III renal cancer trials that accompany this editorial further define treatment options for metastatic renal cancer. The first is a randomized phase III trial of temsirolimus and 722
© 2014 by American Society of Clinical Oncology
bevacizumab versus interferon alfa and bevacizumab,5 and the second is a phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib.6 Notably, at the time these trials were designed the original temsirolimus sponsor, Wyeth, was sold to Pfizer. Because Pfizer already sponsored sunitinib, there was interest in solidifying a market leadership position in renal cancer, without competing against its own product. This was an important driver for the decision to conduct a first-line trial versus the least commonly used regimen, namely, bevacizumab and interferon. There was also a preclinical rationale for combining an mTOR and VEGF pathway inhibitor inasmuch as mTOR inhibition leads to decreased translation of the hypoxia-inducible transcription factor, and thus the combination could lead to a “double hit” on the downstream VEGF angiogenic pathway. Nevertheless, it is notable that the trial was initiated with essentially no clinical data on combination mTOR and VEGF pathway inhibition in renal cancer. The second-line trial of temsirolimus versus sorafenib was also initiated with limited preliminary clinical data. In fact, the preliminary data consisted essentially of the phase III results from the alternative mTOR inhibitor everolimus, which demonstrated a modest improvement in progression-free survival versus placebo in this disease setting. The obvious presumption was that progression of disease in the context of a VEGFR inhibitor would predict poor response to a second agent with the same mechanism, especially if it was biochemically less potent. Given this background, it is perhaps not surprising that neither trial was able to demonstrate an advantage in progression-free or overall survival over the respective control. Several important lessons can be learned. First and foremost is the need for robust preliminary data before embarking on a large and expensive phase III trial. The amount of data necessary is debatable and has been the subject of multiple editorials; nevertheless, there is increasing recognition that the failure rate for oncology phase III trials is too high.7 A recent review showed that 62% of published oncology phase III trials were negative.8 Given known publication biases, the reality is likely even worse. Along these lines, several phase II trials have been presented that clearly question the principal hypotheses under which these phase III studies were initiated. As Rini et al5 note, two randomized phase II trials initiated before his study suggested that the temsirolimus combination was unlikely to provide a significant benefit over standard of care and may be more toxic.9,10 In addition, a number of observational studies reported measurable objective Journal of Clinical Oncology, Vol 32, No 8 (March 10), 2014: pp 722-724
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
Editorial
response rates and impressive progression-free survival rates in uncontrolled trials of second- and even third-line VEGFR-directed agents.11 In retrospect, waiting for the phase II and retrospective data would have been wise. The clinical activity with second- and third-line VEGFR inhibitors is unlike that of other kinase inhibitors such as those that target EGFR or BCR-ABL. In these cases, one commonly finds additional mutations of the receptor in resistant tumors, and additional tyrosine kinase inhibitors are effective only if they inhibit these new mutations. However, in these cases the alterations exist in mutable cancer cells, whereas the VEGFR receptor is expressed principally in genetically stable blood vessels. Although mechanisms for resistance to VEGF pathway inhibitors are still being identified, mutations are not common, and adaptive phenomena, including upregulation of other angiogenic mediators, are most relevant.12-14 In preclinical models, the system appears to “reset” after a break such that retreatment with the same drug after a drug-free interval is once again effective.12 That this is relevant in patients is supported by the aforementioned responses to second-line inhibitors, as well as the observation that intermittent sunitinib therapy on the standard schedule may have a progression-free survival advantage over lower dose continuous therapy.15 Thus, the result that second-line sorafenib may provide a survival benefit over temsirolimus may not be so surprising, and in fact raises the hypothesis that long-term VEGF pathway inhibition may be critical for treatment of this cancer. Further support for this concept comes from a separate trial of tivozanib versus sorafenib in the first-line setting in which a potential survival advantage in the sorafenib arm was also noted.16 This trial was conducted mainly in countries with limited access to newer agents and had a specified cross-over design. Thus, on a practical level, this was a study of one VEGF pathway inhibitor versus a more prolonged course of treatment with two VEGF pathway– directed therapies. Treatment with these drugs beyond arbitrarily defined progression metrics may be useful and should be formally studied. Finally, the primary end point for both studies was progression-free survival. This is a pragmatic decision based on the multiple agents now available for renal cancer, and on concerns that postprogression therapy might affect outcome, as in the aforementioned tivozanib trial. However, progression-free survival has not been demonstrated to be a surrogate end point for renal cancer trials, and in fact, the correlation of progression-free with overall survival is modest at best.17 This strongly suggests that additional end points that meet surrogate end point criteria, or that provide objective measures of clinically significant patient outcomes, are needed. In conclusion, Rini et al5 and Hutson et al6 have provided two studies defining treatment of metastatic renal cancer. Combination therapies with mTOR and VEGF pathway– directed agents cannot be considered standard and are unlikely to be useful with any set of drugs, and more prolonged and sustained treatment with VEGF pathway inhibitors may be important. Where and how mTOR inhibitors should fit into the treatment of renal cancer, mechanisms of resistance to VEGF pathway– directed agents, and the optimal duration of VEGF pathway– directed therapy all remain to be determined. It should also be noted that these concluwww.jco.org
sions and discussions are relevant for clear-cell tumors, but may or may not be relevant for the multiple subsets of non– clear-cell renal cancer, which were excluded from the Rini trial and made up only a small proportion of patients on the Hutson trial. Finally, for an investigator whose career began developing renal cancer therapeutics when there were essentially no active treatments, the maturing of the field such that combination, sequencing, and specific drug questions can be raised is an extremely gratifying development. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Walter M. Stadler, Novartis (C), Genentech (C), Caremark (C) Stock Ownership: None Honoraria: None Research Funding: Walter M. Stadler, Pfizer, Genentech, Novartis, GlaxoSmithKline Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002 2. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271-2281, 2007 3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 4. Motzer RJ, Hutson TE, Tomczak P, et al: Phase III randomized trial of sunitinib malate versus interferon-alfa (IFN-␣) as first-line systemic therapy for patients with metastatic renal cell carcinoma. J Clin Oncol 24, 2006 (suppl; abstr LBA3) 5. Rini BI, Bellmunt J, Clancy J, et al: Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 32:752-759, 2014 6. Hutson TE, Escudier B, Esteban E, et al: Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32:760-767, 2014 7. Booth B, Glassman R, Ma P: Oncology’s trials. Nat Rev Drug Discov 2:609-610, 2003 8. Gan HK, You B, Pond GR, et al: Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer. J Natl Cancer Inst 104:590-598, 2012 9. Ne´grier S, Gravis G, Perol D, et al: Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): A randomised phase 2 trial. Lancet Oncol 12:673-680, 2011 10. McDermott DF, Manola J, Pins M, et al: The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC). J Clin Oncol 31, 2013 (suppl; abstr 345) 11. Sablin MP, Negrier S, Ravaud A, et al: Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 182:29-34; discussion 34, 2009 12. Zhang L, Bhasin M, Schor-Bardach R, et al: Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression. PLoS One 6:e19144, 2011 13. Hammers HJ, Verheul HM, Salumbides B, et al: Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
723
Editorial
renal cell carcinoma: Evidence from a xenograft study. Mol Cancer Ther 9:1525-1535, 2010 14. Huang D, Ding Y, Zhou M, et al: Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70:10631071, 2010 15. Motzer RJ, Hutson TE, Olsen MR, et al: Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as firstline therapy for advanced renal cell carcinoma. J Clin Oncol 30:1371-1377, 2012
16. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J Clin Oncol 31:3791-3799, 2013 17. Halabi S, Rini B, Escudier B, et al: Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma. Cancer [epub ahead of print on October 8, 2013]
DOI: 10.1200/JCO.2013.54.1748; published online ahead of print at www.jco.org on February 10, 2014
■ ■ ■
Not an ASCO Member? Subscribe to Journal of Oncology Practice Journal of Oncology Practice (JOP) is ASCO’s bimonthly forum for providing its subscribers with information, news, and tools to enhance practice efficiency and promote a high standard of quality for patient care. Every issue of JOP includes important features on cancer policy issues and their practical effect on cancer care, methods for enhancing the quality of patient care, and tools for improving practice management. Whether practitioners are in an office or hospital setting, a community or academic environment, JOP provides practical information and advice that oncologists and other oncology professionals can apply immediately to their practices. Key features include: ● Articles for all members of the practice—physicians, nurses, and administrators ● Timely and relevant information to help practices succeed ● Focus on improving practice efficiency and quality of care ● Coverage of legal, financial, technology, and personnel issues Subscribe today at jop.ascopubs.org.
724
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at J S GERICKE LIBRARY on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 146.232.129.75
