TY - JOUR
T1 - Six-month progression-free survival as the primary endpoint to evaluate the activity of new agents as second-line therapy for advanced urothelial carcinoma
AU - Agarwal, Neeraj
AU - Bellmunt, Joaquim
AU - Maughan, Benjamin L.
AU - Boucher, Kenneth M.
AU - Choueiri, Toni K.
AU - Qu, Angela Q.
AU - Vogelzang, Nicholas J.
AU - Fougeray, Ronan
AU - Niegisch, Guenter
AU - Albers, Peter
AU - Wong, Yu Ning
AU - Ko, Yoo Joung
AU - Sridhar, Srikala S.
AU - Tantravahi, Srinivas K.
AU - Galsky, Matthew D.
AU - Petrylak, Daniel P.
AU - Vaishampayan, Ulka N.
AU - Mehta, Amitkumar N.
AU - Beer, Tomasz M.
AU - Sternberg, Cora N.
AU - Rosenberg, Jonathan E.
AU - Sonpavde, Guru
PY - 2014/4
Y1 - 2014/4
N2 - Objective Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents. Methods Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction. Results In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R2 = 0.55, Pearson correlation = 0.66) and individual levels (82%, Òš = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Òš = 0.36), and the trial level association was not statistically significant (R2 = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Òš = 0.44) appeared stronger than the correlation of response (76%, Òš = 0.17) with OS12 in the external validation dataset. Conclusions PFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.
AB - Objective Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents. Methods Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction. Results In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R2 = 0.55, Pearson correlation = 0.66) and individual levels (82%, Òš = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Òš = 0.36), and the trial level association was not statistically significant (R2 = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Òš = 0.44) appeared stronger than the correlation of response (76%, Òš = 0.17) with OS12 in the external validation dataset. Conclusions PFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.
KW - Advanced urothelial carcinoma
KW - Intermediate endpoint
KW - Overall survival
KW - Progression-free survival at 6 months
KW - Second-line treatment
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U2 - 10.1016/j.clgc.2013.09.002
DO - 10.1016/j.clgc.2013.09.002
M3 - Article
C2 - 24220220
AN - SCOPUS:84896329384
SN - 1558-7673
VL - 12
SP - 130
EP - 137
JO - Clinical Genitourinary Cancer
JF - Clinical Genitourinary Cancer
IS - 2
ER -