Six-month progression-free survival as the primary endpoint to evaluate the activity of new agents as second-line therapy for advanced urothelial carcinoma.
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 (R(2) = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R(2) = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 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.
Department of Internal Medicine/Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Neeraj
N
Agarwal
University Hospital del Mar-IMIM, Barcelona, Spain.
Joaquim
J
Bellmunt
Department of Internal Medicine/Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Benjamin L
BL
Maughan
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Kenneth M
KM
Boucher
Department of Medicine/Solid Tumor Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
Toni K
TK
Choueiri
Department of Medicine/Solid Tumor Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
Angela Q
AQ
Qu
Comprehensive Cancer Centers of Nevada, Las Vegas, NV.
Nicholas J
NJ
Vogelzang
Institut de Recherche Pierre Fabre, Boulogne, France.
Ronan
R
Fougeray
Department of Urology, Heinrich Heine University, Dusseldorf, Germany.
Guenter
G
Niegisch
Department of Urology, Heinrich Heine University, Dusseldorf, Germany.
Peter
P
Albers
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA.
Yu-Ning
YN
Wong
Department of Medicine, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.
Yoo-Joung
YJ
Ko
Department of Medicine, Princess Margaret Hospital, Toronto, ON, Canada.
Srikala S
SS
Sridhar
Department of Internal Medicine/Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Srinivas K
SK
Tantravahi
Department of Medicine/Hematology and Medical Oncology, Tisch Cancer Center Institute, Mount Sinai School of Medicine, New York, NY.
Matthew D
MD
Galsky
Department of Internal Medicine/Medical Oncology, Yale University Cancer Center, New Haven, CT.
Daniel P
DP
Petrylak
Department of Oncology, Wayne State University, Detroit, MI.
Ulka N
UN
Vaishampayan
Department of Medicine/Hematology-Oncology, UAB Comprehensive Cancer Center, Birmingham, AL.
Amitkumar N
AN
Mehta
Department of Medicine/Hematology-Oncology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR.
Tomasz M
TM
Beer
Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
Cora N
CN
Sternberg
Department of Medicine/Hematology-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
Jonathan E
JE
Rosenberg
Department of Medicine/Hematology-Oncology, UAB Comprehensive Cancer Center, Birmingham, AL. Electronic address: gsonpavde@uabmc.edu.
Guru
G
Sonpavde
D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000401:mortality*; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D006801:Humans; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000401:mortality*
Advanced urothelial carcinoma; Intermediate endpoint; Overall survival; Progression-free survival at 6 months; Second-line treatment