Relationship between 6‐ and 9‐month progression‐free survival and overall survival in patients with metastatic urothelial cancer treated with first‐line cisplatin‐based chemotherapy

Abstract

BACKGROUND: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with metastatic urothelial carcinoma (UC) is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). METHODS: Data was pooled from 7 phase 2 and 3 trials evaluating cisplatin-based chemotherapy in metastatic UC. An independent cohort of patients enrolled on a phase 3 trial was used for external validation. Landmark analyses for progression at 6 and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS: A total of 364 patients were included in the initial cohort. The median PFS was 8.21 months (95% confidence interval 5 7. 43, 8.39) and the median OS was 13.50 months (95% confidence interval 5 11.80, 15.67). In the landmark analysis, the median OS for patients who progressed at 6 months was 3.87 months compared with 15.06 months for those patients who did not progress (P <.0001) and the median OS for patients who progressed at 9 months was 5.65 months compared with 21.39 months for those patients who did not progress (P <.0001). A Fleischer model demonstrated a statistically significant dependent correlation between PFS and OS. The findings were externally validated in an independent cohort. CONCLUSIONS: PFS at 6 and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy and could potentially serve as endpoints in (randomized) phase 2 trials to screen the activity of novel regimens. Cancer 2013;119:3020-6. V C 2013 American Cancer Society.KEYWORDS: urothelial cancer; bladder cancer; chemotherapy; clinical trials; progression-free survival; overall survival; cisplatin. INTRODUCTIONMetastatic urothelial cancer (UC) is a chemosensitive disease. With contemporary cisplatin-based combination chemotherapy, approximately 50% to 60% of patients will achieve an objective response to treatment and approximately 10% to 20% will achieve a complete response. 1,2 Despite these relatively high response proportions in the context of other solid tumors treated with cytotoxic agents, response durations in metastatic UC are generally short-lived, and median overall survival is only approximately 14 months. 2 Recent attempts to improve contemporary cisplatin-based regimens have proven unsuccessful, with no advances in the efficacy of therapy in the past 30 years. 3 The relatively high response rates achieved with first-line cisplatin-based chemotherapy in metastatic UC has created a challenge with regard to appropriate endpoints for phase 2 trials exploring novel therapeutic regimens. A high barrier must be overcome to detect a signal of enhanced antitumor activity (as measured by objective response rate) compared with historical controls. 4 At the same time, tumor response rate has not convincingly proven useful in selecting phase 2 regimens worthy of moving forward to definitive randomiz...

The Safety and Efficacy of Single-Agent Pemetrexed in Platinum-Resistant Advanced Urothelial Carcinoma: A Large Single-Institution Experience

“…Recent data suggest that the 6-month PFS rate is a more robust predictor of overall survival and treatment efficacy than response rate in advanced UC and so should be reported in analyses of treatment efficacy [7,23]. In a large meta-analysis of phase II clinical trials in this setting, the aggregate 6-month PFS rate was 22% (95% CI: 19%-26%), and as mentioned in the Baseline Patient Characteristics section, a nomogram was created to predict the likelihood of individual patients achieving 6-month PFS [7].…”

Future Directions and Targeted Therapies in Bladder Cancer

“…91,92 The use of PFS at 6 or 9 months as an intermediate end point may provide a signal of improved activity in the first-line setting. 93 The switch maintenance design using highly tolerable biologic agents warrants evaluation because patients generally progress after a brief treatment-free interval.…”

Progression-free survival is an adequate endpoint for clinical trials of locally advanced and metastatic urothelial carcinoma

“…In alternative, a time-to-event endpoint, such as PFS endpoints, may be preferable to evaluate the activity of novel first-line treatment regimens in metastatic urothelial cancer. In fact, PFS has the potential to account for an aspect of ‘disease control’ that is not captured by tumor shrinkage alone [17]. In the metastatic setting as well, no ICE has been proved to meet the Prentice criteria.…”

“…In the metastatic setting as well, no ICE has been proved to meet the Prentice criteria. Yet, progression within 6 and 9 months of treatment initiations have been proposed as proxy of OS amongst patients receiving first-line platinum-based chemotherapy [17].…”