Background

A Phase III trial (Study 301; NCT00337103) in MBC comparing eribulin (E) with capecitabine (C) showed a trend for improved overall survival (OS) (hazard ratio [HR] 0.88; 95% CI 0.77, 1.00; P = 0.056) but not progression-free survival (PFS) (HR 1.08; 95% CI 0.93, 1.25; P = 0.30) with E. In order to investigate this apparent discordance, post-hoc analyses assessed the effect of PPT and events defining disease progression on OS.

Methods

Pts with locally advanced or MBC who had received an anthracycline and a taxane (≤2 prior chemotherapy regimens for advanced disease), were randomized to E (554) or C (548). Co-primary endpoints were OS and PFS. The impact of PPT on OS was assessed by analysis of exploratory PPT subgroups. Analyses of OS sensitivity censoring at time of PPT, and OS adjusted by PPT as a time-dependent covariate in a Cox regression model, were performed. The relationship between OS and progression events (appearance of a “new” lesion or metastasis [NM]; increase in size of pre-existing lesions [IPEL]; or other [death, clinical progression, or censored]) was investigated using Cox regression.

Results

PPT was received by 70% and 62% of E and C pts, respectively. For E pts, there were no significant OS differences by PPT (Table 1). Excluding 56 pts (22 E, 34 C) who received anti-HER2 therapy as PPT from the intent-to-treat OS analysis, OS was longer with E (HR 0.86; 95% CI 0.76, 0.99; nominal P = 0.03). OS sensitivity analysis censoring at time of PPT was consistent with the overall study results (HR 0.82; 95% CI 0.65, 1.03). Assessment of the overall effect of PPT, adjusting by PPT as a time-dependent covariate in a Cox regression model, showed that OS was longer with E (HR 0.85; 95% CI 0.75, 0.97; nominal P = 0.02). Progression due to NM or IPEL occurred in 271 and 147 of E pts, and 285 and 129 of C pts, respectively. Median OS was similar between arms in pts with IPEL and longer with E vs C in pts with NM (Table 2). Pts who progressed due to NM were at higher risk of death (HR 2.12; 95% CI 1.84, 2.43; nominal P<0.01).

Conclusions

Treatment with C or any other PPT after progression on E did not account for the trend in OS benefit with E observed in the primary analysis. Pts who progressed with NM had a worse prognosis than those with IPEL. The appearance of NM was highly correlated with OS, and the apparent discordance between PFS and OS seems to be related to these different progression events.

Tab 1: OS by PPT after E

PPT All pts C as 1st Other than C as 1st C at any time Other than C at any time None 
N 554 221 169 275 115 164 
Median OS, months (95% CI) 15.9 (15.2, 17.6) 18.3 (15.8, 20.9) 19.9 (17.6, 24.0) 19.6 (17.6, 21.5) 18.0 (15.4, 22.7) 7.4 (6.2, 9.1) 
PPT All pts C as 1st Other than C as 1st C at any time Other than C at any time None 
N 554 221 169 275 115 164 
Median OS, months (95% CI) 15.9 (15.2, 17.6) 18.3 (15.8, 20.9) 19.9 (17.6, 24.0) 19.6 (17.6, 21.5) 18.0 (15.4, 22.7) 7.4 (6.2, 9.1) 
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Tab 2: OS by progression event

  Progression event 
  NM IPEL Other 
  E C E C E C 
N 271 285 147 129 136 134 
Median OS, months (95% CI) 15.5 (14.2, 17.5) 12.9 (11.3, 14.5) 17.4 (14.4, 19.7) 17.4 (15.3, 20.9) 16.7 (14.8, 24.2) 15.5 (11.7, 18.3) 
HR (95% CI) 0.81 (0.68, 0.97) 1.13 (0.87, 1.46) 0.78 (0.59, 1.03) 
Nominal P -value 0.02 0.35 0.08 
Time to NM or death, months (95% CI) 5.8 (5.2, 6.5) 5.2 (4.3, 5.9) NA NA 
HR (95% CI) 0.90 (0.77, 1.05) NA NA 
Nominal P-value 0.17 NA NA 
  Progression event 
  NM IPEL Other 
  E C E C E C 
N 271 285 147 129 136 134 
Median OS, months (95% CI) 15.5 (14.2, 17.5) 12.9 (11.3, 14.5) 17.4 (14.4, 19.7) 17.4 (15.3, 20.9) 16.7 (14.8, 24.2) 15.5 (11.7, 18.3) 
HR (95% CI) 0.81 (0.68, 0.97) 1.13 (0.87, 1.46) 0.78 (0.59, 1.03) 
Nominal P -value 0.02 0.35 0.08 
Time to NM or death, months (95% CI) 5.8 (5.2, 6.5) 5.2 (4.3, 5.9) NA NA 
HR (95% CI) 0.90 (0.77, 1.05) NA NA 
Nominal P-value 0.17 NA NA 
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Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-03.