Determining the rate of tumor growth and decay in patients with metastatic breast cancer as an early efficacy endpoint: A study assessing ixabepilone efficacy.

Abstract

246 Background: Early efficacy assessment in drug development should help find new cancer therapies. We have developed a novel method to analyze tumor response to therapy by quantifying the rate of tumor regression (d) and growth (g). We have shown g is slower when pts are on effective therapy and that g correlates with survival (Stein et al, Oncologist 2008). We utilized this method to evaluate a phase III trial of capecitabine (CAP) ± IXA in second line therapy (Tomas et al, JCO 2007) and a three-cohort phase II trial in second and subsequent lines of therapy in pts with MBC consisting of (1) Daily X 5 IXA given to taxane (TAX)-naïve patients (Denduluri et al, JCO 2007); (2) Daily X 5 IXA in pts previously treated with TAX (Low et al, JCO 2005); and (3) Daily X 3 IXA in pts previously treated with TAX (Denduluri et al, Invest New Drug 2007). Methods: Using tumor measurements assessed by RECIST and a two-phase mathematical equation we determined d and g. Results: In the phase III study g was superior to PFS identifying a significant difference between the arms very early—before the 200th pt had enrolled. In an individual patient the g values could be estimated as early as the 3rd evaluation, long before tumor growth was observed clinically. IXA + CAP in second line (g = 0.0018) was more effective than CAP (g = 0.0023) at reducing g, and more effective (p=0.0085) than single agent IXA in the Phase II study (g = 0.0027). Single agent IXA was comparably effective (p=0.814) in reducing the g of tumors previously exposed to a TAX (g = 0.0032) as in reducing the g of TAX-naïve tumors (g = 0.0035), consistent with its development as an agent active in TAX-refractory disease. Unlike differences in g, the d of single agent IXA (0.118) was comparable to that of IXA+CAP (0.0074) suggesting differences were primarily driven by effect on the growth of residual tumor. Conclusions: Unlike PFS, an incremental measure of efficacy, g is a continuous variable and can more accurately assess differences between treatments. Because calculations of g are indifferent to assessment intervals, estimating a tumor’s g allows comparison of efficacy across trials.