Abstract P3-06-31: Etirinotecan pegol in patients with metastatic breast cancer (mBC): Modeling CA27.29 response and its correlation with tumor response
Authors: Chia YL , Hoch U , Hannah A , Eldon MA 
Published: August 2014

Abstract
Background: Etirinotecan pegol (NKTR-102) is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In a Phase 2 study in pts with mBC whose disease had failed prior taxane-based treatment (Tx) etirinotecan pegol given q14d or q21d demonstrated a 29% overall response rate (J Clin Oncol 29: 2011 (suppl; abstr 1034)). Here we present the relationship between the dynamics of serum tumor marker CA27.29, etirinotecan pegol pharmacokinetics, and tumor response.
Methods: Data from 45 pts with at least two CA27.29 measurements (pre- & post-first dose), were fitted with a PK/PD model developed to correlate CA27.29 dynamics with SN38 exposure predicted from individual pt dosing history: d[CA27.29]/dt = Kin*exp(beta*t)*(1−[SN38]/(IC50+[SN38]))-Kout*[CA27.29]. Correlation of CA27.29 and RECIST response was investigated; % change of CA27.29 from baseline was also correlated with progression-free survival (PFS).
Results: CA27.29 vs time profiles were well described by the model, with a population mean plasma SN38 IC50 of 1.6 ng/mL. Typical minimum/maximum SN38 concentrations during Tx were 1.5/ 3 ng/mL for q14d and 0.9/ 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA27.29 decline was 15 days. 41 pts had pre- and post-Tx tumor measurements for correlation of CA27.29 response with tumor size. Of the 15 pts with RECIST CR or PR, 14 (93%) exhibited at least 10% declines in CA27.29 during Tx; all 5 pts with RECIST SD ≥ 6 months (mths) also manifested ≥10% declines, whereas only 45% (5/11) of pts with SD &lt; 6 mths showed ≥10% decline in CA27.29. Among the 10 pts with RECIST progressive disease (PD), 80% showed ≥10% CA27.29 elevations during Tx. The median maximum % reduction in observed CA27.29 from baseline during the course of Tx ranged from −55% to +30% and correlated with responder status as tabulated below.

To investigate whether response in CA27.29 can serve as early indicator of Tx outcome, we assessed the impact of a reduction of ≥25% after 6 weeks (wks) of Tx (2 or 3 Tx cycles for q21d and q14d schedules, respectively) on PFS. Among the 26 pts who had not had tumor progression or discontinued Tx by wk 6, median PFS for pts with ≥ 25% reduction in CA27.29 (n = 9) was 12 mths. Pts with &lt;25% reduction (n = 4) or elevations (n = 13) in CA27.29 by wk 6 had a median PFS of only 5.6 mths. (NB: the overall median PFS of all pts was 4.6 mths). CA27.29 vs time simulations for 1000 pts receiving 145 mg/m2 NKTR-102 q21d projected that 46% of pts achieve ≥25% reduction in CA27.29 in the absence of dose reduction/interruption.
Conclusions: The PK/PD model described CA27.29 dynamics well and provides a tool to predict response based on etirinotecan pegol pharmacokinetic data. 25% reduction in CA27.29 at wk 6, may constitute an early marker for Tx response to etirinotecan pegol. A Phase 3 global pivotal study (BEACON) utilizing the q21 day dosing schedule is underway in pts with advanced breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-31.