Abstract 2964: On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC)
Authors: Wongchenko Matthew J. , Lipson Doron , Clark Travis , Kennedy Mark , Greene Mandy , Breese Virginia , Tsiros Alyssa , Kim Sung-Bae , Saura Cristina , Oliveira Mafalda , Baselga Jose , Kapp Amy V. , Chan Wai Y. , Singel Stina M. , Gendreau Steven , Dent Rebecca 
Published: August 2018

Abstract
Purpose: There is high interest in longitudinal analysis of plasma ctDNA as an early predictor of response and long-term outcomes. We report a retrospective longitudinal analysis of ctDNA in the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS (NCT02162719) trial of the oral Akt inhibitor IPAT + PAC for mTNBC.
Methods: Pre-treatment plasma samples were analyzed to identify and quantify genomic alterations in ctDNA using a hybrid-capture-based NGS assay that interrogates 62 genes (FoundationACT). A narrow ctDNA panel quantified the same mutations in on-treatment samples collected at 8 wks (d1, cycle 3). The ctDNA fraction (CTF) was defined as the highest mutant allele frequency in each sample. The ratio of CTF in on-treatment vs pre-treatment samples was compared with objective response (RECIST v1.1) and progression-free survival (PFS) in the experimental (IPAT + PAC) and control (PBO + PAC) arms.
Results: Paired on-treatment samples were evaluable from 66 of 88 patients with evaluable pre-treatment samples. The most common reason for no on-treatment sample was disease progression (PD) before cycle 3. In 81 baseline samples, 149 mutations were identified. Calculated CTF ratios ranged from 0% (not detected in on-treatment sample) to 648% (increase in on-treatment sample). In both arms and the pooled population, a greater CTF decrease was associated with objective response and longer PFS (Table).
Conclusions: On-treatment change in CTF shows a meaningful association with objective response and PFS in LOTUS. This effect was seen in the experimental and control arms, suggesting independence from the specific mechanism of therapy. Evaluation of samples from the time of PD is ongoing. Inclusion of additional timepoints will likely improve the predictive ability of CTF, possibly allowing its use as an early surrogate trial endpoint.
IPAT + PAC (n=32)PBO + PAC (n=34)Pooled arms (n=66)Median CTF ratio, % (IQR)Confirmed complete/partial response(n=14)(n=14)(n=28)0.4 (0-14.3)0.2 (0-46.9)0.3 (0-17.8)Stable/progressive disease(n=18)(n=20)(n=38)8.2 (4.4-45.9)26.9 (8.4-91.4)20.7 (4.9-67.9)Median PFS, months (95% CI)CTF ratio ≤5%(n=15)(n=14)(n=29)7.2 (3.7-NE)6.3 (3.6-NE)7.2 (5.1-12.9)CTF ratio &gt;5%(n=17)(n=20)(n=37)3.7 (3.5-5.3)3.7 (2.8-5.4)3.7 (3.6-5.0)PFS hazard ratio (95% CI)0.46 (0.19-1.09)0.43 (0.17-0.97)0.43 (0.23-0.78)CI = confidence interval; IQR = interquartile range; NE = not estimable.
Citation Format: Matthew J. Wongchenko, Doron Lipson, Travis Clark, Mark Kennedy, Mandy Greene, Virginia Breese, Alyssa Tsiros, Sung-Bae Kim, Cristina Saura, Mafalda Oliveira, Jose Baselga, Amy V. Kapp, Wai Y. Chan, Stina M. Singel, Steven Gendreau, Rebecca Dent. On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2964.