Abstract 5157: ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer
Authors: Lee Dae-Won , Han Sae-Won , Lim Yoojoo , Kim Hwang-Phill , Roh Hanseong , Kim Min Jung , Ryoo Seung-Bum , Park Ji Won , Jeong Seung-Yong , Park Kyu Joo , Kang Gyeong Hoon , Kim Tae-You 
Published: June 2022

Abstract
Introduction: Regorafenib is a multikinase inhibitor which showed clinical benefit in patients with treatment refractory metastatic colorectal cancer. However, as only a subset of patients derives clinical benefit from regorafenib, it is essential to identify biomarker to predict therapeutic response. Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in patients with metastatic colorectal cancer treated with regorafenib.
Methods: This is a prospective biomarker study including patients with refractory metastatic colorectal cancer treated with regorafenib (ClinicalTrial.gov Identifier: NCT01996969). Patients with metastatic colorectal cancer who were refractory to standard therapies (fluoropyrimidine, oxaliplatin, and irinotecan) were eligible for the current study. Patients received oral regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle and were treated until disease progression, death, unacceptable toxicity, or decision by the treating physicians. Blood samples were obtained prior to regorafenib treatment and after every two cycles of regorafenib treatment until disease progression. ctDNA was detected by AlphaLiquid® 100 target capture panel (IMBdx, Inc., Seoul, South Korea). Alphaliquid® 100 is a tumor agnostic panel consist of 106 genes, including 10 gene fusion and MSI. Variant allele frequency (VAF) amount was calculated by adding the VAF value of all altered genes.
Results: A total of 110 patients were included in the present study. Baseline blood samples were successfully acquired in 107 patients (97.3%) with a total of 713 genetic alteration. Mutation was most frequently found in TP53 (76.6%) followed by APC (75.7%), KRAS (43.0%), PIK3CA (17.8%), and SMAD4 (17.8%). BRAF mutation was found in 8.4% of patients and NRAS was detected in 3.7% of patients. Blood samples after two cycle of regorafenib was acquired in 106 patients, and was acquired in 95 patients after disease progression. Among 104 patients with baseline and follow-up cfDNA, the mean VAF at baseline was 12.8% and 7.2% in follow-up. This resulted in a mean VAF change of -5.61% (absolute value) and -43.7% (relative change). VAF decreased markedly after 2 cycles of regorafenib in several genes, including CSF1R, JAK3, KIT, ROS1, and TERT. Although, VAF change of specific gene was not associated with regorafenib outcome, VAF change of whole gene was an early predictive marker for regorafenib. Reduction in VAF amount of ≥ 50% after two cycles of regorafenib were associated with a significantly improved PFS (6.1 vs. 2.7 months, p = 0.002), OS (11.3 vs. 5.9 months, p = 0.001), and higher disease control rate (86.3% vs. 51.1%, p &lt; 0.001).
Conclusions: Serial ctDNA could be used as an early predictive biomarker in metastatic colorectal cancer treated with regorafenib.
Citation Format: Dae-Won Lee, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim. ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5157.