Actionable Genomic Landscape Of Metastatic Colorectal Cancer Patients In Korea: Interim Data From K-Master Project

The K-MASTER cancer precision medicine diagnosis and treatment enterprise (K-MASTER project) is a precision medicine cancer treatment clinical trial platform, which uses NGS assay to screen the actionable mutations in 10,000 Korean patients with refractory solid tumors and assigns the patients to matched clinical trials. K-MASTER project was initiated at June 2017 and 52 sites, 4930 patients have participated. As of November 30 in 2019, total 889 metastatic colorectal cancer (mCRC) patients were submitted. Tumor DNA was analyzed by FIRST cancer panel (Seoul National University Hospital) and CancerSCAN (Samsung Genomic Institute) which allow to detect variations of 183 and 409 genes irrespectively. The failure rate of sequencing was 5.5% of patients with samples submitted. The mean depth was 650x (FIRST) and 701x (CancerSCAN). Average turn-around time was 3 weeks (CancerScan) and 6 weeks (FIRST). In Korean mCRC patients, variations were mainly identified in TP53 (60.9%), APC (56.9%), KRAS (41.4%), BRCA2 (19.2%), PIK3CA (14.5%), ATM (14.2%), KMT2D (13.4%), NOTCH1(13.4%), SMAD4 (11.6%), FBXW7 (10.2%), ALK (9.7%), NOTCH3 (9.2%), BRAF (8.8%). MSI-high or POLE mutant mCRC patients were enrolled in KM-01 (Avelumab). Several drugs were already approved in the other countries but not in Korea; ERBB (7.5%) with anti-HER2 agents, and MSI high such as MSH6 (3.9%), MSH2 (3.7%), MLH1 (3.4%) with immune checkpoint inhibitors. In addition, there were potentially actionable variants outside of approved label in Korea; translocation of NTRK3 (n=4), RET (n=3), ALK/EML4 (n=2). Promising drugs could be possible to incorporate in clinical trials using PIK3CA (14.5%) with PIK3CA/Akt/mTOR pathway inhibitor, DNA damage response (DDR) genes such as BRCA2 (19.2%), ATM (14.2%), FANCA (6.6%), POLE (5.8%), BRIP1(4.8%), RAD50 (4.5%), BRCA(4.0%), PALB2 (4.0%), PARP2 (3.7%), CDK12 (3.4%), MUTYH (2.7%), RAD54L (2.5%) with immune checkpoint inhibitor and/or PARP inhibitor, KRAS G12C (n=18) with AMG 510 (KRAS inhibitor), amplification of FGFR1 (n=4) and MET (n=1). There are 2 clinical trials which mCRC patients can participate in early 2020; MET alteration in KM-08 (Tepotinib), high tumor mutation burden in KM-12 (Ipilimumab and nivolumab). In conclusion, this project is efficient to detect actionable variations in mCRC. This novel knowledge provides an intriguing background to investigate new clinical trials with biomarker and give therapeutic opportunity for mCRC patients. By help of regulatory approval of innovative drugs and off-label use, biomarker-driven early phase clinical trials, it could be a huge therapeutic opportunity for refractory mCRC patients. (This research was supported by a grant of the Korea Health Technology RD 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3620.