528PDImpact of clonality and DNA repair mutations on plasma tumour mutation burden (pTMB) and immunotherapy efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) in CCTG CO.26

Abstract Background We previously showed pTMB selects patients (pts) deriving benefit from PD-L1 and CTLA-4 inhibition with durvalumab and tremelimumab (D+T) compared to best supportive care (BSC) in refractory mCRC in CCTG CO.26. Methods We investigated somatic variants contributing to pTMB in MSS pts using cell-free DNA (cfDNA) analysis performed with the GuardantOMNITMassay (2.1Mb) on 166 pts from CO.26. Results Median pTMB was 16.3 mutations/megabase (mts/Mb). Using a minimum p-value approach, pts with pTMB>28 mts/Mb (21% of MSS pts) had the greatest overall survival (OS) benefit for D + T (HR 0.34, 90% CI 0.18-0.63, p-interaction=0.070) and worse OS in the BSC arm (HR 2.59, 90% CI 1.46-4.62). Of 4044 mts detected, 2718 (67.2%) were subclonal (