Exploratory Biomarker Analysis Of Destiny-Crc01, A Phase Ii, Multicenter, Open-Label Study Of Trastuzumab Deruxtecan (T-Dxd, Ds-8201) In Patients (Pts) With Her2-Expressing Metastatic Colorectal Cancer (Mcrc)

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. In primary analyses of DESTINY-CRC01 (NCT03384940), T-DXd showed antitumor activity and a manageable safety profile in HER2+ mCRC pts (Siena ASCO 2020). We present exploratory biomarker data and its relation to response in HER2+ mCRC. Pts with centrally confirmed HER2-expressing, RAS wildtype mCRC that progressed after ≥2 prior regimens received 6.4 mg/kg of T-DXd Q3W in 3 cohorts (A: HER2+, IHC3+, or IHC2+/ISH+, n = 53; B: IHC2+/ISH−, n = 15; C: IHC1+, n = 18). Circulating tumor DNA (ctDNA) samples at baseline (BL), cycle 4, day 1, and end of treatment, along with BL serum HER2 extracellular domain (HER2ECD) were analyzed as exploratory biomarkers. To correct for variation in plasma tumor fraction between samples, adjusted plasma ERBB2 copy number (ApCN) was calculated based on the maximum variant allele fraction (Siravegna CCR 2019). Exploratory cutoff values for ApCN in ctDNA and HER2ECD were defined as those with the maximum value of the Youden index for ORR. In cohort A, higher clinical response to T-DXd was observed with higher tumor or plasma HER2 expression (Table). Antitumor activity of T-DXd was seen in pts with or without ctDNA-detected activating RAS or PIK3CA mutations and was lower in pts with blood TMB high vs low (Table). In paired ctDNA samples collected at BL and disease progression from 30 pts, acquired alterations were observed in several genes, but none was common across pts (n = 12).Table: 386OORR by BL Biomarker GroupBiomarker GroupN = 53ORR, % (95% CI)Tumor HER2 ExpressionHER2+5345.3 (31.6-59.6)IHC3+4057.5 (40.9-73.0)IHC2+/ISH+137.7 (0.2-36.0)Blood biomarkersERBB2 ApCN≥30.92462.5 (40.6-81.2)<30.9 or not detected2832.1 (15.9-52.4)ERBB2 plasma amplificationFocal3655.6 (38.1-72.1)Aneuploidy or not detected1625.0 (7.3-52.4)HER2ECD≥23.5 ng/mL2263.6 (40.7-82.8)<23.5 ng/mL2729.6 (13.8-50.2)NRAS/KRAS mutationActivating633.3a (4.3-77.7)WT or other4647.8 (32.9-63.1)PIK3CA mutationActivating633.3 (4.3-77.7)WT or other4647.8 (32.9-63.1)TMBHigh (≥20 mut/Mb)1323.1 (5.0-53.8)Low (<20 mut/Mb)3953.8 (37.2-69.9)aResponders had KRAS mutations. Open table in a new tab aResponders had KRAS mutations. This exploratory analysis of biomarker data in HER2+ mCRC pts administered T-DXd indicates that antitumor activity appears to be correlated with BL HER2 expression or amplification in tumor and liquid biopsy. Further investigations into potential mechanisms of resistance to and patient selection for T-DXd in HER2+ mCRC are warranted.