1206P HER2 copy number variation (CNV), HER2 expression and primary resistance mechanisms in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) receiving first-line chemotherapy (CT) + trastuzumab (T) +/- pertuzumab (P) in the JACOB trial

Abstract

In JACOB trial, P added to T-CT did not significantly improve overall survival (OS) in pts with HER2+ mGC/GEJC despite a 3.3 mos increase vs placebo. We previously showed a negative prognostic role of AMNESIA panel, including KRAS/PIK3CA/MET mutations and KRAS/EGFR/MET amplifications (Pietrantonio et al, CCR 2018), whereas higher HER2 CNV may be associated with better outcomes on T. These biomarkers may allow to better identify pts with higher benefit from HER2 inhibition. Among 780 pts enrolled in JACOB and 580 with available baseline tumor DNA, 327 samples were sequenced by Oncomine Focus DNA assay. In a post-hoc analysis, HER2 CNV, HER2 expression by IHC and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS) and OS by uni-/multivariable models. Median HER2 CNV was 4.7 (IQR 2.2-16.9). By pooling treatment arms, HER2-high vs low status using the median as the cut-off value was associated with longer PFS (mPFS: 10.5 vs 6.4 mos; hazard ratio (HR)=0.48, 95%CI: 0.38-0.62; p<.001) and OS (mOS: 20.3 vs 13.0 mos; HR=0.54, 0.42-0.72; p<.001). Combining HER2 CNV and IHC improved the discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR=1.35 (0.98-1.86) for PFS; 1.43 (1.00-2.03) for OS. HER2-high subgroup was enriched for AMNESIA-neg and HER2 3+ status. In multivariable models with main variables including treatment arm, only HER2 CNV status remained statistically significant for PFS (p<.001) and OS (p=.004). Higher ORR was significantly associated with IHC 3+ [61% vs 34% in 2+; odds ratio(OR)=3.11 (1.89-5.17)] and HER2-high [59% vs 43% in HER2-low; OR=1.84 (1.16-2.94), with highest OR in the top CNV quartile. The selected biomarkers were not associated with activity and efficacy of P added to T-CT. HER2-high CNV assessed by NGS is associated with significantly better ORR, PFS, OS in a pts subgroup from the JACOB trial, independent from treatment arm and especially if combined with HER2 3+.