Data from <i>HER2</i> Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

Abstract

<div>AbstractPurpose:<p>In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. <i>HER2</i> copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (<i>KRAS/PIK3CA/MET</i> mutations, <i>KRAS/EGFR/MET</i> amplifications) may improve patients’ selection for HER2 inhibition.</p>Experimental Design:<p>In a <i>post hoc</i> analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), <i>HER2</i> CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models.</p>Results:<p>Median <i>HER2</i> CNV was 4.7 (interquartile range, 2.2–16.9). <i>HER2</i> CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38–0.62; <i>P</i> < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42–0.72; <i>P</i> < 0.001). Combining <i>HER2</i> CNV and IHC improved discriminative ability, with better outcomes restricted to <i>HER2</i>-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.</p><p>In multivariable models, only <i>HER2</i> CNV status remained significant for PFS (<i>P</i> < 0.001) and OS (<i>P</i> = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89–5.17)] and <i>HER2</i>-high [59% vs. 43% in <i>HER2</i>-low; OR = 1.84 (1.16–2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab.</p>Conclusions:<p><i>HER2</i> CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.</p></div>