Negative hyper-selection of patients with HER2-positive and RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade: the PRESSING-HER2 study.

To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by NGS in patients with HER2-positive, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy number variation (CNV) was ≥6. With a case-control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant (PFS <4 months and no RECIST response) vs sensitive cohorts, respectively, 35 patients were needed per group. PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant vs sensitive patients (P=0.005) and 63% predictive accuracy. Overall, HER2 non-amplified status by NGS had 10% prevalence. Median PFS and OS were worse in PRESSING-HER2-positive vs negative (2.2 vs 5.3 months, P<0.001; 5.4 vs 14.9 months, P=0.001) and in HER2 non-amplified vs amplified (1.6 vs 5.2 months, P<0.001; 7.4 vs 12.4 months, P=0.157). These results were confirmed in multivariable analyses (PRESSING-HER2 positivity: PFS HR=3.06, 95%CI: 1.40-6.69, P=0.005; OS HR=2.93, 95%CI: 1.32-6.48, P=0.007). Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. PRESSING-HER2 panel and HER2 non-amplified status by NGS warrant validation as potential predictive markers in this setting.