Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T‐DM1) vs . treatment of physician's choice in previously treated HER2‐positive advanced breast cancer

In the phase III TH3RESA study (NCT01419197), 602 patients with HER2‐positive advanced breast cancer who received prior taxane therapy and ≥2 HER2‐directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T‐DM1) or treatment of physician's choice (TPC). A statistically significant progression‐free survival (PFS) benefit favoring T‐DM1 was demonstrated. Here, we examine the relationship between HER2‐related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 ( n  = 505) and HER3 ( n  = 505) mRNA expression, PIK3CA mutation status ( n  = 410) and PTEN protein expression ( n  = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T‐DM1 vs . TPC. The PFS benefit favoring T‐DM1 vs . TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs . 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28–0.59; p  < 0.0001) vs . ≤median subgroup (5.5 vs . 3.9 months; HR, 0.68; 95% CI, 0.49–0.92; p  = 0.0131). The PFS benefit with T‐DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T‐DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2‐transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T‐DM1 (HR, 0.84; 95% CI, 0.75–0.94; interaction p value = 0.0027). In summary, T‐DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs . ≤median.