Triple-negative breast cancer (TNBC) is a very variable disease, and molecular subtyping may enable more precise diagnosis and treatment. Our earlier work categorized TNBCs into four subgroups, each with its own set of potential treatment targets. To assess the effectiveness of these targets, we performed the study, a phase Ib/II subtyping-based and genomic biomarker-guided umbrella study. Patients with refractory metastatic TNBC were enrolled and assigned to one of seven arms: (A) pyrotinib plus capecitabine, (B) androgen receptor inhibitor plus CDK4/6 inhibitor, (C) anti-PD-1 plus nab-paclitaxel, (D) PARP inhibitor plus nab-paclitaxel, (E) and (F) anti-VEGFR plus nab-paclitaxel, or (G The major outcome measure was the rate of objective response (ORR). We included 69 patients with resistant metastatic TNBC who had previously received a median of three lines of treatment (range, 1-8). Twenty-nine (29.0 percent, 95 percent confidence interval (CI): 18.7 percent -41.2 percent ) of the 69 intention-to-treat (ITT) patients obtained an objective response. Our findings indicated that immunotherapy (arm C) had the greatest ORR (52.6 percent, 95 percent confidence interval [CI]: 28.9 percent -75.6 percent ) in the ITT group. Arm E had a good ORR (26.1 percent, 95 percent CI: 10.2 percent -48.4 percent in the ITT group), but was associated with a higher prevalence of severe adverse events (grade 3). Somatic mutations in TOP2A and CD8 immunohistochemistry score may be able to predict immunotherapy response in patients with TNBC classified as immunomodulatory. In conclusion, the phase Ib/II study demonstrated the therapeutic benefit of subtyping-based targeted therapy for refractory metastatic TNBC.
Phase Ib/IIa study of RX-5902, a novel orally bioavailable inhibitor of phosphorylated P68, which prevents nuclear β-catenin translocation in patients with triple negative breast cancer