Table 2.
Efficacy of Genomic-Based Targeted Therapies in Clinical Trials in Triple-Negative Breast Cancer.
| Pathway | Drug | Mechanism | Patient population |
Trial design (Total N patients) |
Intervention | Exploratory biomarker |
Efficacy |
Clinicaltrials.gov
Identifier |
|---|---|---|---|---|---|---|---|---|
| PI3K/AKT/mTOR | Buparlisib | PI3K inhibitor | Locally advanced/metastatic HER2-negative | Randomized phase II (n=416) (43) | Buparlisib + Paclitaxel vs. Placebo + Paclitaxel |
Stratification by PI3K pathway activation | PFS (full population): 8.0 vs. 9.2 (HR 1.18; 95% CI: 0.82-1.68) | NCT01572727 |
| PFS (PI3K-activated): 9.1 vs. 9.2 (HR 1.17; 95% CI: 0.63-2.17) | ||||||||
| PFS (TNBC): 5.5 vs. 9.3 (HR 1.86; 95% CI: 0.91-3.79) | ||||||||
| Ipatasertib | AKT inhibitor | Locally advanced/metastatic TNBC | Randomized phase II (n=124) (44) | Ipatasertib + Paclitaxel vs. Placebo + Paclitaxel |
Stratification by tumor PTEN status | PFS (intent-to-treat): 6.2 vs. 4.9 (HR 0.60; 95% CI: 0.37-0.98; p=0.037) | NCT02162719 | |
| PFS (PTEN-low): 6.2 vs. 3.7 (HR 0.59; 95% CI: 0.26-1.32; p=0.18) | ||||||||
| PFS (PIK3CA/AKT1/PTEN-altered): 9.0 vs. 4.9 (HR 0.44; 95% CI: 0.20-0.99; p=0.041) | ||||||||
| MK2206 | AKT inhibitor | Neoadjuvant stage II-III breast cancer (any subtype) | Randomized phase II (n=149) (45) | Paclitaxel +/− MK2206 (followed by AC) | NA | pCR (all): 35.2 vs. 21.1 | NCT01042379 | |
| pCR (TNBC): 40.2 vs. 22.4 | ||||||||
| Temsirolimus, Everolimus | mTORC1 inhibitor | Metastatic metaplastic TNBC | Phase I dose expansion (n=52) (46) | Liposomal doxorubicin + Bevacizumab + (Temsirolimus or Everolimus) | Exploratory analysis by PI3K pathway activation | ORR (all): 21 (95% CI: 11-35) | NCT00761644 | |
| ORR (PI3K-activated): 31 (95% CI: 16-50) | ||||||||
| Everolimus | mTORC1 inhibitor | Neoadjuvant stage II-III TNBC | Randomized phase II (n=145) (47) | Cisplatin + Paclitaxel + Everolimus vs. Cisplatin + Paclitaxel + Placebo |
Exploratory analysis of mutated genes, TNBC subtype, Ki67, AR and TILs | pCR (all): 36 vs. 48 (p=0.41) | NCT00930930 | |
| EGFR | Panitumumab | EGFR monoclonal antibody | Locally advanced/metastatic TNBC | Non-randomized phase II (n=71) (49) | Panitumumab + Carboplatin + Gemcitabine | EGFR amp, p53 loss, PTEN loss, PIK3CA mut | PFS (all): 4.4 (95% CI: 3.2-5.5) | NCT00894504 |
| PFS (EGFR-amp): 3.42 (95% CI: 1.51-NR) | ||||||||
| Cetuximab | EGFR monoclonal antibody | Neoadjuvant stage II-IIIA TNBC | Non-randomized phase II (n=28) (50) | Cetuximab + Docetaxel | EGFR, Ki67, Cytokeratins, CD8/FOXP3 | pCR (intent-to-treat): 25 (95% CI: 9-41) | NCT00600249 | |
| Lapatinib | EGFR/HER2 inhibitor | Locally advanced/metastatic HER2-negative | Randomized phase III (n=580) (51,149) | Lapatinib + Paclitaxel vs. Placebo + Paclitaxel |
EGFR | EFS (TNBC): 4.6 vs. 4.8 (HR: 1.25; 95% CI: 0.85-1.83) EFS (TNBC EGFR+): 4.2 vs. 4.9 EFS (TNBC EGFR−): 5.2 vs. 4.3 |
NCT00075270 | |
| RAS/MAPK | Cobimetinib | MEK1/2 inhibitor | Locally advanced/metastatic TNBC | Open-label safety run-in (n=16), randomized phase II (n=90) (55) | Cobimetinib + Paclitaxel vs. Placebo + Paclitaxel |
TNBC subtype, genetic alterations, PD-L1 expression | PFS (intent-to-treat): 5.5 vs. 3.8 (HR 0.73; 95% CI: 0.43-1.24; p=0.25) | NCT02322814 |
| JAK/STAT | Ruxolitinib | JAK1/2 inhibitor | Metastatic TNBC or IBC of any subtype | Non-randomized phase II (n=21) (66) | Ruxolitinib | JAK2 amplification, pSTAT3 | PFS (all): 1.2 (95% CI: 0.97-1.84) | NCT01562873 |
| NOTCH | PF-03084014 | Gamma-secretase inhibitor | Metastatic HER2-negative breast cancer | Phase I dose-finding/dose-expansion (n=29) (67) | PF-03084014 + Docetaxel | NA | ORR: 16 (95% CI: 4.5-36.1) | NCT01876251 |
Main efficacy analyses of biomarker-selected subgroups of interest are highlighted. HR, 95% CI and p values are included when available. TNBC: triple-negative breast cancer; PFS: progression-free survival (months); pCR: pathologic complete response (%); ORR: objective response rate (%); IBC: inflammatory breast cancer; AR: androgen receptor; AC: adriamycin/cyclophosphamide; HR: hazard ratio; CI: confidence interval; N: number; NA: data not available; NR: not reached; amp: amplification; EFS: event-free survival (months).