Table 2.

Efficacy of genomic-based targeted therapies in clinical trials in TNBC

PathwayDrugMechanismPatient populationTrial design (total N patients)InterventionExploratory biomarkerEfficacyClinicaltrials.gov identifier
PI3K/AKT/mTORBuparlisibPI3K inhibitorLocally advanced/metastatic HER2-negativeRandomized phase II (n = 416; ref. 43)Buparlisib + paclitaxel vs. placebo + paclitaxelStratification by PI3K pathway activationPFS (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)
IpatasertibAKT inhibitorLocally advanced/metastatic TNBCRandomized phase II (n = 124; ref. 44)Ipatasertib + paclitaxel vs. placebo + paclitaxelStratification by tumor PTEN statusPFS (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)
MK2206AKT inhibitorNeoadjuvant stage II–III breast cancer (any subtype)Randomized phase II (n = 149; ref. 45)Paclitaxel ± MK2206 (followed by AC)NApCR (all): 35.2 vs. 21.1NCT01042379
pCR (TNBC): 40.2 vs. 22.4
Temsirolimus, everolimusmTORC1 inhibitorMetastatic metaplastic TNBCPhase I dose expansion (n = 52; ref. 46)Liposomal doxorubicin + bevacizumab + (temsirolimus or everolimus)Exploratory analysis by PI3K pathway activationORR (all): 21 (95% CI, 11–35)NCT00761644
ORR (PI3K-activated): 31 (95% CI, 16–50)
EverolimusmTORC1 inhibitorNeoadjuvant stage II–III TNBCRandomized phase II (n = 145; ref. 47)Cisplatin + paclitaxel + everolimus vs. cisplatin + paclitaxel + placeboExploratory analysis of mutated genes, TNBC subtype, Ki67, AR, and TILspCR (all): 36 vs. 48 (P = 0.41)NCT00930930
EGFRPanitumumabEGFR monoclonal antibodyLocally advanced/metastatic TNBCNonrandomized phase II (n = 71; ref. 49)Panitumumab + carboplatin + gemcitabineEGFR amp, p53 loss, PTEN loss, PIK3CA mutPFS (all): 4.4 (95% CI, 3.2–5.5)NCT00894504
PFS (EGFR amp): 3.42 (95% CI, 1.51-NR)
CetuximabEGFR monoclonal antibodyNeoadjuvant stage II–IIIA TNBCNonrandomized phase II (n = 28; ref. 50)Cetuximab + docetaxelEGFR, Ki67, cytokeratins, CD8/FOXP3pCR (intent-to-treat): 25 (95% CI, 9–41)NCT00600249
LapatinibEGFR/HER2 inhibitorLocally advanced/metastatic HER2-negativeRandomized phase III (n = 580; refs. 51, 149)Lapatinib + paclitaxel vs. placebo + paclitaxelEGFREFS (TNBC): 4.6 vs. 4.8 (HR: 1.25; 95% CI, 0.85–1.83)NCT00075270
EFS (TNBC EGFR+): 4.2 vs. 4.9
EFS (TNBC EGFR): 5.2 vs. 4.3
RAS/MAPKCobimetinibMEK1/2 inhibitorLocally advanced/metastatic TNBCOpen-label safety run-in (n = 16), randomized phase II (n = 90; ref. 55)Cobimetinib + paclitaxel vs. placebo + paclitaxelTNBC subtype, genetic alterations, PD-L1 expressionPFS (intent-to-treat): 5.5 vs. 3.8 (HR, 0.73; 95% CI, 0.43–1.24; P = 0.25)NCT02322814
JAK/STATRuxolitinibJAK1/2 inhibitorMetastatic TNBC or IBC of any subtypeNonrandomized phase II (n = 21; ref. 66)RuxolitinibJAK2 amplification, pSTAT3PFS (all): 1.2 (95% CI, 0.97–1.84)NCT01562873
NOTCHPF-03084014Gamma-secretase inhibitorMetastatic HER2-negative breast cancerPhase I dose-finding/dose expansion (n = 29; ref. 67)PF-03084014 + docetaxelNAORR: 16 (95% CI, 4.5–36.1)NCT01876251
  • NOTE: Main efficacy analyses of biomarker-selected subgroups of interest are highlighted. HR, 95% CI, and P values are included when available.

  • Abbreviations: 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); TIL, tumor-infiltrating lymphocyte.