In the I-SPY 2 TRIAL, the allosteric AKT inhibitor MK2206 was available to all HR/HER2 subtypes and graduated in the HR-/HER2+ signature. Qualifying biomarker analysis was performed on 26 proteins/phosphoproteins in the HER-AKT-mTOR pathway to identify candidate proteins correlated with pCR in the HER2+ and HER2- populations treated with MK2206. We postulated that response to MK2206 could be predicted by the relative level of phosphorylation of AKT kinase substrates.
Of 151 patients in the MK2206 and control arms, 138 patients (MK2206: 87, controls: 51) had RPPA and pCR data. Data for 26 (phospho-) proteins involved in HER-AKT-mTOR signaling were assessed for association between biomarker and response in the MK2206 and control arms alone (likelihood ratio test), and relative performance between arms (biomarker x treatment interaction) using a logistic model. Analysis was also performed adjusting for HR/HER2 status. Markers were analyzed individually; p-values are descriptive and were not corrected for multiple comparisons.
In the HER2+ cohort, phosphorylation of the AKT kinase substrates mTOR S2448 (p = 0.004), GSK3 S21/9 (p = 0.009), FOXO1 S256 (p = 0.007), FOXO1 T24/FOXO3a T32 (p = 0.026), S6RP S240/S244 (p = 0.036), Tuberin/TSC1 Y1571 (p = 0.043) and eIF4G S1108 (p = 0.047) were associated with response. FOXO1 S256 also had a significant interaction with treatment in logistic model testing. In the HER2- population, AKT S473 (p = 0.012), AKT T308 (p = 0.011), Estrogen Receptor alpha (p = 0.013), mTOR (p = 0.04), NFkB S536 (p = 0.017) and Tuberin/TSC2 Y1571 (p = 0.03) were negatively associated with MK2206 response. FOXO S253 (p = 0.031) and ERBB2 Y877 (p = 0.02) were both positively associated with response and had a significant interaction with treatment in this cohort.
While our sample size is too small to draw definitive conclusions, our results suggest that the measurement of AKT kinase substrate phosphoproteins could be predictive of MK2206 clinical activity in both HER2+ and HER2- tumors regardless of HR status. These results will need to be validated in independent study sets in order to judge the significance of these initial findings. Clinical trial information: NCT01042379