A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors

Abstract

Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1-2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI₉₀, and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3β, and mTOR) were inhibited in paired on-treatment biopsies. Preliminary antitumor activity was observed; 16 of 52 patients (30%), with diverse solid tumors and who progressed on prior therapies, had radiographic stable disease, and many of their tumors had activation of AKT.

Significance: Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7(1); 102-13. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

Trial registration: ClinicalTrials.gov NCT01090960.

Figure 1

Preclinical cancer cell line and xenograft models with alterations in PTEN or PIK3CA are significantly more sensitive to ipatasertib both in vitro and in vivo. A, IC₅₀ values of ipatasertib on cell viability in cancer cell lines with alterations in PTEN, including loss of expression, or in PIK3CA, including mutations, are plotted against those cell lines without known alterations in these genes. Cell lines with PTEN alterations are indicated with a cyan fill, whereas those with PIK3CA mutations that are found in the Catalogue of Somatic Mutations in Cancer (COSMIC) but not in the Single Nucleotide Polymorphism database (dbSNP) are indicated with a purple border. Cells with no PIK3CA mutations, or with PIK3CA mutations that are either not found in COSMIC or are present in the dbSNP, have black borders. Median values of each group are indicated as a green horizontal line, and P values are calculated by the Student t test between indicated groups. Ipatasertib treatment in cell lines with PTEN loss or PIK3CA mutations showed a significantly lower mean and median IC₅₀ values (mean IC₅₀ ±SEM 4.8 ± 0.56 μmol/L and median IC₅₀ 2.2 μmol/L) than those without known alterations (mean IC₅₀ 8.4 ± 0.48 μmol/L and median IC₅₀ 10 μmol/L). B, Cancer cell lines or patient-derived tumors were implanted into immunocompromised mice as xenograft models, and percentage tumor growth inhibition (%TGI) at day 21 after daily oral treatment with 100 mg/kg ipatasertib was calculated as described in Methods. The %TGI in xenograft models with alterations in PTEN (cyan fill) or PIK3CA (purple border for mutations, red border for amplifications) is significantly higher (mean %TGI ± SEM 95 ± 11% and median %TGI 97%) than in those models without alterations (mean %TGI 38 ± 12% and median %TGI 44%). C, Ipatasertib decreases the growth in vivo of the melanoma cell line 537Mel (PTEN -null) in a dose-dependent manner, as measured by mixed modeling that analyzes the repeated measurements of tumor volumes from the same animals over time. This method of analysis addresses both repeated measurements and modest dropout rates due to non–treatment-related discontinuation prior to study end. QD, once daily. D, Ipatasertib decreases the growth in vivo of the breast cancer cell line KPL4, which has a PIK3CA^H1047R mutation. E, Ipatasertib does not suppress the growth of the colon cancer cell line HCT116, which has a KRAS^G13D mutation despite having a PIK3CA^H1047R mutation.

Figure 2

Ipatasertib shows evidence of PD inhibition of AKT signaling in patients as evaluated by the suppression of pGSK3β in PRP. The ratio of pGSK3β to total GSK3β was evaluated in PRP from patients in all the dosing cohorts (25–800 mg) on day 1 (top) and on day 15 (bottom) of cycle 1 and was graphed as a function of time (in hours) following a single dose of ipatasertib. In all patients, pGSK3β decreased in a time-and dose-dependent manner, reaching a nadir at 2 hours after dose and remaining suppressed at 24 hours after dose. Inhibition of pGSK3β was also sustained at day 15 of dosing (bottom).

Figure 3

Downregulation of AKT pathway targets by ipatasertib in on-treatment tumor biopsies compared with pretreatment biopsies by RPPA analysis. A, On-treatment tumor biopsies from consenting patients were evaluated by RPPA for multiple AKT pathway targets, including pAKT, pPRAS40, p4EBP1, pS6, and pERK. Protein expression of the target from the on-treatment biopsy was compared with the pretreatment biopsy to determine if ipatasertib caused upregulation (marked in red, up to 5-fold increase as shown in the legend along the bottom), downregulation (blue, up to 5-fold), or no significant changes (yellow). Each horizontal row shows a patient, ranked by increasing doses of ipatasertib from 100 mg (bottom) to 800 mg (top). The targets were organized by hierarchical clustering of expression levels. Inhibition of AKT with ipatasertib resulted in a dose-dependent accumulation of pAKT (Thr³⁰⁸ and Ser⁴⁷³, highlighted in red, right side), consistent with its mechanism of action. Consequently, ipatasertib downregulated multiple targets of AKT, including pPRAS40, p4EBP1, pS6, and pmTOR (highlighted in blue, left side). Downregulation of these targets occurred in a dose-dependent manner, as a greater degree of target inhibition occurred with ipatasertib ≥400 mg. A compensatory feedback mechanism following ipatasertib also occurred, as upregulation of pERK and pHER3 (highlighted in red, right side) was observed with ipatasertib as low as 100 mg. B, As an example, ipatasertib downregulated four targets of AKT: pPRAS40, pGSK3β, p4EBP1, and pmTOR, in the on-treatment biopsy compared with the pretreatment biopsy (expressed as log ₂ ratio with each circle representing a patient). This inhibition can be observed at doses of ipatasertib as low as 100 mg, and the degree of inhibition increases in a dose-dependent manner. C, As an example, AKT inhibition by ipatasertib modulated two signaling pathways, pHER3 and pERK, in the on-treatment biopsy compared with the pretreatment biopsy. These modulations are directionally heterogeneous across the doses; upregulation can be observed at doses of ipatasertib as low as 100 mg.

Figure 4

Patients with MBC with tumors having PTEN loss and/or PIK3CA/AKT mutations showed target lesion metabolic responses by [¹⁸ F]FDG-PET following ipatasertib. A, Nine patients with MBC, with archival tumors having activation of the PI3K/AKT pathway as determined by the investigator, were dosed with ipatasertib 600 mg and had [¹⁸F]FDG-PET scans done at screening and in cycle 1 after two weeks. The maximum percentage change in SUV between the on-treatment and pretreatment PET scans (SUV_max) in target lesions was then graphed for each patient, ranked by order of response. Eight of the nine evaluable patients (89%) had a metabolic PET response, as defined by an SUV_max decrease ≥20% in the target lesions. One patient (ID# 26102) did not have a PET response, but this patient also stopped the study drug in cycle 1 at the time of the PET scan. Most of the patients with metabolic PET responses also had archival tumors with activation of the PI3K/AKT pathway, including decreased PTEN expression (n = 6), PIK3CA mutations (n = 3), and an AKT1 mutation (n = 1), as determined centrally. WT, wild-type. B, One patient with MBC (HER2-negative) harboring an AKT1^E17K mutation in the archival tumor sample exhibited a complete metabolic response at cycles 1 and 2. All FDG-avid target lesions identified at baseline were indistinguishable from background on the on-treatment PET scans (% SUV_max decrease set to 100%).