Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors

Filip Janku, David S Hong, Siqing Fu, Sarina A Piha-Paul, Aung Naing, Gerald S Falchook, Apostolia M Tsimberidou, Vanda M Stepanek, Stacy L Moulder, J Jack Lee, Rajyalakshmi Luthra, Ralph G Zinner, Russell R Broaddus, Jennifer J Wheler, Razelle Kurzrock, Filip Janku, David S Hong, Siqing Fu, Sarina A Piha-Paul, Aung Naing, Gerald S Falchook, Apostolia M Tsimberidou, Vanda M Stepanek, Stacy L Moulder, J Jack Lee, Rajyalakshmi Luthra, Ralph G Zinner, Russell R Broaddus, Jennifer J Wheler, Razelle Kurzrock

Abstract

Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

Conflict of interest statement

CONFLICT OF INTEREST

Filip Janku has research support from Novartis. Razelle Kurzrock has research support from GlaxoSmithKline, Novartis, Merck, and Bayer.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Proportion of PIK3CA mutations and PTEN aberrations in 1,090 patients who had both PIK3CA and PTEN testing.
Figure 2
Figure 2
PIK3CA mutations are more frequent in tumors with simultaneous KRAS mutations (42/225, 19% vs. 89/975, 9%; p<0.001).
Figure 3
Figure 3
Therapies targeting the PI3K/AKT/mTOR pathway. Most patients (104, 76%) received mTORC1 inhibitor (rapalog)-based therapy, 20 (15%) PI3K inhibitor-based therapy, 6 (4.5%) dual PI3K and mTOR kinase inhibitor-based therapy, and 6 (4.5%) AKT inhibitor-based therapy.
Figure 4
Figure 4
Waterfall plot shows best response for patients with PIK3CA mutations or PTEN aberrations treated with PI3K/AKT/mTOR inhibitors. Of the 136 treated patients, 135 are depicted in the waterfall plot (one patient died of unrelated causes prior to her first restaging). A total of 25 PRs and 33 minor regressions less than PR were observed. The overall PR rate was 18%.
Figure 5
Figure 5
Kaplan-Meier plot for progression-free survival (PFS). Tick marks represent patients who were progression-free at last follow up and are censored at that point. A. Patients with PIK3CA mutations and/or PTEN aberrations treated with combination therapies (yellow, n=95) compared to patients treated with single-agent therapies (blue, n=41) had a longer median PFS than (3.0 months, 95% CI 2.0–4.0 vs. 1.8 months, 95% CI 1.6–2.0; p<0.001). B. Patients with PIK3CA mutations and/or PTEN aberrations and simultaneous KRAS mutations in codon 12 or 13 (yellow) compared to patients without KRAS mutations in codon 12 or 13 (blue) had a shorter median PFS compared to 81 (1.8 months, 95% CI 1.6–2.0 vs. 2.9 months, 95% CI 1.9–3.9; p=0.004). C. Patients with a H1047R mutation (yellow) compared to patients with other PIK3CA mutations (blue) had a longer median PFS (4.6 months, 95% CI 0.6–8.6 vs. 2 months, 1.6–2.4; p=0.03).

Source: PubMed

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