Abstract B161: PIK3CA mutations H1047R are associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.

Abstract

Abstract Background: Activating mutations in the PIK3CA gene have been identified in many malignancies. Preclinical and early clinical data suggest that these mutations predict response to PI3K/AKT/mTOR inhibitors in subsets of patients. Sensitivity and resistance mutation have not been reported to date. Methods: Patients with diverse cancers referred to the Phase I Clinical Trials Program for targeted therapy starting from October 2008 were analyzed for PIK3CA, and if, possible for KRAS mutations using PCR-based DNA sequencing. Patients with any tumor type and any PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR signaling pathway. Treatment outcomes with respect to mutation types were analyzed. Results: Overall, 1012 patients were tested and 105 (10%) had PIK3CA mutations. Of the 105 patients with PIK3CA mutations, 66 (median number of prior therapies, 3) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Of these 66 patients, 11 (17%) achieved a partial response (PR) and 4 (6%) stable disease ≥ 6 months (SD≥6). The total of SD≥6/PR was 15 (23%). Patients with PIK3CA H1047R mutation (n=16) compared to patients with other PIK3CA mutations (n=50) had higher PR rate (6/16, 37.5% vs. 5/50, 10%; p=0.018), higher rate of SD≥6/PR (7/16, 44% vs. 8/50, 16%; p=0.037), and trend toward longer median progression-free survival (PFS) (5.7 months, 95%CI 0.4–11.0 vs. 2.0 months, 95%CI 1.8–2.2; p=0.064). Patients with a PIK3CA E542K mutation (n=11) compared to others (n=55) trended toward a worse median PFS (1.8 months, 95%CI 1.4–2.2 vs. 2.6 months, 95%CI 1.4–3.8; p=0.058). Of the 66 treated patients with PIK3CA mutations, 55 (83%) had enough tissue for KRAS testing. None of the 16 patients with PIK3CA and simultaneous KRAS mutations in codon 12 or 13 had a PR (0/16, 0% vs. 9/39, 23%; p=0.046) or SD≥6/PR (0/16, 0% vs. 13/39, 33.3%; p=0.011) as compared to patients with PIK3CA, but not KRAS codon 12 or 13 mutations, whereas 2 of 2 (100%) patients with PIK3CA and Q61H KRAS mutation in codon 61 had SD≥6 (n=1) and PR (n=1). Conclusion: Despite the small number of patients, our data suggest that PIK3CA mutations H1047R are associated with response to PI3K/AKT/mTOR inhibitors, whereas codon 12 and 13, but not codon 61 KRAS mutations are associated with resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B161.