PD09-03: Phase I/II Study of BKM120 in Combination with Trastuzumab in Patients with HER2 Overexpressing Metastatic Breast Cancer Resistant to Trastuzumab-Containing Therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 24_Supplement; p. PD09-03
• Main Authors: Saura, C, Bendell, J, Jerusalem, G, Graña-Suárez, B, Su, S, Ru, Q, De Buck, S, Devisme, C, Bosch, A, Urruticoechea, A, Beck, JT, DiTomaso, E, Rouyrre, N, Sternberg, DW, Massacesi, C, Hirawat, S, Dirix, L, Baselga, J
• Format: Journal Article
• Language: English
• Published: 15-12-2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS11-PD09-03

Introduction: HER2 amplification can activate the phosphatidylinositol-3-kinase (PI3K) pathway in breast cancer. Furthermore, trastuzumab (T) resistance can be associated with loss/deregulation of PTEN, which also causes activation of PI3K pathway signaling. BKM120, a potent orally bioavailable pan-class I PI3K inhibitor, could reverse resistance to T in vitro. Furthermore, administration of BKM120 with T demonstrated synergistic activity in preclinical models. The potential for combining BKM120 with T in heavily pretreated HER2+ metastatic breast cancer (MBC) patients (pts) will be determined in this study to substantiate the hypothesis for future development.
Methods: HER2+ MBC pts resistant to T-containing therapy (progression on or within 4 weeks since last T administration) received treatment in the dose-escalation portion of this multicenter trial. Prior anti-HER2−directed therapies were allowed. The primary objective was to determine the maximum tolerated dose (MTD) of BKM120 in combination with the standard dose of weekly T. A Bayesian logistic regression model with overdose control guided the dose escalation.
Results: Seventeen pts with MBC have been enrolled: 5 at 50 mg/day and 12 at 100 mg/day dose of BKM120. Escalation was conducted up to the MTD level of single agent BKM120, 100 mg/day. Patient characteristics: median age 46 years (range 34–70); most pts were heavily pretreated (reported range of prior chemotherapy lines 1–4). In preliminary results (cut-off date 1st June 2011), 7 pts discontinued treatment. BKM120 in combination with T showed a mean peak drug concentration and half-life similar to single-agent BKM120. T trough levels remained above the single agent efficacy threshold. Only one dose-limiting toxicity (G3 asthenia) was reported at the BKM120 dose of 100 mg/day. The MTD was determined to be 100 mg/day. Reported G3 adverse events were asthenia, altered mood, rash, GGT increase, hypokalemia, and hypersensitivity in 1pt each. No G4 toxicity has been observed so far. With regards to activity, 2 partial responses (1 confirmed) and 3 occurrences of disease stabilization have been observed.
Conclusions: BKM120 in combination with T in heavily pretreated HER2+ MBC pts with T-resistance has an acceptable safety profile and has shown encouraging preliminary activity. The Phase II portion of the study is ongoing. An updated analysis of efficacy, the potential correlation with PI3K pathway alteration status overlaying HER2 activation, and pharmacodynamics study will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-03.