Ph Ib/Ii Study Of BKM120 Plus Trastuzumab (T) in Patients With T-resistant HER2+ Advanced Breast Cancer (BC)

ABSTRACT Background PI3K/AKT/mTOR pathway upregulation has been implicated in T resistance, and thus the impact of pathway inhibition on restoration of therapeutic sensitivity is being investigated. The RP2D of BKM120, an oral pan-class I PI3K inhibitor, plus T is 100 mg/d. Here, we present Ph II results of BKM120 + T in pts with T-resistant advanced HER2+ BC. Methods Pts with HER2+ locally adv/metastatic BC resistant to T (progression while on T, or within 4 wks [metastatic] or 12 mths [adjuvant] of last T dose) received daily BKM120 (100 mg) and the standard wkly dose of T. Ph II eligibility criteria: ≥1 measurable lesion, ≥1 but ≤4 prior anti-HER2 regimens (incl. trastuzumab [required], lapatinib, and/or T-DM1), and ≤3 lines of prior chemotherapy for metastatic disease. Ph IB pts treated at the RP2D who met Ph II eligibility criteria were included in the analysis. Results As of 23 March 2012, 53 pts were included in the Ph II analysis (safety set; incl. 8 pts from Ph IB). 49 pts were evaluable for response (full analysis set); median age 52 yrs (28–75); median no. prior antineoplastic regimens 4 (1–10); 5 pts had a baseline CNS lesion (3 measurable target; 2 non-target). At data cut-off, 9 pts were still on study. Most pts discontinued treatment due to disease progression (55%); 8 pts (16%) withdrew due to AEs. Mean duration of BKM120 exposure was 11 wks (0.1–41). Most common suspected study-drug related G3/4 AEs: ALT increased (5 pts); rash (5 pts); AST increased (4 pts); asthenia (3 pts); nausea, anxiety, skin photosensitivity, hyperglycemia (2 pts each). Partial responses (RECIST) were seen in 4 pts (8%), and stable disease (SD) was noted in 20 pts (41%); the disease control rate (CR, PR, or SD) was 49%. Preliminary results indicate that, of the 5 pts with baseline brain mets (BM), 2 pts had SD in the CNS without evidence of progression at study withdrawal; 2 pts had overall SD (1 for 90 days and 1 for 106 days) before progression in the CNS; 1 pt was not evaluated in the CNS after study entry. Conclusion BKM120 in combination with T has an acceptable safety profile, and has shown encouraging preliminary activity in heavily pretreated HER2+ metastatic BC pts with T resistance, including pts with BM. Disclosure Q. Ru: Employee of Novartis. S. Ruquet: Employee of Novartis. D.W. Sternberg: Employee of Novartis. All other authors have declared no conflicts of interest.