RÉSUMÉ
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.