Abstract P6-13-11: Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer
Authors: Jain S , Nye L , Santa-Maria C , Bontemps L , Williams A , Garrett H , Dammrich E , Giles F , Gradishar W 
Published: May 2016

Abstract
BACKGROUND: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3K alpha isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib in combination with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that has progressed on or after trastuzumab and/or taxane-based regimens. METHODS: This phase I study enrolled patients with HER2-positive MBC who received alpelisib daily (cohort 1: 300 mg, cohort (-)1: 250 mg) and T-DM1 3.6 mg/m2 on Day 1 of a 3 week cycle using a 3+3 design with dose expansion at the MTD. Treatment was continued until progression, unacceptable toxicity, or patient preference. Blood was collected for pharmacokinetic (PK) and pharmacodynamic (PD) markers. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3 or 4 adverse events (AE) during the first cycle. Imaging and echocardiogram were obtained every 3 cycles. RESULTS: Dose escalation is completed and included in this analysis (N=8). Median age was 53 (range 46-79) with median ECOG Performance Status of 1. Median prior lines of therapy in the metastatic setting was 6 (range 0-12) including 5 patients who progressed on prior T-DM1 (after median 6 cycles). Two patients had de novo MBC and 3 with ER and/or PR positive disease. Median number of metastatic sites was 2 (range 1-5) including brain (inactive), liver, and lung. Median number of cycles of alpelisib and T-DM1 per patient was 5.5 (range 1-12). Five patients were enrolled in cohort 1 with 2 DLTs (both grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common treatment-related AEs were fatigue (n=7, 86%), nausea (n=6, 75%), aspartate aminotransferase increase (n=4, 50%), and thrombocytopenia (n=4, 50%). Grade 3 AEs were rash (n = 3), hyperglycemia (n=1), hypertension (n=1) and thrombocytopenia (n=1), which occurred in only cohort 1. Grade 3 rash typically occurred during cycle 1, which resolved with temporary interruption and subsequent dose reduction of alpelisib and the use of topical steroids for median 9.3 days (range 6-12). Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. A total of 4 dose reductions occurred in cohort 1. No Grade 3/4 AEs or dose reductions occurred in cohort -1. In total, only 0.07% of all AEs were Grade 3 and none Grade 4. The MTD for alpelisib was established as 250 mg daily. In 7 evaluable patients, there were 6 objective responses after 3 cycles, a response rate of 86% (1 confirmed complete response, 2 confirmed partial response [PR], and 3 unconfirmed PR). Five (67%) of these patients continue to have durable responses (median 6.5 cycles) at doses 200-250 mg daily. One patient had progression of disease. PK/PD results and PIK3CA mutation testing are pending. CONCLUSION: The combination of alpelisib and T-DM1 appears to be safe, well tolerated, with clinical activity in HER2-positive MBC patients including those who progressed on prior T-DM1 therapy. The study is currently in dose expansion with goal of enrolling 10 additional patients with T-DM1 and alpelisib 250 mg daily.
Citation Format: Jain S, Nye L, Santa-Maria C, Bontemps L, Williams A, Garrett H, Dammrich E, Giles F, Gradishar W. Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-11.