Abstract P5-19-07: Randomized Phase II trial of afatinib alone or with vinorelbine versus investigator's choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-Breast 3 (2015)

Abstract Background: Over one-third of patients (pts) with HER2-positive (+) advanced breast cancer (BC) develop brain metastases (BM), which often leads to short survival. Afatinib (A), an irreversible ErbB family blocker, demonstrated activity in pts with heavily pretreated, HER2+ metastatic BC (MBC) progressing after trastuzumab (T) therapy, with partial responses (PR) in 10% and clinical benefit in 46% of pts (Lin 2012a). We evaluated the activity of A alone or in combination with vinorelbine (V), versus investigator’s choice of therapy for MBC (IC), in pts with HER2+ BC with BM after prior T and/or lapatinib (L) therapy. Methods: Eligible pts had at least one measurable and progressive lesion in the central nervous system (CNS; ≥10 mm on magnetic resonance imaging) after prior systemic and/or radiation therapy. Pts were randomized to receive A (40 mg/day oral), AV (40 mg/day oral + 25 mg/m2/week i.v.) or IC in 3-week cycles. Stratification factors were: ECOG performance status (PS, 0–1 vs 2), number of BM (≤3 vs &amp;gt;3) and prior exposure to L (yes/no). The primary endpoint was pt benefit at 12 weeks (i.e. absence of CNS and extra-CNS disease progression per RECIST 1.1, and no tumor-related worsening of neurological signs/symptoms or increase in steroid dosage). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) in CNS/extra-CNS lesions, and safety. Results: 121 pts were randomized (2 were not treated): median age, 53 years; ECOG PS 0–1, 83%; &amp;gt;3 BM, 59%; prior L therapy, 78.5%. The IC treatment consisted of: T+ chemotherapy (CT) (22 pts); T+L+CT (3 pts); L+CT (10 pts); L alone (1 pt); or CT alone (6 pts). Results for efficacy endpoints are shown (Table). A (n=40)AV1 (n=38)IC1 (n=43)Pt benefit rates at 12 weeks, n (%)12 (30)13 (34)18 (42)Median PFS, weeks11.912.318.4Median OS, weeks57.737.352.1ORR (PR), n (%): CNS lesions03 (8)6 (14)Extra CNS lesions03 (8)2 (5)Disease control, n (%): CNS lesions27(68)27 (71)31 (72)Non CNS lesions17 (43)19 (50)26 (61)1One pt randomized but not treated In the treated set (n=119), the most frequent treatment-related adverse events (AEs) in the A and AV arms were diarrhea (90% and 84%) and rash (38% and 54%); neutropenia (51%) was also common in the AV arm. Diarrhea (33%), neutropenia (21%) and asthenia (21%) were the most frequent related AEs in the IC arm. Grade (G) 3/4 treatment-related AEs were observed in 50%/3% (A), 57%/24% (AV; G4 AEs were mainly neutropenias) and 14%/7% (IC) of pts; there were no treatment-related G5 events. Conclusions: Approximately one third of pts with HER2+ MBC benefited from the assigned treatments and two thirds had CNS lesions controlled per RECIST in each group. Objective response in CNS was infrequent (0 to 14%) with all treatments. Overall, AEs were manageable in this heavily pretreated pt population. aLin et al. Breast Cancer Res Treat 2012;133:1057–1065. Citation Format: Javier Cortés, Veronique Dieras, Jungsil Ro, Jérôme Barriere, Thomas Bachelot, Sara Hurvitz, Emilie Le Rhun, Marc Espie, Sung-Bae Kim, Andreas Schneeweiss, Joo Hyuk Sohn, Jean-Marc Nabholtz, Pirkko-Liisa Kellokumpu-Lehtinen, Julie Taguchi, Federico Piacentini, Eva Ciruelos, Petri Bono, Mahmoud Ould-Kaci, Flavien Roux, Heikki Joensuu. Randomized Phase II trial of afatinib alone or with vinorelbine versus investigator's choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-Breast 3 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-07.