Abstract CT013: NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC)
Authors: Abraham Jame , Puhalla Shannon L. , Sikov Wiliam M. , Montero Alberto J. , Beumer Jan H. , Buyse Marc E. , Adamson Laura M. , Srinivasan Ashok , Pogue-Geile Katherine L. , Jacobs Samuel A. 
Published: July 2017

Abstract
Background:
T-DM1, an antibody-drug conjugate that delivers the maytansinoid antimicrotubule agent DM1 to antigen-expressing HER2+ cells thereby improving the therapeutic index, is FDA- approved as 2nd-line therapy in HER2+ MBC patients (pts) after prior trastuzumab (T) and a taxane. Most pts currently receive T and pertuzumab (P) as neoadjuvant for 1st-line therapy for MBC. A retrospective analysis of T-DM1 after T-P found a much lower tumor response rate (17%) than T-DM1 after T and taxane, as reported in EMILIA (43%). In NSABP FB-8, combining T, N, and paclitaxel achieved responses after T-DM1 progression, raising the possibility that N could reverse resistance to T-DM1.
Methods:
Eligible pts had prior T-P as neoadjuvant therapy for 1st-line metastatic treatment for HER2+ measurable disease, ECOG PS &lt;2, adequate hematologic, renal, and liver function. Treatment consisted of T-DM1 at 3.6 mg/kg iv q 3 wk and N at escalating doses of 120, 160, 200, and 240 mg/d continuously, using 3+3 design. Each cycle was 21 d. Clinical endpoints include determination of safety and efficacy. Primary diarrhea prophylaxis with intensive loperamide was required. To compare steady-state blood levels of N across dose levels samples were drawn at the start of cycle 2.
Results:
The RP2D is still undergoing evaluation. 17 T-P resistant pts were enrolled. Treatment-related grade 3 toxicities included diarrhea (2 pts), thrombocytopenia (3 pts), hypertension (2 pts), ALT elevation (1 pt), nausea (1 pt), and neutropenia (1 pt). Of 14 pts who were evaluable after 2 cycles of therapy, 3 had CRs and 6 had PRs (ORR 64%).
Dose (mg/day)No. of objective responses (CR/PR)/No. of evaluable (CR/PR/SD/PD)Duration of objective response (weeks)DLTs1205/5 (CR 2, PR 3)66+,51,26,15,91 (nausea and dehydration)1602/4 (CR 1, PR 1, PD 2)39+,6No2001/3 (PR 1, SD 1, PD 1)21No2401/2 (PR 1, SD 1)152 (diarrhea, nausea, vomiting)
Conclusions:
T-DM1 plus N was well tolerated at doses of 120, 160, and 200 mg/d. Anti-tumor activity did not appear to be dose-dependent. 5 evaluable pts treated at lowest dose of N (120 mg/d) responded. A randomized phase II study comparing N at 120 mg/d and 200 mg/d with T-DM1 is planned to better define efficacy and tolerance.
Support: Puma Biotechnology
Citation Format: Jame Abraham, Shannon L. Puhalla, Wiliam M. Sikov, Alberto J. Montero, Jan H. Beumer, Marc E. Buyse, Laura M. Adamson, Ashok Srinivasan, Katherine L. Pogue-Geile, Samuel A. Jacobs. NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT013. doi:10.1158/1538-7445.AM2017-CT013