NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+breast cancer (MBC)

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 ≤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 steadystate 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%). 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.