Abstract P5-18-05: Interim Results from a Phase 1b/2a Study of Trastuzumab Emtansine and Docetaxel, With and Without Pertuzumab, in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer

Abstract

Abstract Introduction: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab, a stable linker, and DM1 (a microtubule inhibitor). In 2 randomized trials in patients (pts) with HER2-positive metastatic breast cancer (MBC), T-DM1 significantly prolonged progression-free survival (PFS) compared with standard therapy (Hurvitz, ESMO 2011; Blackwell, ASCO 2012). The combination of T-DM1 and docetaxel (D) or pertuzumab (P) has shown enhanced antitumor activity in preclinical models of HER2-positive BC (Lewis Phillips, AACR 2008; Fields, AACR 2010). Methods: This phase 1b/2a dose-escalation study examines the safety, tolerability, efficacy, and pharmacokinetics (PK) of T-DM1 (starting dose 2.4 mg/kg every 3 weeks [q3w]) combined with D (starting dose 75 mg/m2 q3w) in pts with MBC, and T-DM1 with D±P (840 mg loading dose, then 420 mg q3w) in pts with newly diagnosed locally advanced BC (LABC; clinical stage IIa-IIIc). The maximum tolerated dose (MTD) for T-DM1+D is established in pts with MBC and used as the starting dose for feasibility of T-DM1+D±P (up to 6 cycles) in pts with LABC. Eligibility criteria include HER2-positive MBC (locally assessed) or LABC (centrally confirmed). This interim report includes data from pts who completed at least 1 treatment cycle in phase 1b. Results: During MBC feasibility, 21 pts were enrolled; median age was 47.0 years (yr; range, 33–70); median number of prior lines of MBC therapy was 2 (range, 0–10). Four pts experienced 6 DLTs (Table 1). The MTD was T-DM1 3.6 mg/kg q3w + D 60 mg/m2 q3w. Common grade (G) 3/4 adverse events (AEs): neutropenia (81%), leukopenia (52%), and thrombocytopenia (29%). ORR was 76.2% (16/21); median PFS was 11.8 months (range, 1.6–26.9). In LABC feasibility, 18 pts were enrolled; median age was 49.5 yr (range, 34–74). Four pts experienced 4 DLTs (Table 2). The MTD for T-DM1+D was 3.6 mg/kg q3w + 75 mg/m2 q3w; MTD for T-DM1+D+P was 3.6 mg/kg q3w + 75 mg/m2 q3w + 840 mg (with G-CSF primary prophylaxis). Common G3/4 AEs: T-DM1+D, neutropenia (2/9; 22%), increased alanine aminotransferase (ALT; 2/9; 22%), thrombocytopenia (TCP; 1/9; 11%); T-DM1+D+P, neutropenia (5/9; 56%), TCP (2/9; 22%), increased ALT (2/9; 22%), and cytolytic hepatitis (1/9; 11%). With 9 pts enrolled in the T-DM1+D LABC cohorts and 8 pts currently evaluable, pCR rate (ypT0N0) is 87.5%. Conclusions: Full-dose T-DM1 can be safely combined with D in pts with MBC, and with D±P in pts with LABC. G-CSF is needed with higher doses of D. Pathological assessment for all LABC patients and PK analyses will be available for the full presentation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-05.