Abstract P3-14-01: A Phase Ib/II Trial of Trastuzumab-DM1 with Pertuzumab for Patients with HER2-Positive, Locally Advanced or Metastatic Breast Cancer: Interim Efficacy and Safety Results
Authors: Diéras V , Harbeck N , Albain K , Burris H , Awada A , Crivellari D , Andre F , Choi YJ , Huang J , Miller KD. 
Published: April 2011

Abstract
Background
The HER2-targeted antibody-drug conjugate trastuzumab-DM1 (T-DM1) contains the cytotoxic maytansine derivative DM1 coupled to trastuzumab (T) through a stable thioether SMCC linker. This unique linker allows for the intracellular release of DM1 following T binding to HER2-overexpressing tumor cells, thereby minimizing systemic exposure to free DM1. T-DM1 monotherapy has shown robust efficacy and safety in patients with heavily-pretreated HER2-positive MBC. Pertuzumab, the first HER2-directed dimerization inhibitor for the treatment of MBC, has demonstrated clinical activity and tolerability in combination with T in phase II trials. Pertuzumab combined with T-DM1 has shown synergistic antitumor activity in HER2-positive xenograft models.
Methods This phase Ib/II study, TDM4373g, evaluated pertuzumab (q3wk, 840 mg cycle 1, 420 mg in subsequent cycles) combined with T-DM1 (3.6 mg/kg q3wk, the established dose from phase Ib) in patients with HER2- positive MBC. Patients received pertuzumab and T-DM1 first-line (FL), or in a relapsed (R) setting (defined as progression on prior HER2-directed therapy for MBC). Patients were required to have an LVEF of ≥55%. The primary endpoints were safety and tolerability, pharmacokinetics (to be reported elsewhere) and objective response rate (ORR) by RECIST per investigator assessment. The planned sample size was 60 patients (40 R patients; 20 FL patients), which powers the trial to detect a 20% increase in ORR from 30%.
Results Enrollment was completed in March 2010 with 67 patients (R, n=45; FL, n=22). Results as of March 30, 2010, from patients with a minimum of 3 weeks follow-up, are reported here. The median age was 53 years (range, 28-74). The median number of prior systemic agents excluding hormonal therapy for all patients was 7; R patients had a median of 8 and FL patients had a median of 4. All of the R patients had received prior T and 34 of 45 had prior lapatinib therapy. For FL patients, 19 of 22 had received prior T and 2 of 22 had prior lapatinib therapy. Patients received a median of 5 cycles of T-DM1 and pertuzumab. One grade 5 serious adverse event (SAE) of pneumonia was reported in a patient who died concomitantly due to disease progression. The most common SAEs were pleural effusion in 3 patients and dyspnea and pneumonia in 2 patients each. The most common grade ≥3 AEs were thrombocytopenia (TCP) (11.9%), fatigue (9.0%), increased ALT (7.5%), and increased AST (6.0%). For AEs of all grades, the most frequent were fatigue (53.7%), nausea (44.8%), and TCP (31.3%). Ten patients had T-DM1 dose reductions due to AEs, with 5 secondary to grade 3 AST and/or ALT elevation and 3 due to TCP. Five patients (all R) discontinued the study due to AEs, one of which was due to grade 3 LVEF dysfunction.
In R patients (n=45), 19 responses were observed (15 confirmed) with a median follow-up of 8 cycles. In FL patients (n=22), 9 responses were observed (2 confirmed) with a median follow-up of 3 cycles.
Conclusions The preliminary efficacy profile of full dose T-DM1 and pertuzumab is encouraging. The tolerance of the combination was sufficient and responses were sufficiently encouraging to justify phase III investigation.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-01.