Abstract P5-16-05: The combination of trastuzumab and HER2-directed peptide vaccines is safe in HER2-expressing breast cancer patients
Authors: Hale DF , Vreeland TJ , Perez SA , Berry JS , Ardavanis A , Trappey AF , Tzonis P , Sears AK , Clifton GT , Shumway NM , Papamichail M , Ponniah S , Peoples GE , Mittendorf EA 
Published: August 2014

Abstract
Background: Cardiotoxicity is the most concerning toxicity associated with the commonly used HER2-directed immunotherapy, trastuzumab (Tz). In general, a significant decline of left ventricular ejection fraction (EF) in asymptomatic patients is accepted as a decrease of at least 10% or an absolute value of below 50%. We are currently conducting multiple trials of HER2-directed peptide vaccines, often given either concurrently or in close temporal proximity to Tz. This has raised the issue that combining therapies could increase the risk of cardio-toxicity. Here, we present safety data from multiple trials in which the combination of these HER2-directed therapies was administered.
Methods: Phase I and II trials were conducted in disease-free breast cancer patients after completion of chemotherapy when indicated. Patients (pts) who were determined by treating oncologists to qualify for Tz received this therapy per standard-of-care. These pts were enrolled onto HER2-directed peptide vaccine trials per each trial's inclusion criteria, with vaccinated (VG) pts receiving peptide + GM-CSF and control (CG) pts receiving GM-CSF alone. All patients were monitored for local and systemic toxicity to peptide inoculations (graded by the NCI's Common Terminology Criteria for Adverse Events). In addition, patients who received Tz had EF tracked through either echocardiogram or MUGA according to local standard of practice. Our database was queried for patients who received Tz and peptide, and had documented measures of EF pre-vaccine (Pre), during vaccine (D) and post-vaccine (Post). These pts were then placed in two groups based on the timing of Tz and vaccine therapy: concurrent(C) group and sequential(S) group. Mean EF at each time point was compared using a t-test.
Results: Overall, the peptide vaccines were well tolerated (max local tox: 1% Grade 0, 65% Gr 1, 33% Gr 2, 1% Gr 3; max systemic tox: 19% Gr 0, 63% Gr 1, 18% Gr 2, 0% Gr 3). These toxicities are likely secondary to the GM-CSF immunoadjuvant as control pts receiving GM-CSF alone have similar toxicity profiles (max local tox: 0% Gr 0, 76% Gr 1, 23% Gr 2, 1% Gr 3; max systemic tox: 20% Gr 0, 65% Gr 1, 15% Gr 2, 0% Gr 3). There have been no serious or non-serious cardiac-related adverse events in our trials. In total, 71 pts treated with Tz and enrolled in a vaccine trial had EF measurements available for analysis; 54 in the S group (35 VG, 19 CG) and 17 in the C group (10 VG, 7 CG). Overall, neither VG nor CG pts had significant changes in EF (VG Pre: 65±0.8%, D: 63±0.9%, Post: 64±0.3%; CG Pre: 63±1.2%, D: 64±1.8%, Post: 63±1.1%). Separating VG pts into C and S pts, there were again no significant changes in EF, (C Pre: 65±1.0%, D: 63±1.0%, Post: 63±1.4%; S Pre: 65±1.7%, D: 61±1.3%, Post: 65±1.8%).
Conclusions: HER2-directed peptide vaccines are safe and well tolerated. Initial data indicate that the combination of Tz and HER2-directed peptide vaccines, whether concurrent or sequential, does not cause significant cardiac toxicities as measured by changes in the EF during and after therapy. We will continue to track this safety data to confirm early findings as we pursue additional combination trials.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-05.