P5-16-05 The combination of trastuzumab and HER2-directed peptide vaccines is safe in
 

P5-16-05
The combination of trastuzumab and HER2-directed peptide
vaccines is safe in HER2-expressing breast cancer patients
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. Brooke Army Medical
Center, San Antonio, TX; Cancer Immunology and Immunotherapy
Center, Athens, Greece; MD Anderson Cancer Center, Houston, TX;
Uniformed Services University of the Health Sciences, Bethesda, MD
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 + GMCSF
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 nonserious
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.