Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity: A Phase I Trial

Abstract

Objectives: This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor-positive breast cancer who developed mild cardiotoxicity.

Background: Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity.

Methods: Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%.

Results: All 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001).

Conclusions: It may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021).

Keywords: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HER, human epidermal growth factor receptor; HER2; LV, left ventricular; LVEF, left ventricular ejection fraction; breast cancer; cDLT, cardiac dose-limiting toxicity; cardiomyopathy; trastuzumab.

© 2019 The Authors.

Figures

Graphical abstract

Figure 1

Number of Trastuzumab Doses Received Before and After Enrollment, by Participant ID Participants #5 and #11 discontinued trastuzumab permanently because of cardiac dose-limiting toxicity. Participant #19 completed treatment after 12 months of trastuzumab, amounting to 17 cycles; there was no plan to administer 18 cycles to this participant.

Central Illustration

Continuing Trastuzumab Despite Mild Cardiotoxicity: LVEF Over Time (A) Left ventricular ejection fraction (LVEF) progressively increased despite ongoing trastuzumab in individuals with mild trastuzumab cardiotoxicity when trastuzumab was accompanied by the administration of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and/or a beta-blocker. #p < 0.001 as compared with the enrollment left ventricular ejection fraction indicating significant improvement in left ventricular ejection fraction as compared with the left ventricular ejection fraction at enrollment. (B) Left ventricular ejection fraction while continuing trastuzumab and after completion of trastuzumab. *p = 0.53 compared with left ventricular ejection fraction at enrollment; #p = 0.025 compared with left ventricular ejection fraction at enrollment.

Figure 2

LVEF Over Time Stratified by Participant This spaghetti plot demonstrates that all but 2 participants exhibited stable left ventricular ejection fraction (LVEF) while continuing to receive trastuzumab and that the 2 participants who experienced deterioration in left ventricular ejection fraction had improvement in left ventricular ejection fraction after permanently discontinuing trastuzumab.