Table 1.

Cardiac endpoints for clinical trials with HER2-targeted therapies

Trial	Arms of trial	Anthracycline exposure	Cardiac safety endpoint(s)	Reported cardiovascular events
Adjuvant trials
HERA[1] (11-year follow-up)	H × 1 year vs. H × 2 years vs. observation All patients completed CTX and radiation prior to H	94% received anthracyclines across all arms	Primary CE*	Placebo: 0.1% 1 year H: 1.0% 2 year H: 1.0%
			Secondary CE**	Placebo: 0.9% 1 year H: 4.4% 2 year H: 7.3%
BCIRG 006[3, 9](10 year follow-up)	AC-T vs. AC-TH vs. TCH × 1 year	67% received anthracyclines across all arms	> 10% relative reduction in LVEFCHF	AC-T: 11.2% AC-TH: 18.6% TCH: 9.4%
			(NYHA grade III or IV HF)	AC-T + H: 2% AC-T: 0.7% TCH: 0.4% No cardiac related deaths across arms
APHINITY[10, 11] (6-year follow-up)	Placebo + H + CTX vs. P + H + CTX H + / − P × 1 year	78% received anthracyclines across all arms	Primary CE: CHF (NYHA Class II, III, IV)	H alone: < 1% P + H: < 1%
ALTTO[12, 13] (7-year follow-up)	H vs. L vs. H L vs. H + L × 1 year L alone arm dropped due to futility	95% received anthracyclines in H and H + L arms	Symptomatic CHF (NYHA II—IV) LVEF ≥ 10% decrease from baseline to < LLN	L + H: 3%, H – L: 2%, L + T: 3% L + H: 5% T – L: 3% T: 5%
KATHERINE[31] (41 month follow-up)	T-DMI × 14 cycles vs trastuzumab × (H) 14 cycles	76% received anthracycline in 4 arm 78% revieved anthracycline in T-DMI arm	Cardiac events -death from cardiac cause of HF or NVHA class III or IV, with decrease in LVEF of at least 10% from base to a value of less than 50%	H – 0.6% T – DMI–0.1%
ExteNET[14, 15] (8-year follow-up)	Neratinib vs. placebo × 1 year (following 1 year of CTX and H)	78% received anthracyclines in both arms	LVEF ≥ 10% decrease from baseline (CTCAE version 3.0)	1% (both arms)
Metastatic trials
CLEOPATRA[7, 16] (8-year follow-up)	H + docetaxel + placebo vs. P + H + docetaxel	37.3% received anthracyclines in the pertuzumab arm	LV dysfunction LV dysfunction ≥ grade 3	H + P: 5.4% H + placebo: 8.6% H + P: 1.2% H + placebo: 1.8%
EMILIA[17] (2-year follow-up)	Trastuzumab emtansine (T-DM1) vs. capecitabine + L	61% received anthracyclines in both arms	Composite Cardiac Endpoint ¥	T-DM1: < 1% Cap + L: < 1%
DESTINY-BREAST01[18, 19] (1-year follow-up)	Trastuzumab deruxtecan every 3 weeks	N/A	LV dysfunction LV dysfunction ≥ grade 2	1.6%
ALTERNATIVE[20] (1-year follow-up)	LHA vs HA vs LA	N/A	LV dysfunction (CTCAE v 4.0)	LHA: 7% HA: 3% LA: 2%
NALA[21] (3-year follow-up)	Neratinib + capecitabine vs L + capecitabine	N/A (patients with cumulative doxorubicin dose > 450 mg/m2 excluded)	Cardiac Events***	Arrhythmia 3.3% neratinib vs. 3.5% lapatinib, ischemic heart disease 0.7% neratinib vs. 0.6% lapatinib, QT prolongation 2.3% neratinib vs. 3.9% lapatinib, LVEF decrease 4.3% neratinib vs. 2.3% lapatinib
HER2CLIMB[22, 23] (1-year follow-up)	Tucatinib + H + capecitabine vs. Placebo + H + capecitabine	N/A	LVEF < 55% and decrease ≥ 10% from baseline or absolute decrease ≥ 16%#	Tucatanib: 5.2% Tucatanib + H + capecitabine: 7.1%

Abbreviations: AC-T, Doxorubicin + Cyclophosphamide + Docetaxel; AC-T, Doxorubicin + Cyclophosphamide + Docetaxel + Trastuzumab; ALTERNATIVE, Study of Dual HER2 Blockade with Lapatinib Plus Trastuzumab in Combination with an Aromatase Inhibitor in Postmenopausal Women with HER2 + , Hormone Receptor + Metastatic Breast Cancer; ALTTO, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial; APHINITY, Study of Pertuzumab in Addition to Chemotherapy and Trastuzumab as Adjuvant Therapy in Participants with HER2 + Primary Breast Cancer; BCIRG006, Breast Cancer International Research Group 006 Trial; CE, Cardiac Endpoints; CHF, Congestive Heart Failure; CLEOPATRA, Clinical Evaluation of Pertuzumab and Trastuzumab Trial; CTCEA, Cancer Treatment Criteria for Adverse Events; CTX, Chemotherapy; DESTINY-BREAST01, Study of DS-8201a, an ADC for HER2 + , Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated with T-DM1; EMILIA, Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants with HER2 + Locally Advanced or Metastatic Breast Cancer; ExteNET, Neratinib After Trastuzumab-Based Adjuvant Therapy in HER2 + Breast Cancer Trial; H, Trastuzumab; HERA, Herceptin Adjuvant Trial; HER2CLIMB, Study of Tucatinib vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with HER2 + Breast Cancer; HER2 + , Human Epidermal Growth Factor Receptor 2 Positive; L, Lapatinib; LA, Lapatinib + Aromataze Inhibitor; LLN, Lower Limit of Normal; LHA, Lapatinib + Trastuzumab + Aromatase Inhibitor; LV, Left Ventricular; LVEF, Left Ventricular Ejection Fraction; NALA, Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients with HER2 + Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting; NYHA, New York Heart Association; P, Pertuzumab; HA, Trastuzumab + Aromatase Inhibitor; TCH, Docetaxel + Carboplatin + Trastuzumab

*Primary cardiac endpoint (CE): New York Heart Association (NYHA) class III or IV toxicity, confirmed by a cardiologist, and a clinically significant LVEF drop of at least 10 percentage points from baseline to an absolute LVEF below 50%, or cardiac death

**Secondary CE: asymptomatic (NYHA class I) or mildly symptomatic (NYHA class II) with a clinically significant LVEF drop of at least 10 percentage points from baseline and to an absolute LVEF below 50% confirmed by repeat assessment

***ECG assessed for cardiac arrhythmias, ischemic heart disease, QT prolongation, LVEF decrease

¥ Composite term: pulmonary edema, cardiac asthma, cardiac failure, cardiac output, cardiogenic shock, cardiomyopathy, cardiopulmonary failure, cardiorenal syndrome, cardiotoxicity, diastolic/systolic dysfunction, decreased EF, hepatic congestion, hepatojugular reflux, ventricular dysfunction, ventricular failure, low cardiac output syndrome, obstructive shock, edema (cardiac/pulmonary), stroke volume

#FDA independent analysis of cardiac safety data from HER2CLIMB