Cardiotoxicity in metastatic melanoma patients treated with BRAF and MEK inhibitors in a real-world setting

Figures & data

Table 1. Baseline characteristics.

Baseline characteristics	All patients	Patients with no LVEF decline	Patients with minor cardiotoxicity	p-value (minor vs. no)	Patients with major cardiotoxicity	p-value (major vs. no)
Number of patients	139	93	31		15
Gender, male	80 (58)	55 (59)	18 (58)	0.762	7 (47)	0.292
Age (mean ± SD)	60.7 ± 13.5	60.7 ± 14.1	61.8 ± 11.4	1	58.1 ± 14	1
BMI (mean ± SD)	26.5 ± 5.5	25.3 ± 4.9	29.4 ± 5.7	0.001	28.0 ± 5.7	0.2
Performance status:
0–1	111 (80)	73 (78)	26 (84)	0.546	12 (80)	0.918
≥2	18 (20)	20 (22)	5 (16)		3 (20)
Metastatic disease status:
Stage M1a/M1b	18 (3)	7 (8)	9 (29)	0.006	2 (13)	0.359
Stage M1c	74 (53)	53 (57)	11 (35)		10 (67)
Stage M1d	47 (34)	33 (35)	11 (35)		3 (20)
LDH
<ULN	62 (46)	41 (45)	13 (43)	0.817	8 (53)	0.590
>ULN	74 (54)	50 (55)	17 (57)		7 (47)
Missing	3	2	1		0
BRAF/MEKi as 1. line treatment	78 (56)	52 (55)	18 (58)	0.878	8 (53)	0.821
Comorbidities
Hypertension	54 (39)	28 (30)	22 (71)	<0.001	4 (27)	0.631
Hypercholesterolemia	31 (22)	16 (17)	11 (35)	0.018	4 (27)	0.280
Ischemic heart disease	61 (43)	33 (35)	23 (74)	<0.001	5 (33)	0.108
Cardiac arrhythmia	9 (6)	6 (6)	3 (10)	0.475	0	0.335
Diabetes	11 (8)	6 (6)	5 (16)	0.140	0	0.289
COLD	5 (4)	1 (1)	3 (10)	0.026	1 (7)	0.161
Other cancers	17 (12)	11 (12)	4 (13)	0.585	2 (13)	0.641
Previous chemotherapy or thoracic radiation	5 (4)	3 (3)	1 (3)	0.793	1 (7)	0.367
Smoking, previous/current	65 (47)	43 (46)	14 (45)	0.945	8 (53)	0.594
Abnormal ECG	22 (16)	15 (16)	3 (10)	0.528	4 (27)	0.222
MUGA values (means ± SD)
LVEF (%)	69 ± 10	66 ± 9	81 ± 6	<0.001	63 ± 9	0.289
LVEDV (mL)	89 ± 26	94 ± 27	74 ± 20	0.01	93 ± 22	1
LVESV (mL)	29 ± 14	32 ± 13	15 ± 7	<0.001	36 ± 14	0.873
HR (beats/min)	76 ± 14	74 ± 13	80 ± 14	0.093	80 ± 15	0.349
LVPER (mL/s)	3.6 ± 0.9	3.4 ± 0.8	4.5 ± 0.8	<0.001	3.2 ± 0.9	1
LVPFR (mL/s)	3.0 ± 1.0	2.8 ± 0.9	3.6 ± 1.0	<0.001	3.0 ± 1.2	1
LVPERadj (mL)	2.8 ± 0.6	2.7 ± 0.5	3.4 ± 0.5	<0.001	2.4 ± 0.7	0.047
LVPFRadj (mL)	2.4 ± 0.6	2.3 ± 0.5	2.7 ± 0.5	0.003	2.3 ± 0.7	1
Systolic BP (mmHg)	129 ± 19	129 ± 20	133 ± 19	0.962	126 ± 15	1
Diastolic BP (mmHg)	76 ± 11	76 ± 11	78 ± 13	1	76 ± 10	1

Baseline characteristics of the study population and multiple comparison analyses of baseline characteristics for patients with minor and major cardiotoxicity, respectively, compared to patients with no decline in LVEF.

Continuous variables are given as means ± standard deviation (SD), and categorical variables are given as numbers and percentages.

BMI: body mass index; LDH: lactate dehydrogenase; ULN: upper limit of normal; BRAF/MEKi: BRAF and MEK inhibitor; COLD: chronic obstructive lung disease; ECG: electrocardiogram; LVEF: left ventricular ejection fraction; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; HR: heart rate; LVPFR; left ventricular peak filling rate; LVPFRadj: LVPFR adjusted for heart rate; LVPER: left ventricular peak emptying rate; LVPERadj; LVPER adjusted for heart rate; BP: blood pressure.

Table 2. Changes in paraclinical values.

Patient group:	LVEF (%)	LVEDV (mL)	LVESV (mL)	LVPER (mL/s)	LVPFR (mL/s)	LVPERadj (mL)	LVPFRadj (mL)
No LVEF decline (n = 93)	−6 ± 5	1 ± 16	6 ± 7	−0.50 ± 0.75	−0.42 ± 0.80	−0.28 ± 0.43	−0.21 ± 0.45
Minor cardiotoxicity (n = 31)	−20 ± 5	10 ± 18	19 ± 11	−1.41 ± 0.73	−1.22 ± 0.91	−0.80 ± 0.60	−0.68 ± 0.60
Major cardiotoxicity (n = 15)	−19 ± 9	23 ± 29	32 ± 22	−1.12 ± 0.88	−1.15 ± 1.30	−0.64 ± 0.47	−0.71 ± 0.85

Changes in paraclinical values between baseline and the lowest measured left ventricular ejection fraction (LVEF) given as the mean change for the different patient groups ± standard deviation.

LVEDV: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; LVPFR: left ventricular peak filling rate; LVPFRadj: LVPFR adjusted for heart rate; LVPER; left ventricular peak emptying rate; LVPERadj: LVPER adjusted for heart rate.

Table 3. Time to cardiotoxicity.

Patient group	Median time to decline in LVEF (days)	Range (days)
All patients with cardiotoxicity	94	42–442
Minor cardiotoxicity	98	42–442
Major cardiotoxicity	83	57–194

Time to cardiotoxicity in days from the initiation of treatment with MEK inhibitor to the date of the multigated acquisition (MUGA) scans with a decline in left ventricular ejection fraction.

Table 4. Multivariate analysis of potential risk factors associated with the development of major cardiotoxicity.

Clinical variable	RR (95% CI)	p Value
Gender, male	1.54 (0.5–5.2)	0.483
Age at first treatment	0.98 (0.9–1.1)	0.615
BMI	1.08 (0.99–1.2)	0.074
Performance status ≥2	1.65 (0.3–9.4)	0.574
Metastatic disease, stage M1c/M1d	1.11 (0.2–6.3)	0.905
LDH > ULN	1.37 (0.4–5.1)	0.637
Hypertension	2.20 (0.6–8.0)	0.232
AMI/CABG/PCI	3.38 (0.7–16.0)	0.125
Abnormal ECG at baseline	2.09 (0.3–14.3)	0.452
Smoking	1.51 (0.8–3.0)	0.238
MEKi as 1^st line of treatment	0.90 (0.2–3.3)	0.871
LVEF	1.06 (0.8–1.3)	0.619
LVEDV	0.99 (0.9–1.03)	0.529
LVESV	1.02 (0.95–1.1)	0.594
LVPFR adjusted for heart rate	0.75 (0.196–2.86)	0.670
LVPER adjusted for heart rate	0.159 (0.055–0.46)	0.001
Systolic blood pressure	1.02 (0.96–1.07)	0.573
Diastolic blood pressure	0.98 (0.9–1.04)	0.519

Backward stepwise cox regression analysis for major cardiotoxicity depending on baseline characteristics.

BMI: body mass index; LDH: lactate dehydrogenase; ULN: upper limit of normal; AMI: acute myocardial infarction; CABG: coronary artery bypass graft; PCI: percutaneous cardiac intervention; ECG: electrocardiogram; MEKi: MEK inhibitor; LVEF: left ventricular ejection fraction; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; LVPFR: left ventricular peak filling rate; LVPER: left ventricular peak emptying rate.

Figure 1. Kaplan-Meier estimation of (A) progression free survival and (B) overall survival in patients with no decline in left ventricular ejection fraction (LVEF), patients with minor cardiotoxicity, and patients with major cardiotoxicity.