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Monitoring and treatment of cardiovascular complications during cancer therapies. Part II: Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are a group of targeted anticancer therapies that have significantly improved the treatment of many malignancies by disrupting specific pathways in cancer cells which are involved in cancer growth. TKIs are categorised into distinct subgroups according to their mechanism of action and biological targets and are associated with a diverse cardiovascular (CV) toxicity profile which include hypertension, corrected QT (QTc) prolongation, and cardiac dysfunction. The key to successful cardiotoxicity management includes individualised cardiac monitoring based on drug specific risk stratification at baseline, aggressive CV risk factor optimisation and early cardioprotective strategies coordinated by cardio-oncology multidisciplinary teams.

Cardio-Oncology


Keywords

Cardio-oncology, cardiotoxicity, tyrosine kinase Inhibitors

 

Abbreviation list

CTRCD:              cancer therapy related cardiac dysfunction

CTR-CVT:           cancer therapy-related cardiovascular toxicity

CVRF:                 cardiovascular risk factors

MDT:                   multidisciplinary team

TKIs:                   tyrosine kinase inhibitors

 

Take-home messages

  1. Tyrosine kinase inhibitors (TKIs) offer unique anticancer therapy in a targeted manner by counteracting signal transduction pathways that are important for cancer growth, proliferation, and differentiation.
  2. Despite their targeted design, most TKIs also have off-target effects resulting from on- and off-target kinase inhibition in other tissues leading to their toxicity profile. When the heart and/or vasculature is affected, this is called cancer therapy-related cardiovascular toxicity (CTR-CVT).
  3. Hypertension, cardiac therapy-related cardiac dysfunction (CTRCD), dyslipidaemia, QTc interval prolongation, arrhythmias, arterial and venous thrombotic events are the main CTR-CVTs encountered during TKI therapy.
  4. Monitoring strategies for patients on TKI’s will depend on their past cardiac history and baseline cardiotoxicity risk profile, the specific TKI and its CV risk profile, prior CV toxicity related to other cancer therapies including previous TKI-related CTR-CVT.
  5. For all the nine classes of TKI discussed below, the assessment and optimisation of baseline cardiovascular risk factors and of any pre-existing cardiovascular disease (CVD) are key in the management of patients before and during TKI therapy.

 

Central illustration. Identification of high-risk factors for the assessment of patients scheduled to start a TKI; follow-up and management of associated CTR-CVT events during therapy.

320_Lyon_Central illustration_LR_final.jpg

ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; BB: beta blockers; BP: blood pressure; CCB: calcium channel blockers; CTRCD: cancer therapy-related cardiac dysfunction; CTR-CVT: cancer therapy-related cardiovascular toxicity; CV: cardiovascular; CVD: cardiovascular disease; CVRF: cardiovascular risk factors; ECG: electrocardiogram; HF: heart failure; LVEF: left ventricular ejection fraction; MDT: multidisciplinary team; TKI: tyrosine kinase inhibitors; TTE: transthoracic echocardiography

Introduction

Tyrosine kinases (TK) are phosphorylating enzymes involved in the signal transduction pathways central to survival, proliferation, and differentiation in human cells. Abnormal activation of TK due to dysregulation (genomic rearrangements, autocrine activation, overexpression, and gain- or loss-of-function mutations) have been implicated in tumorigenesis and cancer cell proliferation. Thus, targeting such abnormal TK either by small molecule inhibitors (TKIs) or through monoclonal antibodies, has revolutionised certain cancer treatments [1]. Conversely, in the cardiovascular system, and in particular the cardiac muscle cells, these pathways are often beneficial and activation protects myocyte function and survival in the context of cardiac stress or injury.

TK can be categorised into receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs), and a small group of dual-specificity kinases (DSKs) which can phosphorylate serine, threonine, and tyrosine residues. RTKs are transmembrane receptors that include vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), the insulin receptor (InsR) family, and the ErbB receptor family which includes epidermal growth factor receptors (EGFR) and the human epidermal growth factor receptor-2 (HER2). NRTKs are cytoplasmic proteins that consist of nine families, including Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, Bruton kinase (BK) and Tec with the addition of a tenth separate group (Brl/Sik, Rak/Frk, Rlk/Txk, and Srm), which fall outside the nine defined families [2]. The most notable example of DSKs are the mitogen-activated protein kinases (MEKs), which are principally involved in the MAP pathways. All of these TKs have become targets of inhibition by small molecule TKIs which work by interrupting the abnormal phosphorylation cascade and signal transduction involved in cancer proliferation and or differentiation [3].

In 2022, there were 72 FDA-approved TKIs for cancer treatment (57 of these were against solid tumours including breast, lung, and colon, 10 against non-solid tumours such as leukaemia, and 4 against both solid and nonsolid tumours: acalabrutinib, ibrutinib, imatinib, and midostaurin) [1].

This article focuses on TKI drug groups which are commonly encountered in clinical practice and that have a higher risk of CV side effects (see Table 1 and Table 2).

 

Table 1. Common TKI groups and indications.

TKI groups Main indications in oncology Commonly used drugs

BCR-ABL TKI

(Breakpoint cluster region–Abelson oncogene locus tyrosine kinase inhibitors)

Chronic myeloid leukaemia (CML)

imatinib, bosutinib, dasatinib, nilotinib, ponatinib asciminib

 

 

BTKI

(Bruton tyrosine kinase inhibitors)

Chronic lymphocytic leukaemia (CLL)

Mantle cell lymphoma (MCL)

Waldenström macroglobulinaemia (WM)

Marginal zone lymphomas (MZL)

ibrutinib, acalabrutinib, zanubrutinib

 

EGFR-TKI

(Epidermal growth factor receptor tyrosine kinase inhibitors)

Locally advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC)

gefitinib, erlotinib, icotinib, afatinib dacomitinib, osimertinib

HER2-TKI

(Human epidermal growth factor 2 tyrosine kinase inhibitors)

HER2 overexpressed/amplified metastatic breast cancer (MBC)

lapatinib, neratinib, tucatinib, (pyrotinib)

VEGF-TKI

(Vascular endothelial growth factor multi-targeted tyrosine kinase inhibitors)

Renal cell carcinoma (RCC)

Thyroid cancer

Hepatocellular carcinomas

Soft tissue sarcoma (STS)

axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib 

sorafenib, sunitinib, vandetanib, anlotinib, apatinib

 

ALK / ROS1 – TKI

(Anaplastic lymphoma kinase inhibitors / ROS proto-oncogene 1 kinase inhibitors) 

ALK-mutated NSCLC

 

ROS1-mutated NSCLC, cholangiocarcinoma, glioblastoma, and colorectal cancers

crizotinib, brigatinib, ceritinib, alectinib lorlatinib

entrectinib, repotrectinib

RET-TKI

(Rearranged during transfection inhibitors)

RET fusion-positive NSCLC, RET fusion-positive thyroid cancer

RET-mutant medullary thyroid cancers

selpercatinib, pralsetinib

 

RAF/MEK-TKI

(Rapidly accelerated fibrosarcoma and mitogen-activated extracellular signal-regulated kinase inhibitors) 

RAS and RAF mutation-positive melanomas, metastatic colorectal cancer and lung

adenocarcinoma

MEK inhibition Ttrametinib, cobimetinib, binimetinib, selumetinib,

RAF inhibition: dabrafenib, vemurafenib, encorafenib

 

 

Table 2. Other TKI groups and their CTR-CVT profile and management.

Other TKIs

Main indications in oncology

Commonly used drugs

Main cardiotoxicity profile, and proposed management

MET-TKI

(mesenchymal–epithelial transition factor tyrosine kinase inhibitor)

METex14 positive lung cancer

Multi-targeted TKIs : crizotinib, cabozantinib, merestinib, glesatinib, sitravatinib

Selective MET-TKIs : tepotinib, camaptinib, savolitinib

Main CTR-CVT: Hypertension (BP > 140/90 mmHg)

QTc prolongation

 

blood pressure (BP) profile optimisation (BP target <140 mmHg systolic and <90 mmHg diastolic)

Lifestyle modifications: stress and pain management, avoid excessive alcohol consumption, check for untreated sleep apnoea, avoid excessive salt intake, promote physical activity.

 

check all other CVRF and optimise.

baseline QTc interval measurement

 

Patients at high or very high risk typically due to a high burden of pre-existing CVD should:

- have a baseline echocardiogram

- be referred to a cardiologist or cardio-oncologist

 

Monitoring should be based on regular BP measurement, and ECGs

PDGF-TKI

(platelet-derived growth factor tyrosine kinase inhibitor) 

 

Gastrointestinal stromal tumour (GIST)

Multitarget TKI: sunitinib, regorafenib, avapritinib and ripretinib

KIT – TKI

(KIT tyrosine kinase inhibitor) 

GIST

KIT positive leukaemia,

KIT positive melanoma

Multitargeted TKIs such as imatinib, sunitinib, regorafenib, avapritinib and ripretinib

TRK-TKI

(tropomyosin receptor kinase inhibitor)

 

NTRK gene fusion–positive solid tumours

larotrectinib

entrectinib (multi-kinase inhibitor)

Small molecule cyclin-dependent kinase (CDK) inhibitor – CDK 4/6 inhibitors

Hormone receptor-positive/ HER2-negative metastatic breast cancer (in combination with endocrine therapy)

palbociclib, ribociclib, and abemaciclib

Significant potential for QTc prolongation

Baseline ECG is recommended.

Repeat ECG at day 14 of the first cycle, before the second cycle, with any dose increase and as clinically indicated (See 2022 ESC Guidelines on cardio-oncology)

ACS: acute coronary syndrome; AF: atrial fibrillation; CCM: continuous cardiac monitoring; CTRCD: cancer therapy-related cardiac dysfunction; CTR-CVT: cancer therapy-related cardiovascular toxicity; CVD: cardiovascular disease; CVRF: cardiovascular risk factors; HF: heart failure; LVEF: left ventricular ejection fraction; TKI: tyrosine kinase inhibitors

 

Breakpoint cluster region–Abelson oncogene locus (BCR-ABL) TKIs and BTKIs are used in haematological malignancies, whilst the 7 other groups are indicated in solid tumours.

General overview of the main TKI-associated CV toxicities and key features in management

Tyrosine kinase inhibitors (TKIs) have revolutionised cancer therapy by providing a more personalised and targeted approach through the inhibition of specific abnormal signal transduction pathways that are important for cancer growth, proliferation, and differentiation. Despite their targeted design, most TKIs also have unwanted on- and off-target effects resulting in their cardiac and vascular toxicity profile, known as cancer therapy-related cardiovascular toxicity (CTR-CVT). Hypertension, QTc interval prolongation, arrhythmias, cancer therapy-related cardiac dysfunction (CTRCD), and arterial and venous thrombotic events are the main CTR-CVT events encountered during TKI therapy (see Table 1 and Table 2).

Given the range and importance of these CV toxicities, a baseline CV evaluation, including blood pressure (BP) measurement and QTc measurement, prior to starting any TKI is recommended (Class Ic), using the appropriate Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) risk proforma (Class IIa) [4]. Cancer patients are then identified as at low, moderate, high, or very high risk of CTR-CVT.  A baseline echocardiogram is recommended in all high-risk patients with pre-existing CVD before starting a TKI (Class I). Baseline measurement of natriuretic peptides (BNP or NT-pro BNP) should be considered in all high-risk patients before starting a TKI (Class IIa) and should definitely be performed if further NP monitoring during treatment is planned. The TKI-specific cardiotoxicity profiles, risk stratification and surveillance during and after exposure to the cancer drug are outlined in the 2022 ESC Guidelines on cardio-oncology (see figures 11, 12, 13, 14, 15, 19, and 22 of the 2022 ESC Guidelines on cardio-oncology) [5]. TKI-specific recommendations on the diagnosis and management of TKI-induced cardiotoxicity can also be found in these guidelines. The key points are summarised below:

1. New-onset hypertension or worsening of existing hypertension as a CTR-CVT is the most common adverse effect of TKIs which inhibit either vascular endothelial growth factor (VEGF) receptor kinases, Bruton kinase and/or RET kinase. BP measurement is recommended in these patients at baseline and at every clinical visit (class I). Cancer patients prescribed these drugs should also consider purchasing a home blood pressure monitor and starting a home BP diary, initially recording daily (VEGF-TKI) or weekly (BTKi) for the first 3 months and then reducing in frequency unless hypertension develops (Class IIb). Pre-existing hypertension and increasing age are the main risk factors for developing TKI-induced hypertension during TKI treatment.

Before and during TKI therapy, the systolic blood pressure (BP) should be consistently less than 140 mmHg and the target diastolic blood pressure should be consistently less than 90 mmHg. Patients with significant hypertension (systolic BP >160 mmHg and diastolic BP >100 mmHg) should preferably be started on combination therapy with an angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) first, and then adding a dihydropyridine calcium channel blocker (CCB), to achieve a more rapid BP control if BP is high. However, most TKIs which cause hypertension also have an increased risk of direct myocardial toxicity and CTRCD (including heart failure). As CCB are contraindicated in heart failure (HF), we recommend starting an ACEi or ARB first, and only starting a CCB if BP is very high or resistant and when LV function is normal. Diltiazem and verapamil are not recommended to treat arterial hypertension in patients with cancer due to their drug–drug interactions with many TKIs. Beta-blockers (BB) such as carvedilol and nebivolol are effective anti-hypertensive drugs and may also reduce the risk of CTRCD and arrhythmias and should be considered second line. Spironolactone is also effective and may protect against TKI-induced CTRCD, whereas loop and thiazide diuretics are generally avoided unless fluid retention and/or oedema are present. Diuretics may cause intravascular volume depletion, and this can increase thrombosis risk in patients on a TKI with prothrombotic effects.

In addition to pharmacological therapy when indicated, all patients scheduled for or undergoing TKI treatment should adopt the following lifestyle modifications: effective stress and pain management, avoiding excessive alcohol consumption, avoiding excessive salt intake, and physical activity should be promoted. It is also important to consider sleep apnoea as a possible modifiable cause and consider an overnight sleep study in the patient’s own home if suspected. In case of severe hypertension (systolic BP > 180 or diastolic BP >110 mmHg), cancer treatment should be temporary interrupted, and a cardio-oncology multidisciplinary team (MDT) discussion should evaluate competing cancer and cardiovascular risks and guide further therapy. 

2. Prolongation of the QTc interval is another important side effect of TKI treatment. The authors recommend that the recent ESC Guidelines on cardio-oncology algorithm for the management of QTc prolongation is used (see Figure 32 of the 2022 ESC Guidelines on cardio-oncology) [5]. Fridericia’s correction (QTcF=QT/3√RR) is recommended when calculating the QT interval in patients with cancer. All patients with abnormal QTc intervals (men >440ms, women >450ms) should have their baseline risk factors for QTc prolongation corrected before starting a TKI, such as avoiding or stopping concomitant QTc prolonging drugs, and potassium and magnesium serum concentrations ideally maintained in the upper normal range (K+  ≥4.0 mmol/L, Mg2+ ≥1.00 mmol/L). TKIs can be started if the QTc interval is <480ms on the baseline ECG, provided there is access to adequate serial ECG monitoring depending on the specific TKI and provided all reversible causes are corrected. If a patient has a baseline QTc >480ms then referral to a cardiologist, preferably a cardio-oncology service if available, is recommended (Class Ic).

When a cancer patient at high risk of QTc prolongation is prescribed a TKI (e.g., nilotinib, pazopanib, sunitib, ribociclib, vandetanib), a reassessment of the QTc with an ECG 7-14 days after starting the new TKI is recommended. Serial ECG monitoring is then recommended monthly during the first 3 months and every 3–6 months thereafter (Class Ic). In addition, a 12-lead ECG is recommended after any dose increase of a TKI associated with a high risk of QTc-prolongation (class Ic).  New QTc prolongation to >480ms during TKI treatment merits review of the patient and their pharmacological treatment. If the QTc intervals become prolonged to >500ms, interrupting the culprit TKI is recommended (Class Ic) whilst also correcting any other reversible causes. Inpatient admission for continuous cardiac monitoring should be considered in patients with severe QTc prolongation (>550 ms).  If the QTc remains >500 ms after correcting reversible causes (e.g., hypokalaemia, hypomagnesemia, hypocalcaemia), an MDT discussion with cardiology and oncology or haemato-oncology is recommended to discuss alternative cancer treatments.  

3. CTRCD is another common CTR-CVT associated with TKIs and can present symptomatically with new heart failure or as an asymptomatic decline in LVEF and global longitudinal strain. Mild asymptomatic CTRCD occurs when there is an isolated fall in global longitudinal strain (GLS) and/or a rise in cardiac biomarkers but the left ventricular ejection fraction (LVEF) remains stable during TKI treatment [6]. Both moderate to severe asymptomatic CTRCD and moderate to severe symptomatic CTRCD require temporary interruption of the culprit TKI, referral to a cardio-oncology service for further cardiac assessment, and initiation and rapid up-titration of guideline-directed HF medication. HF medication will usually include combinations of ACEi or ARB plus BB and spironolactone. In the case of symptomatic CTRCD based on congestion, initial management also includes decongestion with intravenous or oral diuretics. In cases with symptomatic CTCRD a sodium-glucose co-transporter 2 (SGLT2) inhibitor may be considered providing the patient is otherwise well and not susceptible to recurrent infections or sepsis. In cases of severe CTRCD where the LVEF has reduced to <40%, sacubitril-valsartan should be considered in place of the ACEi or ARB. After recovery of the patient’s cardiac function, a review by a cardio-oncology MDT is recommended to discuss re-exposure to TKIs, depending on severity of the left ventricular systolic dysfunction (LVSD) and/or HF syndrome, the intensity of CV medication required to restore normal function, additional CV co-morbidities and, depending on cancer treatment alternatives, cancer disease status and response to cancer therapy.

For patients presenting with acute cardiovascular disease, such as acute coronary syndrome, acute heart failure, hypertensive crisis, and torsades de pointes, general management follows that of the respective ESC guidelines, including the ESC Guidelines on cardio-oncology. It is appropriate to pause the TKI during an acute cardiovascular emergency, particularly if it is the cause, and then once the patient has stabilised a multidisciplinary discussion between cardiology and oncology or haemato-oncology is recommended to discuss the option of restarting the TKI versus alternative treatment options for the cancer. If restarting is the only cancer treatment option, then restarting at a lower dose is usually recommended depending upon the nature and severity of the acute CV complication [7, 8].

Breakpoint cluster region–Abelson oncogene locus – tyrosine kinase inhibitors:  cardiotoxicity profile and management

Breakpoint cluster region–Abelson oncogene locus (BCR-ABL) TKIs are small-molecule inhibitors that have become the mainstay of the treatment of chronic myeloid leukaemia (CML) through their on-target effect inhibiting BCR-ABL-mediated abnormal proliferation of white blood cells [9]. Imatinib is a first-generation BCR-ABL TKI, while bosutinib, dasatinib, and nilotinib are the second generation, and ponatinib and asitinib the third generation. The latest addition to this drug group is asciminib that achieved U.S. Food and Drug Administration (FDA) approval in October 2021 and was designed specifically to target CML forms harbouring the T315I mutation and as a third-line treatment for CML [10].

There are off-target effects, unique to every BCR-ABL TKI, which are responsible for adverse cardiovascular effects. The cardiotoxicity profiles are very diverse depending on the specific BCR-ABL TKI (see Figure 1). In general, patients at higher risk for TKI-related cardiotoxicity are older, have pre-existing CVD, especially heart failure, LVSD, established atherosclerotic burden, as well as uncontrolled cardiovascular risk factors (see Central illustration).

Figure 1. TKI specific cardiotoxicity profiles and key points in baseline risk stratification, and cardiac monitoring during and after the cancer therapy.

320_Lyon_Figure 1_updated_final.jpg

ACEi: angiotensin-converting enzyme inhibitors; ACS: acute coronary syndrome; AF: atrial fibrillation; ARB: angiotensin receptor blockers; AV: atrioventricular; BP: blood pressure; BNP: brain natriuretic peptide; CAD: coronary artery disease; CCB: calcium channel blockers; CML: chronic myeloid leukaemia; cTn: cardiac troponin; CTRCD: cancer therapy-related cardiac dysfunction; CV: cardiovascular; CVD: cardiovascular disease; CTR-CVT: cancer therapy-related cardiovascular toxicity; CVRF: cardiovascular risk factors; DAPT: dual antiplatelet therapy; ECG: electrocardiogram; HF: heart failure; HFA-ICOS: Heart Failure Association – International Cardio-Oncology Society; HTN: hypertension; IHD: ischaemic heart disease; MDT: multidisciplinary team ; MI: myocardial infarction; NP: natriuretic peptides; QTc: corrected QT interval; SCD: sudden cardiac death; SVT: supraventricular tachycardia; TTE: transthoracic echocardiogram; VHD: valvular heart disease; VTE: venous thromboembolism.

 

The cardiac surveillance during and after BCR-ABL TKI therapy illustrated in Figure 1 is based on the 2022 ESC Guidelines on cardio-oncology [5].

Bruton tyrosine kinase inhibitors: cardiotoxicity profile and management

Inhibition of the non-receptor TK, Bruton tyrosine kinase (BTK), which plays an important role in abnormal B-cell proliferation, is now the standard treatment of B-cell haematological malignancies such as chronic lymphocytic leukaemia (CLL), Mantle cell lymphoma (MCL), Waldenström macroglobulinaemia (WM), and marginal zone lymphomas (MZL).

BTKI-induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Ibrutinib, a first-generation irreversible BTKI, is associated with a range of CV toxicities which emerged in the original trials. Of note, BTK inhibitors are also associated with an increased risk of bleeding through platelet dysfunction which is problematic in patients requiring dual antiplatelet therapy (DAPT), surgery and a challenge for patients with BTKI-induced atrial fibrillation (AF), where anticoagulation is also indicated [11].

Third-generation reversible BTK inhibitors such as pirtobrutinib and nemtabrutinib, which were designed to overcome resistance to traditional BTK inhibitors through mutations whilst providing more selective inhibition with less off-target effects, are currently being assessed in phase II clinical trials.

Epidermal growth factor receptor – tyrosine kinase inhibitors: cardiotoxicity profile and management

Epidermal growth factor receptor (EGFR), which is also known as HER1, is an RTK that is mutated in a subtype of non-small cell lung cancer (NSCLC) called EGFR-mutant NSCLC and is thus inhibited by selective EGFR-TKIs. The first-generation EGFR-TKIs, which include gefitinib, erlotinib, and icotinib, are reversible. They are used in the advanced NSCLC setting as well as in the adjuvant setting. Second-generation EGFR-TKIs, including afatinib and dacomitinib, offer irreversible inhibition of the HER oncoprotein family and are generally superior to the first-generation EGFR-TKIs in the treatment of advanced NSCLC but are associated with increased toxicities. Third-generation EGFR-TKIs include osimertinib which was initially designed to overcome resistance to first- and second-generation EGFR-TKI, driven by additional mutation in the mutant EGFR (T790M). Osimertinib has now been shown to be superior to older-generation EGFR-TKIs in EGFR mutant NSCLC, especially in cases of metastasis to the central nervous system, due to its ability to penetrate the blood-brain barrier. Other third-generation EGFR-TKIs such as almonertinib, furmonertinib, lazertinib, and nazartinib have shown promising results in phase I and II trials. Fourth-generation EGFR-TKI’s are also currently being designed to combat osimertinib resistance [3].

EGFR-TKI induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Human Epidermal growth factor receptor 2 – tyrosine kinase inhibitors : cardiotoxicity profile and management

Mutations in the Human Epidermal growth factor receptor 2 (HER2) oncoprotein, which shares a similar structure to EGFR, play a crucial role in the abnormal intracellular signal transduction cascade responsible for oncogenesis and proliferation in the subgroup of breast cancers named HER2-positive (HER2+) breast cancer. Unfortunately, the ERBB2 receptor also plays a key role in cardiomyocyte damage repair, and hence its inhibition is associated with cardiac toxicity [12]. The monoclonal antibody trastuzumab is the standard treatment of HER2+ breast cancer. For more advanced disease, combination treatment with pertuzumab, or trastuzumab-drug conjugates e.g., trastuzumab-emtansine and trastuzumab-deruxtecan, are used. However, in selected patients, the use of HER2-TKIs is recommended, in particular for patients with intracranial metastatic disease, as small-molecule TKIs cross the blood-brain barrier more effectively than trastuzumab.

HER2-TKI induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Lapatinib was the first reversible HER2-TKI approved in the metastatic breast cancer (MBC) setting after failure or resistance to monoclonal antibody HER2-targeting therapies such as trastuzumab [13].

As most algorithms for HER2-positive MBC include several lines of therapy, often based on combination therapies of HER2-TKIs, either with trastuzumab in its standard form or conjugated with chemotherapy, there is an increased risk of CTRCD.

Newer irreversible HER2-TKIs such as neratinib, pyrotinib and tucatinib have since then been introduced and are associated with a similar CTR-CVT profile [14].

Vascular endothelial growth factor multi-targeted tyrosine kinase inhibitors: cardiotoxicity profile and management

The vascular endothelial growth factor (VEGF) signalling pathway plays an important role in several cancers and the inhibition achieved by VEGF receptor-associated multi-targeted TKIs (VEGF-TKI) has become a key component of anticancer therapies against malignancies such as renal, lung, thyroid, and hepatocellular carcinomas [3].

VEGF-TKI induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Anaplastic lymphoma kinase and ROS proto-oncogene 1 inhibitors: cardiotoxicity profile and management

Echinoderm microtubule-associated protein-like 4 and anaplastic lymphocyte kinase (EML4-ALK) is a fusion gene mutation that occurs in 3–5% of NSCLC. Inhibition of ALK-mutant NSCLC by ALK-TKIs has shown significant improvement in survival outcomes [3]. Several ALK-TKIs have also been used to treat ROS-1 mutant cancers including colorectal and cholangiocarcinoma. ALK-TKIs have a range of CTR-CVT.

Crizotinib is a first-generation ALK-TKI which is associated with a range of CTR-CVT outlined in the 2022 ESC Guidelines document and summarised in Figure 1. Baseline risk evaluation and cardiac monitoring during ALK-TKI therapy are also described.

Second-generation TKIs that are characterised by a higher selectivity and central nervous system (CNS) penetration include ceritinib, alectinib and brigatinib. Lorlatinib is a third-generation ALK-TKI designed to overcome acquired resistance due to secondary ALK mutations while on first- or second-generation ALK-TKIs and has a similar CV toxicity profile to crizotinib.

Rearranged during transfection - tyrosine kinase inhibitor: cardiotoxicity profile and management

Abnormal mutations in the rearranged during transfection (RET) tyrosine kinase receptor play an important role in the abnormal signal transduction pathways that lead to cancer growth. RET-TKI are therefore used in patients with RET-altered cancers such as RET fusion-positive NSCLC and RET-mutant medullary thyroid cancers [3]. Selpercatinib is a first-in-class agent that obtained FDA approval in 2020 for RET fusion-positive NSCLC and thyroid cancer based on the LIBRETTO-001 trial [15]. In this pivotal clinical trial, hypertension was the most frequently reported adverse effect in patients treated with selpercatinib.

RET-TKI induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Rapidly accelerated fibrosarcoma and mitogen-activated extracellular signal-regulated kinase inhibitors: cardiotoxicity profile and management

Abnormal signal transduction through the mitogen-activated protein kinase (MAPK) pathway—RAS/RAF/MEK/ERK—is implicated in one-third of all malignancies, especially rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) mutations. For example, the BRAF V600 mutation is found in a significant proportion of melanomas, metastatic colorectal cancer, and lung adenocarcinoma [3].

Although the mutation of MEK, also called mitogen-activated protein kinase (MAPK), is not frequently identified in solid tumours, it is heavily involved in the downstream RAS and RAF signalling cascade and upstream of ERK. This is the rationale for combination therapies with MEK and BRAF inhibition, which are typically used in malignancies such as melanoma, NSCLC and neurofibromas.

RAF/MEK-TKI-induced CTR-CVT, baseline stratification and cardiac monitoring during treatment are summarised in Figure 1.

Other TKIs

Fibroblast growth factor tyrosine kinase inhibitors (FGFR-TKI) have indications in metastatic urothelial cancer, and locally advanced or metastatic cholangiocarcinoma. Although most approved FGFR-TKIs belong to multi-targeted TKIs, more specific FGFR-TKIs such as erdafitinib and pemigatinib are also available.

Platelet-derived growth factor tyrosine kinase inhibition (PDGF-TKI) is achieved by most VEGFR-associated multikinase inhibitors and play an important role in the treatment of gastrointestinal stromal tumour (GIST; e.g.,  sunitinib, regorafenib, avapritinib and ripretinib).

Dysregulation of the KIT proto-oncogene plays a central role in some malignancies such as leukaemia, GIST, and melanoma. KIT inhibition (KIT-TKI) is usually present in multitargeted TKIs such as imatinib, sunitinib, regorafenib, avapritinib and ripretinib.

Oncogenic activation of tropomyosin receptor kinase (TRK) is involved in several solid tumours harbouring these gene fusions. Larotrectinib and entrectinib are two approved first-generation Tropomyosin receptor kinase inhibitor (TRK-TKI) that target this abnormal oncoprotein [3].

Conclusion and Impact on Daily Practice statement 

The success of targeted cancer treatments such as TKIs highlights a trend toward personalised and individualised cancer management. Cardio-oncology management in the setting of TKI therapy should aim at maximising cancer treatment outcomes whilst mitigating the adverse cardiovascular toxicity through careful baseline risk stratification and individualised cardiac surveillance during and after the cancer treatment.

References


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Notes to editor


Authors:

Nana Poku1 , MD; Sivatharshini Ramalingam2, MD; Maria Sol Andres2, MD; Sofie Gevaert3, MD, PhD, FESC;  Alexander R. Lyon4, MD, MA, BM BCh, PhD, FRCP, FHFA, FICOS

  1. Cardiology Division, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland;
  2. Cardio-Oncology Service, Royal Brompton Hospital, London, UK;
  3. Department of Cardiology, Ghent University Hospital, Ghent, Belgium;
  4. National Heart and Lung Institute, Imperial College London and Cardio-Oncology Service, Royal Brompton Hospital, London, UK.

 

Address for correspondence:

Nana Poku, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.

E-mail: Nana.K.Poku@hcuge.ch

 

Author disclosures:

A.R. Lyon is supported by the Foundation Leducq Network of Excellence in Cardio-Oncology and has received speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Takeda, Roche, Janssens-Cilag, Ltd, Clinigen, Eli Lily, Eisai Ltd, Bristol-Myers Squibb, Ferring Pharmaceuticals, Boehringer Ingelheim, Myocardial Solutions, iOWNA Health Ltd and Heartfelt Technologies, Ltd. S. Ramalingam has received speaker, advisory board, consultancy fees and/or research grants from Astra Zeneca, Ferring and Microsoft. The other authors have no conflicts of interest to declare.

 

 

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.