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

15 May, 2023

Scientific

Cardio-Oncology

Doctor Sivatharshini Ramalingam

Associate Professor Sofie Gevaert

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. Topic(s): 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

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.
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).
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.
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.
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.

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.

B-lines

Cardiogenic pulmonary oedema

Multiple, diffuse, bilateral
Homogeneous distribution over the chest with a gravity-dependent gradient
Usually separated or coalescent in more severe cases
No spared areas

Non-cardiogenic pulmonary oedema

Multiple, diffuse, often bilateral
Patchy distribution over the chest without a gravity-dependent gradient
More often coalescent
Spared areas

Pulmonary fibrosis

Multiple but not necessarily diffuse or bilateral
Usually more prevalent at the lung bases
Usually separated or coalescent in more severe cases
Spared areas not typical

Other LUS findings

Pleural line

Cardiogenic: Usually thin and regular
Non-cardiogenic: Usually irregular and “fragmented”
Pulmonary fibrosis: Irregular in moderate/severe cases (can appear thin in mild cases)

Consolidations

Cardiogenic: Usually not present unless compressive atelectasis with large pleural effusion
Non-cardiogenic: Frequent peripheral small consolidations and larger consolidations
Pulmonary fibrosis: Rarely present; can be seen in acute phases (i.e., alveolitis), usually of small size

Pleural effusion

Cardiogenic: Frequent, of variable size; anechoic (transudate), without complex appearance unless coexisting conditions; usually bilateral (often larger on the right side)
Non-cardiogenic: Usually not large
Pulmonary fibrosis: Rare, unless in very advanced cases or acute phases; usually not large

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

Diagnosis
- In-patients:
  - Rule in and rule out cardiogenic pulmonary oedema in patients with acute dyspnoea (multiple, diffuse, bilateral B-lines)
  - Reduce time to correct diagnosis
  - Not inferior in diagnostic accuracy compared to standard strategy (chest X-ray + NT-proBNP)
- Out-patients:
  - Detect subclinical pulmonary congestion in out-patients with HF and no significant signs and symptoms

Monitoring
- In-patients:
  - Dynamic monitoring of decongestion during hospitalisation for acute HF, through reduction of B-lines

Guiding Therapy
- Out-patients:
  - Titrate HF treatment (in particular diuretic therapy) according also to the number of B-lines during follow-up in out-patients after HF admission, to reduce the number of urgent visits and rehospitalisation for acute HF

Prognosis
- In-patients:
  - Detection of subclinical pulmonary congestion at discharge to predict rehospitalisation
- Out-patients:
  - Detection of subclinical pulmonary congestion during ambulatory office visits to predict rehospitalisation

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.

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.

Note to editors

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

Cardiology Division, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland;
Cardio-Oncology Service, Royal Brompton Hospital, London, UK;
Department of Cardiology, Ghent University Hospital, Ghent, Belgium;
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

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 Pharma

References

Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update.Pharmacol Res. 2022;187:106552.
Siveen KS, Prabhu KS, Achkar IW, Kuttikrishnan S, Shyam S, Khan AQ, Merhi M, Dermime S, Uddin S. Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products.. Mol Cancer. 2018;17:31.
Huang L, Jiang S, Shi Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020).J Hematol Oncol. 2020;13:143.
Lyon AR, Dent S, Stanway S, Earl H, Brezden-Masley C, Cohen-Solal A, Tocchetti CG, Moslehi JJ, Groarke JD, Bergler-Klein J, Khoo V, Tan LL, Anker MS, von Haehling S, Maack C, Pudil R, Barac A, Thavendiranathan P, Ky B, Neilan TG, Belenkov Y, Rosen SD, Iakobishvili Z, Sverdlov AL, Hajjar LA, Macedo AVS, Manisty C, Ciardiello F, Farmakis D, de Boer RA, Skouri H, Suter TM, Cardinale D, Witteles RM, Fradley MG, Herrmann J, Cornell RF, Wechelaker A, Mauro MJ, Milojkovic D, de Lavallade H, Ruschitzka F, Coats AJS, Seferovic PM, Chioncel O, Thum T, Bauersachs J, Andres MS, Wright DJ, López-Fernández T, Plummer C, Lenihan D. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.Eur J Heart Fail . 2020;22:1945-60.
Lyon AR, López-Fernández T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, Cutter DJ, de Azambuja E, de Boer RA, Dent SF, Farmakis D, Gevaert SA, Gorog DA, Herrmann J, Lenihan D, Moslehi J, Moura B, Salinger SS, Stephens R, Suter TM, Szmit S, Tamargo J, Thavendiranathan P, Tocchetti CG, van der Meer P, van der Pal HJH; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS).Eur Heart J. 2022;43:4229-361.
Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, Carver J, Dent S, Ky B, Lyon AR, López-Fernández T, Fradley MG, Ganatra S, Curigliano G, Mitchell JD, Minotti G, Lang NN, Liu JE, Neilan TG, Nohria A, O'Quinn R, Pusic I, Porter C, Reynolds KL, Ruddy KJ, Thavendiranathan P, Valent P. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.Eur Heart J. 2022;43:280-99.
Gevaert SA, Halvorsen S, Sinnaeve PR, Sambola A, Gulati G, Lancellotti P, Van Der Meer P, Lyon AR, Farmakis D, Lee G, Boriani G, Wechalekar A, Okines A, Asteggiano R. Evaluation and management of cancer patients presenting with acute cardiovascular disease: a Consensus Document of the Acute CardioVascular Care (ACVC) association and the ESC council of Cardio-Oncology-Part 1: acute coronary syndromes and acute pericardial diseases.Eur Heart J Acute Cardiovasc Care. 2021;10:947-59.
Gevaert SA, Halvorsen S, Sinnaeve PR, Sambola A, Gulati G, Lancellotti P, Van Der Meer P, Lyon AR, Farmakis D, Lee G, Boriani G, Wechalekar A, Okines A, Asteggiano R, Combes A, Pfister R, Bergler-Klein J, Lettino M. Evaluation and management of cancer patients presenting with acute cardiovascular disease: a Clinical Consensus Statement of the Acute CardioVascular Care Association (ACVC) and the ESC council of Cardio-Oncology-part 2: acute heart failure, acute myocardial diseases, acute venous thromboembolic diseases, and acute arrhythmias.Eur Heart J Acute Cardiovasc Care. 2022;11:865-74. ?login=false
Roskoski R Jr. Targeting BCR-Abl in the treatment of Philadelphia-chromosome positive chronic myelogenous leukemia.Pharmacol Res. 2022;178:106156.
Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A, le Coutre P, Ottmann O, Heinrich MC, Steegmann JL, Deininger MWN, Janssen JJWM, Mahon FX, Minami Y, Yeung D, Ross DM, Tallman MS, Park JH, Druker BJ, Hynds D, Duan Y, Meille C, Hourcade-Potelleret F, Vanasse KG, Lang F, Kim DW. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.N Engl J Med. 2019;381:2315-26.
Dickerson T, Wiczer T, Waller A, Philippon J, Porter K, Haddad D, Guha A, Rogers KA, Bhat S, Byrd JC, Woyach JA, Awan F, Addison D. Hypertension and incident cardiovascular events following ibrutinib initiation.Blood. 2019;134:1919-28.
Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hübner N, Chien KR, Birchmeier C, Garratt AN. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.Proc Natl Acad Sci U S A. 2002;99:8880-5.
Ulrich L, Okines AFC. Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib.Breast Cancer (Dove Med Press). 2021;13:361-81.
Dent SF, Moore H, Raval P, Alder L, Guha A. How to Manage and Monitor Cardiac Dysfunction in Patients With Metastatic HER2-Positive Breast Cancer.JACC CardioOncol. 2022;4:404-8.
Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC, Peled N, Weiss J, Kim YJ, Ohe Y, Nishio M, Park K, Patel J, Seto T, Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, Falchook G, Ebata K, Nguyen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg SM, Goto K, Subbiah V. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.N Engl J Med . 2020;383:813-24.