Abstract
Aims
Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib‐related cardiotoxicity in mRCC patients.
Methods
We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echocardiogram and plasma biomarkers assay were assessed at baseline, 3 and 6 months after cabozantinib initiation.
Results
The study population included 22 mRCC patients. At baseline, 9.1% had a reduced left ventricular ejection fraction (LVEF), but none had a left ventricular systolic dysfunction. Patients with baseline reduced LVEF did not show further significant LVEF modification after 3 months. After 6 months, only 1 had an LVEF decline >10% compared to baseline, resulting in LV systolic dysfunction. At baseline, 64.7% and 27.3% of patients had elevated precursor brain natriuretic peptide (proBNP) and high‐sensitivity troponin I (hsTnI), respectively. Among patients with basal normal proBNP and hsTnI, none had elevated values at 3 and 6 months. No correlation was found between basal elevated proBNP and basal reduced LVEF (P = .29), and between elevated proBNP and reduced LVEF after 6 months (P = .37). Similarly, we found no correlations between elevated hsTnI and reduced LVEF or elevated proBNP at baseline (P = .47; P = .38), at 3 (P = .059; P = .45) and after 6 months (P = .72; P = 1.0).
Conclusions
This prospective study revealed a modest risk of developing left ventricular systolic dysfunction related to cabozantinib. A lack of correlation between elevated cardiac biomarkers and reduced LVEF at different time‐points was detected. Assessments of the cardiac function should be reserved at the occurrence of clinical symptoms.
Keywords: cabozantinib, cardiotoxicity, high‐sensitivity troponin I, metastatic renal cell carcinoma, precursor brain natriuretic peptide
1.
What is already known about this subject
Vascular endothelial growth factor receptor tyrosine kinase inhibitors have associated cardiotoxic effects, with a mechanism that is not yet intimately known.
No prospective data are available regarding the impact of cabozantinib on the myocardial function.
What this study adds
A modest risk of developing left ventricular systolic dysfunction was found in a prospective cohort of 22 mRCC patients treated with cabozantinib.
No correlation between elevated high‐sensitivity troponin I and precursor brain natriuretic peptide and reduced left ventricular ejection fraction was found.
Cardiac function assessments can be reserved only in case of clinical symptoms.
2. INTRODUCTION
Small‐molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptors (VEGFRs)—sunitinib, pazopanib, sorafenib, axitinib and cabozantinib—have revolutionized the treatment algorithm of patients with metastatic renal cell carcinoma (mRCC), by improving clinical outcomes in randomized phase III trials.1 In the last 10 years, as a result of the routine use of VEGFRs‐TKIs in clinical practice, the median overall survival (OS) of mRCC patients reached 30 months, with variations depending on the patients prognostic risk group. Cabozantinib (a MET, VEGFRs and AXL TKI) represents the only one that demonstrated an OS—besides progression‐free survival (PFS) and objective response rate—advantage compared with everolimus in pretreated mRCC patients in the phase III METEOR study.2 Moreover, a phase II study (CABOSUN trial) tested the activity of cabozantinib in first‐line in previously untreated mRCC patients of intermediate‐ or poor‐risk according to the International Metastatic Renal Cell Carcinoma Database Consortium risk model.3 Albeit with concerns regarding the relatively poor efficacy of the control arm in which sunitinib had worse survival than expected, cabozantinib resulted in significant PFS and objective response rate improvements also in this setting.4 Indeed, cabozantinib is broadly recognized as a valid therapeutic option for mRCC management.
It has become clear that VEGFRs‐TKIs have associated cardiotoxic effects, such as hypertension, asymptomatic left ventricular (LV) dysfunction, up to congestive heart failure (CHF).4, 5, 6, 7, 8 The drug inhibition of tyrosine kinases normally expressed in non‐neoplastic tissues (including the myocardium and blood vessels) might be responsible for this toxicity. The precise mechanism underlying anti‐VEGFRs‐related cardiotoxicity is not yet intimately known, but is probably being the result of multiple concurrent cofactors. The blockade of VEGF signalling pathway, which plays a key role in preserving cardiac function and cardiomyocyte homeostasis, together with the inhibition of specific kinases (i.e. RSK, AMPK, PDGFR) involved in cardiomyocytes energy metabolism and survival pathway, could at least partially explain the drug‐induced myocyte loss and LV dysfunction.9 Moreover, other TKIs‐related adverse events—including hypothyroidism and hypertension (the latter leading to a decreased vasodilatory nitric oxide production and to capillary density rarefaction)—could indirectly contribute at compromising myocardial function.10
Although the overall cardiotoxic effects of VEGFRs‐TKIs therapy seem not to be excessive, the exact magnitude of the problem and its management has yet to be defined. In particular, no prospective data are available regarding the impact of cabozantinib on the myocardial function. Therefore, we performed a multicentre prospective study to assess the risk of cabozantinib‐related cardiotoxicity in a cohort of mRCC patients.
3. METHODS
3.1. Patients
Between October 2016 and November 2017, patients affected by mRCC referring to the Oncology Departments of 3 Italian tertiary hospitals, were screened to find those with disease progression to a prior oncological treatment and candidates to start a new line of therapy with cabozantinib.
Prior to the start of cabozantinib, we performed a detailed review of patients' medical history, including prior cardiac events, cardiovascular risk factors, and current medications. Moreover, we assessed clinical features (symptoms recording and cardiac medication use), blood pressure measurement, blood sample collection for plasma biomarkers assay, and transthoracic echocardiogram at baseline (before the start of cabozantinib), and during follow‐up visits at 3 months (12 weeks ±7 days) and 6 months (at 24 weeks, ±7 days) after cabozantinib initiation.
Cabozantinib starting dose and dose adjustments were at oncologist's choice. The decision to initiate antihypertensive or other cardiovascular medications was at the discretion of the treating medical provider. The approval of the Ethics Committee was obtained for this study.
3.2. Cardiac eligibility criteria
We only enrolled patients who had a screening before the initiation of cabozantinib therapy with an LV ejection fraction (LVEF) ≥ 50% measured by echocardiography.
On the contrary, we excluded patients with a history of documented coronary artery disease (angina pectoris requiring anti‐anginal medication or transmural infarction on electrocardiography), CHF, clinically significant valvular disease, high‐risk arrhythmias or uncontrolled hypertension (blood pressure systolic ≥180 mmHg or diastolic ≥100 mmHg).
3.3. Doppler echocardiographic LV systolic function quantitation and definition of LV systolic dysfunction
The participating centres performed transthoracic echocardiograms with the assessment of LVEF according to a standardized protocol at baseline (within 7 days of starting treatment with cabozantinib) and during follow‐up visits—3 months (at 12 weeks, ±7 days) and 6 months (at 24 weeks, ±7 days) after cabozantinib initiation.
Quantitation of end‐systolic and end‐diastolic LV volumes was performed. Definition of LVEF derived from the stroke volume, defined as the difference between end‐diastolic and end‐systolic volumes, divided by the end‐diastolic volume.11 We defined reduced LV systolic function as a LVEF <55%; and LV systolic dysfunction as an absolute decline in the LVEF by ≥10% to a resultant value of <50%12, 13 (Table 1).
Table 1.
Definition of left ventricular function
| Outcome | Definition |
|---|---|
| LVEF | The difference between end‐diastolic and end‐systolic volumes divided by the end‐diastolic volume |
| Reduced LV systolic function | LVEF <55% |
| LV systolic dysfunction | An absolute decline in the LVEF by ≥10% to a resultant value of <50% |
LV, left ventricular; LVEF, left ventricular ejection fraction.
3.4. Biomarker analyses
Quantitatively measures of high‐sensitivity troponin I (hsTnI) and precursor brain natriuretic peptide (proBNP) were performed according to standardized local procedures. We considered abnormal elevation in hsTnI > 99th percentile for a population with, or at risk for, comorbid cardiovascular disease (>45 ng/L) and elevation in proBNP > 450 ng/L.
We scheduled to perform hsTnI and proBNP measures at baseline (within 3 days of starting treatment with cabozantinib), and during follow‐up visits 3 months (at 12 weeks, ±1 day), and 6 months (at 24 weeks, ±1 day) after the initiation of cabozantinib.
3.5. Statistical analysis
Patients were eligible for analysis if they received cabozantinib therapy and underwent at least a baseline echocardiogram and clinical assessment. A previous study reported a decrease of the LVEF >10% with sunitinib in the 28% of patients.5 We hypothesized that cabozantinib would increase the incidence of LVEF decline >10% from 28 to 50%. Thirty‐eight patients were necessary to achieve 80% power to show this difference with α error of .05 (2‐tailed P). Unfortunately, the study was stopped early due to low accrual and the results of the first 22 patients enrolled are reported here.
We used descriptive statistics to characterize key demographic and clinical variables at baseline; this was defined as the date of starting of cabozantinib therapy. We evaluated the OS from the starting of cabozantinib to death or last follow‐up whichever occurred first; and the progression‐free survival (PFS) from the starting of cabozantinib therapy to disease progression according to RECIST v1.1 criteria. Patients who did not experience an event of interest were censored at the date of last follow‐up. We used the Kaplan–Meier method to analyse the time‐to‐event endpoints of mRCC‐specific survival. Spearman correlation was used to evaluate correlations between categorical variables, including biomarkers (hsTnI and proBNP) assay and changes in LVEF.
All the variables were significant if P < .05. We used PASW (Predictive Analytics SoftWare; v 21; IBM SPSS) for the analysis.
3.6. Nomenclature of targets and ligands
Key protein targets and ligands in the article are hyperlinked to corresponding enteries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS guide to PHARMACOLOGY14 and are permanently archieved in the Concise Guide to PHARMACOLOGY2017/18.15, 16
4. RESULTS
4.1. Study population
A total of 22 renal cell carcinoma patients had criteria to be included in the analysis. Ten out of 22 patients received cabozantinib as second‐line therapy, the remaining as third‐ to fifth‐line therapy. Baseline characteristics of the included patients are reported in the Table 2.
Table 2.
Baseline patient characteristics
| Clinical feature | n (%) |
|---|---|
| Median age (y) | 67 |
| Tumour histology | |
| Clear cell RCC | 19 (86.4%) |
| Non‐clear cell RCC | 3 (13.6%) |
| Prior nephrectomy | 20 (90%) |
| IMDC prognostic class | |
| Good | 2 (9.1%) |
| Intermediate | 16 (72.7%) |
| Poor | 4 (18.2%) |
| Number of prior systemic line(s) | |
| 1 | 10 (45.5%) |
| 2 | 6 (27.3%) |
| ≥3 | 6 (27.3%) |
| Cardiovascular comorbidities (before cabozantinib initiation) | |
| Hypertension | 16 (72.7%) |
| Ischaemic heart disease | 2 (9.1%) |
| Arrhythmias | 2 (9.1%) |
| Starting dose of cabozantinib | |
| 60 mg daily | 21 (95.5%) |
| 40 mg daily | 1 (4.5%) |
| 20 mg daily | 0 (0%) |
| Dose reduction during cabozantiniba | |
| Yes | 17 (77.3%) |
| No | 5 (22.7%) |
Cabozantinib dose reduction due to adverse events, according to physicians' choice.
IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; RCC, renal cell carcinoma.
4.2. Incidence of LV systolic dysfunction
At baseline, 9.1% of patients had a lower‐than‐normal (reduced) LVEF (50–55%; Table 3). Median LVEF value at baseline was 60% (IQR 59–66).
Table 3.
Cardiac function assessments
| Pt | Echocardiography (LVEF %) | proBNP (>UNL) | hsTnI (>UNL) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline | At 3 mo | At 6 mo | Baseline | At 3 mo | At 6 mo | Baseline | At 3 mo | At 6 mo | |
| 1 | 64 | 65 | 61 | Y | N | Y | N | N | N |
| 2 | 64 | NA | NA | N | NA | NA | N | NA | NA |
| 3 | 60 | 60 | 67 | Y | Y | N | N | N | N |
| 4 | 69 | 66 | 66 | N | N | N | N | N | N |
| 5 | 70 | 60 | 47 | Y | N | Y | N | N | N |
| 6 | 57 | 56 | NA | N | N | N | N | N | N |
| 7 | 52 | 55 | NA | Y | Y | NA | N | N | NA |
| 8 | 66 | 60 | 58 | Y | Y | Y | N | N | N |
| 9 | 62 | 62 | 64 | Y | Y | NA | Y | N | N |
| 10 | 51 | 51 | 64 | Y | N | N | Y | Y | Y |
| 11 | 67 | NA | NA | Y | Y | Y | Y | Y | Y |
| 12 | 60 | NA | NA | Y | NA | NA | N | NA | NA |
| 13 | 70 | 67 | NA | N | N | NA | Y | Y | NA |
| 14 | 61 | 68 | NA | N | N | NA | Y | Y | NA |
| 15 | 66 | 57 | NA | N | N | NA | Y | Y | Y |
| 16 | 60 | 60 | NA | NA | NA | NA | N | N | NA |
| 17 | 60 | 60 | NA | NA | NA | NA | N | N | NA |
| 18 | 60 | 60 | NA | Y | NA | NA | N | N | NA |
| 19 | 55 | 55 | NA | NA | NA | NA | N | N | N |
| 20 | 55 | NA | NA | NA | NA | NA | N | N | NA |
| 21 | 60 | 60 | NA | Y | NA | NA | N | N | NA |
| 22 | 60 | 60 | NA | NA | NA | NA | N | N | NA |
hsTnI, high‐sensitivity troponin I; LVEF, left ventricular ejection fraction; N, No; NA, not available; proBNP, precursor brain natriuretic peptide; Pt, patient; UNL, upper normal limit; Y, yes.
After 3 months of cabozantinib therapy, 18 patients were available for the analysis, 5.5% of whom had reduced LVEF. Median LVEF value at 3 months was 60% (IQR 57–63).
After 3 months of therapy, 33.3% of patients had a decline of the LV systolic function, and a total of 11.1% had a LV systolic function decline of more than 10% compared to the basal value. No patients after a decline in the LVEF had a resultant value of <50%. There was no association between LV systolic function decline and clinical symptoms. Patients with baseline reduced LVEF did not show further significant modification of the LVEF after 3 months of cabozantinib.
After 6 months of therapy, 7 patients were evaluable for the analysis. Median LVEF value at 6 months was 64% (IQR 59.5–65). One patient had reduced LV systolic function. There was no statistically significant difference between the baseline and 6‐months median LV systolic function (P = .64).
After 6 months of cabozantinib therapy, we observed a decline of the LV systolic function compared to baseline in 57.1% of patients, of whom only 1 had a LVEF decline of >10% compared to the basal value. This patient had a LV systolic dysfunction, with a resultant LVEF value of 47% (his detailed clinical history is reported below).
4.3. Changes in cardiac biomarkers
At baseline, 17 patients were available for the analysis. 64.7% of patients (n = 11) had basal elevated proBNP values—upper normal limit (UNL). After 3 months of cabozantinib, 13 patients were evaluable, 40% of which had elevated proBNP values. After 6 months of therapy, data from 8 patients were available, 50% of whom had elevated BNP values (Table 3).
Among patients with basal normal proBNP, at 3 and 6 months no patients had elevated proBNP values.
Among patients with basal elevated proBNP, at 3 months only 1 out of 9 patients had persistent high proBNP (the relative increase was of 9.35%); and at 6 months only 6 patients were evaluable, 4 of whom had persistent elevated proBNP. We found no correlation between basal elevated proBNP and basal reduced LVEF (rs = .27, P = .29). Similarly, after 6 months of cabozantinib, the presence of elevated proBNP values did not significantly correlate with reduced LV systolic function (rs = .45, P = .37).
At baseline, 27.3% of patients had basal elevated hsTnI values—UNL. At 3 months, 25% of patients had hsTnI UNL values. After 6 months of cabozantinib, 27.3% of patients had elevated hsTnI (Table 3).
Among patients with basal normal hsTnI, at 3 and 6 months no patients had elevated hsTnI values. On the contrary, among patients with basal elevated hsTnI, at 3 months 5 out 6 patients had persistent elevated hsTnI values; and at 6 months 3 out of 4 patients had elevated hsTnI. We documented no significant change in hsTnI values after 3 months of cabozantinib.
We found no correlations between basal elevated hsTnI values and basal reduced LV systolic function (rs = .16, P = .47), and basal elevated proBPN (rs = −.23, P = .38).
Analogously, after 3 months of therapy, no correlations were found between elevated hsTnI and reduced LVEF (rs = .45, P = .059), and elevated proBPN values (rs = −.23, P = .45).
After 6 months of cabozantinib, we found no correlations between elevated hsTnI values and reduced LV systolic function (rs = − .17, P = .72), and elevated proBPN (rs = 0, P = 1.0).
4.4. Characteristics and clinical course of patients who developed cardiovascular events
One patient (a 69‐year‐old man) had a sudden death after 4 month of cabozantinib as third‐line therapy. The patient received 13 months of first‐line treatment with sunitinib, and 24 months of axitinib as second‐line. The only cardiovascular comorbidity was therapy‐induced hypertension treated with ramipril 2.5 mg daily. At the beginning of cabozantinib, the patient had reduced LV systolic function (LVEF of 52%), elevated basal proBNP, and normal hsTnI value. During cabozantinib treatment, we saw no changes in the LVEF and proBNP reduced from 620 to 219 ng/L after 3 months of therapy. We observed no modification in the hsTnI. We considered the sudden death to be not directly related to cabozantinib. The patient's autopsy was not carried out.
One 57‐year‐old woman developed a LV systolic dysfunction after 6 months of cabozantinib therapy. The patient was treated with sunitinib as first‐line, with a progression‐free survival of 29 months. At disease progression, she received second‐line therapy with axitinib for 6 months, and third‐line treatment with everolimus for 7 months. She had no cardiovascular comorbidity. At the beginning of cabozantinib, she had normal LV systolic function (LVEF of 70%), elevated basal proBNP, and normal hsTnI value. During cabozantinib, we did not observe modification in the hsTnI; while proBNP values remained persistently elevated. After 3 months of therapy, the LVEF decreased <10% compared to the basal value (LVEF of 60%), and after 6 months of cabozantinib, the LVEF diminished to 47%. This LV systolic dysfunction was completely asymptomatic. The patient started antihypertensive medications with ramipril 2.5 mg daily and bisoprolol 1.25 mg daily, as indicated by the cardiologist, and continued cabozantinib without dose reduction. After 1 month, the LV systolic function was re‐escalated to 55%.
4.5. Treatment outcomes
After a median follow‐up of 14.3 months, 18 patients progressed to cabozantinib therapy and 11 patients died. The median PFS was 6.1 months (95% CI, 2.4–9.9 months) and the median OS was 11.1 months (95% CI, .0–22.2 months).
5. DISCUSSION
The potential impact on cardiac function of VEGFR‐TKI drugs is of utmost importance in mRCC management, given their crucial role in the treatment of this malignancy. In particular, the precise frequency, diagnosis and natural evolution of anti‐VEGFR‐related cardiotoxicity have yet to be definitely outlined.
To date, the greatest body of evidence regarding TKIs‐associated cardiovascular toxicity is related to sunitinib therapy.5, 6, 7, 8, 17, 18 A meta‐analysis of 16 prospective clinical trials (seven of which included RCC patients) confirmed the increased risk of developing sunitinib‐related CHF (risk ratio 1.81; 95% CI 1.30–2.50; P < .001), even if with a low frequency (4.1%). Moreover, sunitinib was associated with a low incidence of high‐grade CHF (1.5%), which however translated into a tripled risk of developing serious cardiovascular events (risk ratio 3.30; 95% CI 1.29–8.45; P < .01).7 Recently, a prospective study evaluating the sunitinib‐induced cardiotoxicity in a cohort of 90 mRCC patients upheld very modest—although statistically significant—declines in LVEF (1.9%; P = .007). The development of LV dysfunction (estimated with a 9.7% probability) tended to occur early during the treatment course—generally within the 1st month of therapy—and to recover to baseline values without the need of disrupting sunitinib therapy.8
The widespread diffusion of cabozantinib in the treatment algorithm of mRCC raised the question about the clinical effects of its exposure on cardiac function. Of note, the development of hypertension as a result of cabozantinib therapy represents 1 of the most frequently reported side effects,19, 20 with an incidence of 37% in the METEOR trial (15% of grade 3–4) and of 81% in the CABOSUN study (28% of grade 3–4).2, 3 A meta‐analysis of randomized trials of cabozantinib (in different indications) confirmed the increased risk of developing all‐ and high‐grade hypertension, the latter of which had a substantially higher frequency compared to other approved VEGFRs‐TKIs (sorafenib, sunitinib, and pazopanib).19 However, to date no prospective data are available regarding the incidence of LV systolic function impairment related to cabozantinib treatment.
Therefore, in order to shed light on the epidemiology, severity, and clinical evolution of cabozantinib‐induced cardiotoxicity, we performed a prospective study evaluating changes in LVEF in a real‐world mRCC population. In particular, we analysed potential subclinical impairment of the cardiac function through echocardiography, and we evaluated cardiomyocytes injury biomarkers assays—including hsTnI and proBNP—as possible surrogate indicators of preclinical myocardial damage.
Our study revealed an extremely modest risk of developing LV systolic dysfunction—only 1 asymptomatic case, which recovered spontaneously and did not require cabozantinib dose‐reduction or treatment discontinuation. A LVEF decline of >10% was observed in 11.1% of cases after 3 months of therapy, the clinical relevance of which is questionable as it was not associated with clinical symptoms or with LV systolic dysfunction.
In addition, we did not observe worsening of the LV systolic function in the 2 patients who had a basal reduced LVEF at the beginning of cabozantinib therapy. However, our population did not include patients with LV systolic dysfunction (LVEF <50%), therefore providing no evidence to support the use of cabozantinib in this subset. Moreover, being a real‐world mRCC cohort, some patients had pre‐existing cardiovascular comorbidities, including hypertension (73% of cases), ischaemic heart disease (9.1%), and arrhythmias (9.1%). This is a potential limit of our study, but it could actually be considered at the same time a point of strength. Indeed, we demonstrated the lack of an increased risk of developing cardiac dysfunction in patients with cardiovascular comorbidities, therefore supporting the use of cabozantinib even in daily clinical practice.
Moreover, we prospectively evaluated increases in plasma cardiac biomarkers as potential early indicators of myocardial injury occurring even in the absence of clinically meaningful LV systolic dysfunction. Indeed, proBNP and hsTnI changes were reported as sensitive markers of drug‐related early cardiac distress.8, 21, 22
Our analysis failed to detect a significant correlation between elevated proBNP or hsTnI and reduced LVEF at different time‐points after the initiation of cabozantinib therapy. Interestingly, a substantial proportion of patients had baseline hsTnI and proBNP abnormalities, as a potential consequence of various confounders (including medical cardiovascular comorbidities, tumour burden and prior antiangiogenic therapies), therefore impairing the clinical utility of these cardiac biomarkers. To further support the supposed futility for hsTnI or proBNP in this setting, among patients with normal baseline values, we did not observe increase in these biomarkers during cabozantinib therapy.
One of the major limits of our study concerns the small sample size, which requires additional studies to validate our findings in larger cohorts. Moreover, the limited number of patients enrolled did not allow assessing the correlation between cabozantinib‐related cardiotoxicity and oncological outcomes.
Taken together these data support the safety of cabozantinib cardiovascular profile, which can be considered substantially similar to that of the other VEGFR‐TKIs. To our knowledge, this is the first prospective study to analyse cabozantinib‐induced cardiotoxicity using predefined detailed assessments of cardiac function obtained at standardized time‐points with echocardiographic evaluations. In addition, the recruitment of a real‐word patient population with common medical comorbidities allows for generalizability of these results to mRCC patients of routine clinical practice. Therefore, these findings give important behavioural guidelines for monitoring and managing cardiotoxicity related to cabozantinib therapy. A routine assessment of the cardiac function should be avoided in asymptomatic patients—given the low probability of a relevant clinical benefit—while reserved at the occurrence of clinical symptoms.
AUTHOR CONTRIBUTIONS
R.I., C.C., and G.T., study design, manuscript draft and final correction. R.I. and C.C., statistical analysis. G.F., V.D.N., C.M., S.E.R., E.F., D.B., and M.G. collection of data. F.G., F.M., A.A., and G.T., correction of the final version.
COMPETING INTEREST
R.I. consulting or advisory role to Ipsen, Pfizer, Novartis, MSD, BMS. Other authors have no competing interests to declare.
Iacovelli R, Ciccarese C, Fornarini G, et al. Cabozantinib‐related cardiotoxicity: A prospective analysis in a real‐world cohort of metastatic renal cell carcinoma patients. Br J Clin Pharmacol. 2019;85:1283–1289. 10.1111/bcp.13895
The authors confirm that the PI for this paper is Dr Roberto Iacovelli and that he had direct clinical responsibility for patients.
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