Entrectinib-Induced Pericarditis with Cardiac Tamponade in a Patient with Neurotrophic Tropomyosin Receptor Kinase 1 Fusion-Positive Breast Cancer Open Access

Advances in clinical sequencing technologies have led to the discovery of the oncogenic drivers of multiple cancer types. Neurotrophic tyrosine receptor kinase (NTRK1/2/3), which encodes the tropomyosin receptor kinase (TRK) A/B/C, is known to play crucial roles in cell proliferation, differentiation, and survival. Gene fusions involving NTRK result in continuously active TRK proteins, which can act as potential oncogenic drivers in various adult and pediatric tumors [1]. Entrectinib is a multi-kinase inhibitor that targets TRK A/B/C, proto-oncogene tyrosine-protein kinase (ROS1), and anaplastic lymphoma kinase (ALK). It is approved for the treatment of patients with NTRK fusion-positive locally advanced or metastatic solid tumors and ROS1-positive metastatic non-small cell lung cancer (NSCLC).

Cardiotoxicity is a notable adverse effect of entrectinib. Of the 355 patients who received entrectinib across 3 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), congestive heart failure (CHF) and myocarditis were documented in 3.4 and 0.3% of cases, respectively [2]. However, complications such as pericarditis and cardiac tamponade have not been well-characterized in the literature. In this report, we present a case of entrectinib-induced pericarditis with cardiac tamponade in a patient with NTRK1 fusion-positive breast cancer, which resolved after withholding entrectinib and initiating appropriate management.

A 31-year-old female with a history of left breast cancer presented with dyspnea and orthopnea 21 days after initiating entrectinib. She was diagnosed with left breast cancer, stage cT2N0M0, at the age of 29 years. The cancer was negative for estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor 2 (HER2). The patient had no family history of cancer. As preoperative systemic therapy, the patient received four cycles of the AC regimen (doxorubicin 600 mg/m² and cyclophosphamide 600 mg/m²), resulting in a partial response, followed by four cycles of docetaxel (75 mg/m²), which led to progressive disease (PD). Subsequently, the patient underwent partial mastectomy and sentinel lymph node biopsy. The pathological diagnosis and stage were invasive ductal carcinoma, ypT2N0M0, and ypStage IIA, respectively. Immunohistochemistry revealed ER, PR, Ki67 index (5, < 1, and 61.4%, respectively), and HER2 0. Following postoperative radiotherapy of the residual breast, she was administered adjuvant chemotherapy (S-1) for 4 months until local recurrence in the left breast and metastasis to the lung and left axillary lymph nodes were found (Fig. 1a). Programmed death-ligand 1 (PD-L1) expression for both the 22C3 and SP142 assays was negative, and the patient had wild-type germline BRCA 1/2. First-line chemotherapy included weekly paclitaxel and bevacizumab. The best response was stable disease. Subsequently, she received an anti-trophoblast cell-surface antigen 2 (Trop-2) antibody-drug conjugate in a clinical trial and eribulin as third-line chemotherapy (the best response was PD). The patient was placed on entrectinib 600 mg/day after genetic evaluation (Foundation One Liquid CDx; Foundation Medicine, Cambridge Massachusetts) identified the CHTOP-NTRK1 fusion gene. Computed tomography (CT) scan before entrectinib treatment showed progressive enlargement of the local recurrence in the left breast and multiple lung metastases (Fig. 1b). The patient had no known cardiovascular risk factors, and the baseline electrocardiogram (ECG) and transthoracic echocardiography (TTE) findings were both within normal limits before initiating entrectinib.

Twenty-one days after commencing entrectinib, the patient presented to our hospital with dyspnea and orthopnea. On admission, she had a temperature of 37.3°C, respiratory rate of 17, and oxygen saturation of 96% on room air. She was hemodynamically stable, with a blood pressure of 125/72 mm Hg and a heart rate of 107 bpm. Laboratory examinations revealed elevated levels of inflammatory markers (C-reactive protein 17.93 mg/dL and white blood cell count 9.2 × 10⁹/L). The brain natriuretic peptide and troponin levels were slightly elevated (brain natriuretic peptide 90.6 pg/mL, troponin I 0.061 ng/mL). Her ECG showed a normal sinus rhythm and a flat T-wave. Chest radiography revealed an enlarged heart and bilateral pleural effusion. TTE revealed a moderate circumferential pericardial effusion with diastolic right atrial and ventricular collapse (Fig. 2a), indicative of cardiac tamponade. Left ventricular ejection fraction was preserved at 66.1%. The patient underwent percutaneous pericardiocentesis and pericardial drain placement, initially yielding 400 mL of pericardial effusion. The pericardial effusion was exudative, with an elevated neutrophil count. Pericardial effusion cytology results showed no malignant cells. Myocarditis and perimyocarditis were considered unlikely due to the absence of elevated cardiac biomarkers, including creatine kinase levels, on serial measurements, supporting a diagnosis of pericarditis. Entrectinib was considered the probable cause.

Therefore, entrectinib was immediately discontinued. In addition to oral loxoprofen, diuretics (intravenous furosemide, oral spironolactone, and tolvaptan, 20, 25, and 3.75 mg daily, respectively) and colchicine therapy were initiated. Considering the persistent pericardial effusion drainage (averaging 150 mL/day), oral dexamethasone 2.0 mg/day was initiated 4 days after drain placement. The drain output tapered, and the drain was removed on day 7. Follow-up TTE 16 days post-pericardiocentesis revealed no pericardial effusion reaccumulation (Fig. 2b), and chest radiography showed resolution of bilateral pleural effusions. A CT scan performed during hospitalization depicted enlargement of the existing lesions and the appearance of new lesions in the contralateral breast and skin, indicating disease progression (Fig. 1c). Owing to the development of cardiac tamponade and disease progression, we permanently discontinued entrectinib.

Twenty-three days after the discontinuation of entrectinib, the patient was started on larotrectinib (200 mg/day). There was no recurrence of pericardial effusion on follow-up echocardiography and CT. However, larotrectinib was discontinued after 14 days due to disease progression. We compiled a timeline of clinical events (Fig. 3).

To the best of our knowledge, this is the first reported case of entrectinib-induced pericarditis with cardiac tamponade. However, CHF and myocarditis have been reported to be adverse cardiovascular events associated with entrectinib treatment. According to the Federal Drug Administration (FDA) drug prescribing information, of the 355 patients who received entrectinib across 3 early clinical trials, CHF and myocarditis occurred in 12 and 1 (3.4 and 0.3%) patients, respectively [2]. To date, 4 real-world cases of cardiovascular adverse events caused by entrectinib have been reported: myocarditis in a 51-year-old female with ROS1 positive NSCLC [3], CHF in a 74-year-old female with NSCLC [4], right heart failure in a 45-year-old woman with NSCLC [5] and myocarditis in a 72-year-old man with ROS1 positive NSCLC [6]. Our patient, who had no history of cardiovascular disease, developed cardiac tamponade after entrectinib initiation. Her clinical symptoms and imaging findings improved after entrectinib discontinuation and appropriate medical management, including pericardiocentesis and steroid administration.

We administered larotrectinib, a TRK-selective inhibitor used to treat NTRK fusion-positive solid tumors, to continue the best cancer treatment while maintaining cardiovascular safety. Regarding grade 2 or 3 CHF, the FDA advises withholding entrectinib until recovery to less than or equal to grade 1 before recommencement at a reduced dose. Concerning grade 4 CHF, the FDA recommends permanent discontinuation of entrectinib [2]. In our patient, we decided to discontinue entrectinib and start treatment with larotrectinib. However, due to disease progression larotrectinib had to be discontinued after 2 weeks. There were no signs of cardiovascular toxicity, including pericarditis or cardiac tamponade, during or after the larotrectinib treatment.

In contrast to entrectinib, no cardiovascular adverse events have been associated with larotrectinib to date [7]. In a real-world pharmacovigilance analysis, larotrectinib demonstrated a lower frequency of cardiac events compared to entrectinib [8]. The exact mechanism underlying the cardiovascular toxicity of entrectinib remains unclear; however, the difference in the side effect profiles of entrectinib and larotrectinib could be partly explained by their varying selectivities. Larotrectinib selectively inhibits TRK, whereas entrectinib targets ALK and ROS1, in addition to TRK, which could potentially result in more off-target toxicities. Similar off-target mechanisms may be involved in the cardiotoxicity of entrectinib and ALK inhibitors, as ALK inhibitors are known to cause cardiotoxicity [9] and pericarditis [10]. Crizotinib, an ALK inhibitor, has been proposed to induce inadequate autophagic activity, thereby leading to mitochondrial injury and cardiomyocyte death [11]. The shared inhibition of ALK pathways between entrectinib and ALK inhibitors, along with similarities in their reported toxicity profiles, support the plausibility that entrectinib-induced pericarditis represents a reproducible, mechanism-based adverse event. Larotrectinib may be a viable alternative for patients unable to continue entrectinib therapy due to adverse cardiovascular events. Next-generation TRK inhibitors are being developed to overcome acquired resistance to first-generation tyrosine kinase inhibitors [12]. This could provide patients with additional treatment options.

Recognizing pericarditis and cardiac tamponade as a rare but potentially fatal adverse events of entrectinib therapy is crucial. Monitoring patients for the clinical signs and symptoms of pericarditis, cardiac tamponade and CHF is important for early diagnosis. Baseline and periodic cardiac evaluation using transthoracic echocardiography, ECG, and cardiac biomarkers may aid in early detection of cardiotoxicity. In cases where cardiovascular adverse events occur, immediate interruption of entrectinib and initiation of appropriate management, such as pericardiocentesis when indicated, is essential. Larotrectinib and other TRK inhibitors may be alternatives for patients who experience adverse cardiovascular events following entrectinib treatment. Further research is warranted to elucidate the mechanisms underlying entrectinib-associated cardiovascular toxicity and to explore strategies for its mitigation.

Ethical approval was not required for this study following the local guidelines. Written informed consent was obtained from the patient for treatment and publication of the case and images. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546503).

Dr. Shimomura reports grants and personal fees from Chugai Pharmaceutical and AstraZeneca, grants from Eisai, and personal fees from Pfizer, MSD, Nihon Medi-Physics, Exact Sciences, Daiichi Sankyo, Eli-Lilly, and Taiho Pharmaceutical, all outside the submitted work. Dr. Shimizu reports participation on a data safety monitoring board or advisory board for Daiichi Sankyo. The other authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funding.

A.A. drafted the manuscript. A.S. critically revised the manuscript. A.A., Y.Y., A.S., Y.K., T.T., A.K., S.K., Y.H., and C.S. were involved in the treatment of the patient. All the authors have approved the final manuscript.

The data supporting the findings of this study are not publicly available for privacy reasons, however, are available from the corresponding author upon reasonable request.