Kondo Masahiro, Nagao Yukiko, Hayashi Shohei, Wakita Eri, Noda Masato, Okada Itsuki, Wachino Chiharu, Yamada-Nishide Keiko, Hori Masayuki, Hotta Yuji, Matsuo Yoichi, Furukawa-Hibi Yoko
Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, Aichi, 467-8601, Japan.
Department of Pharmacy, Nagoya City University East Medical Center, 1-2-23 Wakamizu, Chikusa-Ku, Nagoya, Aichi, 464-8547, Japan.
J Pharm Health Care Sci. 2025 Sep 1;11(1):80. doi: 10.1186/s40780-025-00480-z.
V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations are present in approximately 5% of Japanese patients with colorectal cancer (CRC) who receive BRAF-targeted triplet therapy, consisting of encorafenib (a BRAF inhibitor), binimetinib (a mitogen-activated protein kinase inhibitor [MEKi]), and cetuximab. This combination therapy is associated with an increased risk of cardiac dysfunction (CD), primarily attributed to MEKi. However, the detailed clinical course of this adverse event remains unclear. Here, we report a case of severe symptomatic CD that developed during this triplet therapy.
The patient was a 70-year-old Japanese man diagnosed with BRAF-mutated CRC with multiple metastases. BRAF-targeted triplet therapy was initiated as a third-line treatment. His baseline left ventricular ejection fraction (LVEF) was 66% and he had no history of heart disease. On Day 106, a pharmacist conducting the patient's consultation suspected CD associated with binimetinib because of symptoms such as deterioration of general condition and dyspnea. The pharmacist immediately recommended an echocardiography that revealed a significant decline in LVEF to 33%. The patient was referred to a cardiologist and treatment with enalapril, followed by bisoprolol, was initiated while triplet therapy was discontinued. Within 1 week of treatment interruption, the patient's general condition improved rapidly and his symptoms resolved. Therefore, cancer treatment was resumed as doublet therapy without binimetinib. Under close multidisciplinary monitoring, no recurrence of CD symptoms was observed. Doublet therapy was continued until Day 168, when disease progression occurred. This exceeded the median progression-free survival reported in the phase III BEACON-CRC trial.
This case highlights two crucial insights into BRAF/MEK inhibitor-associated CD. First, even severe symptomatic CD can be effectively managed and reversed upon immediate discontinuation of binimetinib and initiation of cardiotropic medications. Second, in such a severe case, rapid recovery is observed. Once stabilized, BRAF-targeted treatment could be continued as doublet therapy without binimetinib to ensure safety and disease control. However, regular echocardiographic surveillance is essential, with an interval shorter than 4 months, based on the clinical course of this case. Additionally, early recognition of CD may be improved by closely monitoring patients' symptoms and complaints through a multidisciplinary approach.
在接受由恩考芬尼（一种BRAF抑制剂）、比美替尼（一种丝裂原活化蛋白激酶抑制剂[MEKi]）和西妥昔单抗组成的BRAF靶向三联疗法的日本结直肠癌（CRC）患者中，约5%存在V-Raf鼠肉瘤病毒癌基因同源物B1（BRAF）突变。这种联合疗法与心脏功能障碍（CD）风险增加相关，主要归因于MEKi。然而，这种不良事件的详细临床过程仍不清楚。在此，我们报告一例在这种三联疗法期间发生的严重症状性CD病例。
患者为一名70岁日本男性，被诊断为BRAF突变的CRC伴多发转移。BRAF靶向三联疗法作为三线治疗开始。他的基线左心室射血分数（LVEF）为66%，且无心脏病史。在第106天，进行患者咨询的药剂师因患者出现全身状况恶化和呼吸困难等症状怀疑与比美替尼相关的CD。药剂师立即建议进行超声心动图检查，结果显示LVEF显著下降至33%。患者被转诊至心脏病专家处，在停用三联疗法的同时开始使用依那普利治疗，随后使用比索洛尔。在治疗中断的1周内，患者的全身状况迅速改善，症状消失。因此，癌症治疗恢复为不含比美替尼的双联疗法。在多学科密切监测下，未观察到CD症状复发。双联疗法持续至第168天，此时疾病进展。这超过了III期BEACON-CRC试验报告的无进展生存期的中位数。
本病例突出了关于BRAF/MEK抑制剂相关CD的两个关键见解。第一，即使是严重症状性CD，在立即停用比美替尼并开始使用强心药物后也可得到有效管理和逆转。第二，在如此严重的病例中，可观察到快速恢复。一旦病情稳定，BRAF靶向治疗可作为不含比美替尼的双联疗法继续进行，以确保安全性和疾病控制。然而，根据本病例的临床过程，定期进行超声心动图监测至关重要，间隔应短于4个月。此外，通过多学科方法密切监测患者的症状和主诉可能会改善对CD的早期识别。
