Management of severe hypertension due to lenvatinib in patients with advanced thymic carcinoma

Abstract Rationale: Thymic carcinoma (TC) is a malignant mediastinal tumor, and there are no established treatments for pre-treated patients with advanced TC. Recently, lenvatinib was approved for such patients in Japan, ahead of other countries. Higher dose lenvatinib may be more efficacious than conventional treatments, although many patients experience grade 3 hypertension. Therefore, lenvatinib dose reduction remains controversial in terms of efficacy and tolerability. Patient concerns: Case 1 involves a 72-year-old woman who underwent complete resection of TC and was taking cilnidipine and azilsartan for hypertension. Six years later, multiple lung metastases were observed, and lenvatinib was started. Case 2 involves a 60-year-old man with TC, and was taking amlodipine for hypertension. A chest computed tomography showed progression in primary and metastatic lesions, and the patient started lenvatinib. Diagnoses: In both patients, grade 3 hypertension was observed after the administration of lenvatinib. Interventions: In Case 1, lenvatinib dose was reduced 3 times because lenvatinib was not interrupted despite grade 3 hypertension. In contrast, in Case 2, lenvatinib was interrupted when grade 3 hypertension occurred and was resumed after a decrease in blood pressure to baseline. Outcomes: In Case 2, higher tumor regression may have been achieved because of the maintenance of a high dose of lenvatinib compared with that in Case 1. Lessons: Lenvatinib is a promising agent for advanced TC; however, hypertension should be addressed cautiously, especially at the outset of administration. Lenvatinib may have to be appropriately interrupted and resumed as soon as the blood pressure is controlled to maximize efficacy and minimize toxicity.


Introduction
Thymic carcinoma (TC) is a mediastinal malignant tumor that accounts for 12% to 14% of all thymic epithelial tumors. [1] Although surgery is the first-line treatment, most patients are in an advanced stage when diagnosed, which results in a poor prognosis (5-year survival rate of 24.2%). [2] Therefore, cytotoxic chemotherapies are widely used to treat unresectable or metastatic TCs. In terms of efficacy and safety, carboplatin plus paclitaxel is the most recommended first-line treatment for advanced TC. [3] Second-line or higher systemic treatments include sunitinib, pemetrexed, everolimus, paclitaxel, octreotide, 5-fluorouracil, gemcitabine, and etoposide; however, these regimens are not sufficiently efficacious for TC treatment. [4] In March 2021, before other countries, lenvatinib was first approved for pre-treated patients with advanced TC based on the results of a phase 2 trial (REMORA) in Japan. [5] Although lenvatinib showed promising benefits for advanced TC, severe hypertension was reported at a high frequency. Several clinical trials have reported that lenvatinib causes hypertension; the detailed management approaches for lenvatinib doses remain unclear. Here, we present 2 advanced TC patients with hypertension to investigate the optimal dose adjustment of lenvatinib for severe hypertension.

Case 1
A 72-year-old woman, who underwent complete resection of TC 6 years ago, has had controlled hypertension (systolic blood pressure 140 mm Hg and diastolic blood pressure 100 mm Hg); she had been taking cilnidipine (10 mg/day) and azilsartan (20 mg/day). Multiple lung metastases were newly observed in chest computed tomography (CT), and therefore, lenvatinib (24 mg/day) was initiated. From the next day, the patient experienced continuous grade 3 hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg), and 3 antihypertensive agents were required to control hypertension (Fig. 1A). Despite lenvatinib dose reduction without interruption and the aggressive use of antihypertensive agents, grade 3 hypertension had recurred several times. Lenvatinib was decreased to 10 mg/day (3 steps of dose reduction) within 2 weeks of treatment initiation, and finally, interrupted by grade 3 thrombocytopenia, which was completely ameliorated with interruption alone. Lenvatinib was resumed at 4 mg/day, as her blood pressure dropped with the 3 antihypertensive agents. Two months after lenvatinib initiation, a chest CT revealed no remarkable changes in the existing lung metastases ( Fig. 2A). After lenvatinib resumption, grade 3 and higher hypertension was not observed for 4 months, but the patient has been using the 3 antihypertensive drugs.

Case 2
A 60-year-old man, who was diagnosed with TC by thoracoscopic biopsy, had been taking amlodipine (5 mg/day), and his hypertension was under control (systolic blood pressure 140 mm Hg and diastolic blood pressure 100 mm Hg). A chest CT showed the progression of primary lesion and increase in pulmonary and pleural metastases. Thus, lenvatinib (24 mg/day) was commenced as a second-line treatment. He experienced grade 3 hypertension (diastolic blood pressure ≥100 mm Hg) 2 days later, and lenvatinib was interrupted once (Fig. 1B). As his blood pressure dropped to the baseline level, lenvatinib was resumed at 20 mg/day. Lenvatinib at 20 mg/day was then maintained, along with 2 antihypertensive agents. Two months after the start of lenvatinib, a chest CT revealed a decrease in size of the target lesions (from 80.9-67.1 mm) (Fig. 2B). Grade 3 and higher hypertension was not observed with lenvatinib (20 mg/day) and 2 antihypertensive agents 4 months after lenvatinib resumption.

Discussion
Herein, we have presented the clinical course of 2 patients with advanced TC who received lenvatinib. A post hoc analysis of data of the phase 3 trial (SELECT) for thyroid cancer revealed that shorter interruptions of lenvatinib provided more favorable survival benefits. [6] Therefore, we compared patients who did not and did experience interruption in lenvatinib. To the best of our knowledge, this is the first report on drug interruption in patients with advanced TC, especially with pre-existing hypertension.
In the REMORA trial, lenvatinib demonstrated an objective response rate of 38% and a disease control rate of 95% in patients with previously treated advanced TC. [4] Although lenvatinib showed more promising efficacy than existing drugs, all patients experienced at least 1 level of dose reduction because of adverse events (AEs), and over 80% of the patients experienced 3 or more dose reductions.
Lenvatinib dose reduction remains controversial in terms of efficacy and tolerability. In another exploratory analysis of SELECT, a higher dose of lenvatinib contributed to greater tumor size reduction in the first 8 weeks. [7] In the REMORA trial, most patients also showed tumor regression when taking 20 to 24 mg/ day at first 8 weeks after administration. [4] These studies indicate that maximal benefits may be obtained by continuing the administration of lenvatinib at a dose as high as possible.
However, in the REMORA trial, the most common grade ≥3 AE was hypertension (64%), leading to dose reduction (24%). These figures cannot be overlooked and are similar to the results of the SELECT trial; the most frequent grade ≥3 AE was hypertension (41.8%), leading to dose reduction (19.9%). [8] Thus, hypertension is one of the most notable AEs associated with dose reduction. Moreover, in the REMORA trial, the median time to the first occurrence of hypertension was 8 days, which was earlier than the occurrence of any other toxicity, and 80% of the patients experienced hypertension within 8 weeks after lenvatinib administration. [4] These findings suggest that appropriate management of hypertensive toxicity is also essential for early treatment.
In Case 1, lenvatinib was continued without interruption to increase the dose intensity, which led to 3 dose reductions, resulting in no remarkable changes in tumor size. In Case 2, lenvatinib was appropriately interrupted and resumed after the blood pressure dropped; overall, a high dose was maintained and tumor size decreased. Thus, lenvatinib may have to be appropriately interrupted and resumed as soon as blood pressure is controlled to maximize efficacy and minimize toxicity.
In conclusion, this report highlights the importance of appropriate interruption of lenvatinib in hypertension patients with advanced TC. Lenvatinib is a promising agent for suppressing tumor progression, whereas hypertension should be addressed appropriately with drug interruption and antihypertensive agents, especially during the first 8 weeks of treatment initiation. Further studies are warranted to confirm the appropriate management of lenvatinib dosage in clinical settings.