Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with , , and is now complete. Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2–50·3). At 4 months, 13 (72·2%; 95% CI 46·5–90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. Exelixis.

中文翻译：

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卡博替尼单药治疗晚期肾上腺皮质癌：单组 2 期试验

肾上腺皮质癌是一种罕见的恶性肿瘤，对全身化疗反应不佳。米托坦是唯一被批准治疗肾上腺皮质癌的疗法。卡博替尼是一种多激酶抑制剂，已被批准用于多种恶性肿瘤。这是第一个探讨卡博替尼在晚期肾上腺皮质癌患者中的抗肿瘤活性、安全性和药代动力学特征的前瞻性试验。这项由研究者发起的单臂 2 期试验在德克萨斯大学 MD 安德森癌症中心（美国德克萨斯州休斯顿）针对患有晚期肾上腺皮质癌的成年患者（年龄≥18 岁）进行。符合条件的患者患有组织学确诊的肾上腺皮质癌，不适合进行根治性手术，患有可测量的疾病，预计预期寿命至少为 3 个月，且东部肿瘤合作组 (ECOG) 表现状态为 0-2，有足够的器官功能。参与研究6个月内使用过米托坦的患者血清米托坦水平必须低于2 mg/L。患者每日口服卡博替尼 60 毫克，可选择减少剂量以控制不良事件。主要终点是 4 个月时的无进展生存期，对每个方案至少接受一剂研究药物的所有患者进行评估。这项研究已在 、 、 注册，现已完成。 2018年3月1日至2021年5月31日期间，我们招募了18名患者（10名男性和8名女性），他们都接受了至少一剂研究治疗。在 18 名患者中，8 名 (44%) 患者的 ECOG 体力状态为 0，9 名 (50%) 患者的体能状态为 1，1 名 (6%) 患者的体力状态为 2。中位随访时间为36·8 个月（IQR 30·2–50·3）。 4 个月时，18 名患者中有 13 名（72·2%；95% CI 46·5–90·3）无进展生存期，中位无进展生存期为 6 个月（95% CI 4·3 至未达到） 。一名患者仍在接受治疗。 18 名患者中有 11 名 (61%) 发生了 3 级或更严重的治疗相关不良事件。最常见的 3 级不良事件是脂肪酶升高（18 名患者中的 3 名 [17%]）、γ-谷氨酰转移酶浓度升高（2 名 [11%] 患者）、丙氨酸氨基转移酶浓度升高（2 名 [11%] 患者）、低磷血症（两名 [11%] 患者）和高血压（两名 [11%] 患者）。 18 名患者中有 1 名 (6%) 患有 4 级高血压。研究中没有发生与治疗相关的死亡。卡博替尼在晚期肾上腺皮质癌中显示出有希望的疗效，并且具有可管理和预期的安全性。卡博替尼单独使用以及与免疫检查点疗法联合使用的进一步前瞻性研究正在进行中。埃克利西斯。