Department of Dermatology, Skin Cancer Center, University Hospital Zurich, Zurich, Switzerland.
IRCCS Istituto Europeo di Oncologia, Milan, Italy.
Lancet Oncol. 2023 Dec;24(12):e461-e471. doi: 10.1016/S1470-2045(23)00334-0. Epub 2023 Jul 14.
Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases.
TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAF wild-type cohort and a BRAF mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAF wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAF mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAF wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141.
Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAF mutation-positive cohort; the BRAF wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAF mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAF wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAF mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAF wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAF mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAF wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAF mutation-positive cohort and two (13%) of 15 in the BRAF wild-type cohort. No treatment-related deaths occurred.
Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAF-mutated melanoma with CNS metastases.
F Hoffmann-La Roche.
靶向治疗和免疫疗法已显示在伴脑转移的黑色素瘤中有颅内活性，但仍存在未满足的需求，特别是对于有症状性脑转移的患者。我们旨在评估阿替利珠单抗联合 cobimetinib 或 vemurafenib 加 cobimetinib 在伴脑转移的黑色素瘤患者中的疗效。
TRICOTEL 是一项多中心、开放标签、单臂、2 期研究，分为两个队列进行：BRAF 野生型队列和 BRAF 突变阳性队列，在巴西、法国、德国、匈牙利、意大利、西班牙和瑞士的 21 家医院和肿瘤中心招募。纳入标准为年龄 18 岁或以上、未经治疗的转移性黑色素瘤、至少有一个维度为 5mm 或更大的脑转移、东部合作肿瘤学组（ECOG）体能状态为 2 或更低。BRAF 野生型队列的患者接受静脉注射阿替利珠单抗（840mg，每 28 天周期的第 1 天和第 15 天）加口服 cobimetinib（60mg，每天一次，第 1-21 天）。BRAF 突变阳性队列的患者接受静脉注射阿替利珠单抗（840mg，每 28 天周期的第 1 天和第 15 天）加口服 vemurafenib（720mg，每天两次）加口服 cobimetinib（60mg，每天一次，第 1-21 天）；第 1 周期暂停使用阿替利珠单抗。治疗持续至进展、毒性或死亡。主要终点是由独立审查委员会（IRC）使用改良实体瘤反应评价标准（RECIST）1.1 评估的至少 4 周间隔的确认颅内客观缓解率，由于 BRAF 野生型队列提前关闭，该队列未进行 IRC 评估的颅内客观缓解率的主要终点；而是报告了研究者评估的颅内客观缓解率。在至少接受一剂研究药物的所有患者中分析了疗效和安全性。该试验已停止入组，并在 ClinicalTrials.gov 上注册，编号为 NCT03625141。
2018 年 12 月 13 日至 2020 年 12 月 7 日，共纳入 65 例 BRAF 突变阳性队列患者；BRAF 野生型队列在纳入 15 例患者后提前关闭。BRAF 突变阳性队列的中位随访时间为 9.7 个月（IQR 6.3-15.0），BRAF 野生型队列为 6.2 个月（3.5-23.0）。IRC 评估的颅内客观缓解率在 BRAF 突变阳性队列中为 42%（95%CI 29-54），在 BRAF 野生型队列中为 27%（95%CI 8-55）。在 BRAF 突变阳性队列中，60 例接受阿替利珠单抗加 vemurafenib 加 cobimetinib 治疗的患者中，有 41 例（68%）发生与治疗相关的 3 级或更高级别的不良事件，最常见的是脂肪酶升高（60 例患者中有 15 例[25%]）和血肌酸磷酸激酶升高（60 例患者中有 11 例[18%]）。在 BRAF 野生型队列中，15 例接受阿替利珠单抗加 cobimetinib 治疗的患者中有 8 例（53%）发生与治疗相关的 3 级或更高级别的不良事件，最常见的是贫血（2 例[13%]）和痤疮样皮炎（2 例[13%]）。在 BRAF 突变阳性队列中，接受三联疗法的 60 例患者中有 14 例（23%）发生与治疗相关的严重不良事件，在 BRAF 野生型队列中，15 例中有 2 例（13%）。没有与治疗相关的死亡。
阿替利珠单抗联合 vemurafenib 和 cobimetinib 为伴脑转移的 BRAF 突变黑色素瘤患者提供了颅内活性。
F Hoffmann-La Roche。
