Université Paris Cité, INSERM U976 HIPI, Paris, France; Department of Dermatology, DMU ICARE, AP-HP Saint-Louis Hospital, Paris, France.
Université Paris Cité, INSERM U1153, Team ECSTRRA, Paris, France; Department of Biostatistics and Medical Information, AP-HP Saint-Louis Hospital, Paris, France.
Lancet Oncol. 2022 Apr;23(4):491-500. doi: 10.1016/S1470-2045(22)00097-3. Epub 2022 Mar 10.
Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment.
We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0-1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants.
30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1-24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44-90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths.
In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma.
MSD France.
虽然医源性和 HIV 相关卡波西肉瘤的治疗已得到明确界定，且主要基于恢复免疫功能，但经典型和地方性卡波西肉瘤的治疗则尚未明确。对于广泛皮肤或内脏卡波西肉瘤的患者，化疗或干扰素α用于治疗，但可能耐受性差，且长期缓解罕见。我们旨在评估帕博利珠单抗在需要全身治疗的具有皮肤扩展的经典型和地方性卡波西肉瘤中的活性。
我们在法国的三家医院进行了一项多中心、单臂、概念验证、2 期试验，纳入了 18 岁及以上的组织学证实的经典型或地方性卡波西肉瘤患者，这些患者具有进行性皮肤扩展，需要全身治疗，东部合作肿瘤学组（ECOG）体能状态为 0-1。患者接受 200mg 帕博利珠单抗静脉输注，每 3 周 1 次，持续 6 个月（8 个周期）或直至发生严重毒性。主要终点是 6 个月时间内的最佳总体缓解率，根据完全缓解或部分缓解的发生情况，由研究者采用改良的艾滋病临床试验组（ACTG）标准评估。在总共 17 例患者中，需要出现 3 例或更多缓解才能达到主要终点，采用 Simon 的两阶段最优设计，假设 30%的缓解率是理想的。对于最终的研究分析，所有患者均按照意向治疗原则进行了纳入。该研究在 ClinicalTrials.gov 上注册，编号为 NCT03469804，目前已对新入组患者关闭。
有 30 例患者进行了筛选，17 例患者（8 例[47%]为经典型，9 例[53%]为地方性）被纳入研究，时间为 2018 年 7 月 2 日至 2019 年 12 月 16 日。中位随访时间为 20.4 个月（IQR：18.1-24.1）。2 例（12%）患者有完全缓解，10 例（59%）有部分缓解，5 例（29%）疾病稳定是 6 个月治疗时间内的最佳反应，总体缓解率为 71%（95%CI：44-90），达到了预先设定的主要终点（即缓解率超过 30%）。17 例患者中有 13 例（76%）发生了与治疗相关的不良事件，包括 2 例 3 级不良事件（1 例[6%]急性心功能失代偿和 1 例[6%]肉芽肿性反应）。由于 3 级急性可逆性心功能失代偿和 2 级胰腺炎，2 例（12%）患者提前停止治疗，另有 1 例患者纵隔淋巴结出现 3 级肉芽肿性反应，需要使用类固醇和甲氨蝶呤治疗。没有严重不良事件或治疗相关死亡。
在这项前瞻性试验中，帕博利珠单抗在我们所知的首个评估 PD-1 阻断在经典型和地方性卡波西肉瘤患者中的作用的试验中表现出了有希望的抗肿瘤活性，且具有可接受的安全性特征。如果这一结果得到进一步研究的支持，抗 PD-1 治疗可能成为经典型和地方性卡波西肉瘤患者的治疗手段之一。
MSD 法国。
