Movva Sujana, Seier Kenneth, Avutu Viswatej, Banks Lauren B, Chan Jason, Chi Ping, Dickson Mark A, Gounder Mrinal M, Kelly Ciara M, Keohan Mary L, Maki Robert, Rosenbaum Evan, Salcito Tiffany, Rodriguez Kaithleen, Dempsey Rebecca, Meyers Paul A, Cohen Seth M, Hensley Martee L, Konner Jason A, Schram Alison M, Lefkowitz Robert A, Erinjeri Joseph P, Qin Li-Xuan, Tap William D, D'Angelo Sandra P
Department of Medicine, Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medical College, New York, New York.
Clin Cancer Res. 2024 Dec 16;30(24):5612-5619. doi: 10.1158/1078-0432.CCR-24-2519.
Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma.
This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety.
Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively.
We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.
转移性肉瘤患者的生存率仍然很低，迫切需要新的治疗方法。大多数肉瘤亚型对单独的免疫检查点抑制无反应。乐伐替尼是一种靶向肿瘤血管系统的多受体酪氨酸激酶抑制剂，具有免疫调节活性，有助于其抗肿瘤作用。因此，我们假设乐伐替尼和帕博利珠单抗联合使用将改善肉瘤患者的临床结局。
这是一项针对乐伐替尼和帕博利珠单抗的开放标签单臂研究，入组队列如下：（A）平滑肌肉瘤，（B）未分化多形性肉瘤（UPS），（C）血管肉瘤（血管肉瘤和上皮样血管内皮瘤），（D）滑膜肉瘤或恶性外周神经鞘瘤（MPNST），以及（E）骨肉瘤（骨肉瘤和软骨肉瘤）。主要终点是各队列中依据RECIST v1.1在27周记录的最佳总体缓解（BOR）率，阈值为10例患者中≥2例缓解。次要终点包括无进展生存期、总生存期、缓解持续时间和安全性。
46例患者可评估主要终点，UPS队列和MPNST/滑膜队列达到该终点（27周时BOR率分别为25%和30%）。总体有7例部分缓解，血管肉瘤和骨肉瘤中也有额外缓解。任何级别的治疗相关不良事件和3级或更高级别的不良事件分别发生在50/51（98%）和29/51（57%）的患者中。
我们在MPNST、滑膜肉瘤和骨肉瘤中观察到持久缓解。UPS和血管肉瘤患者也有反应。有必要进一步探索这种方法以确认活性并确定最佳给药方案。
