Patel Sapna P, Kim Dae Won, Bassett Roland L, Cain Suzanne, Washington Edwina, Hwu Wen-Jen, Kim Kevin B, Papadopoulos Nicholas E, Homsi Jade, Hwu Patrick, Bedikian Agop Y
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
Moffitt Cancer Center, 12902 USF Magnolia Dr., Tampa, FL, 33612, USA.
Cancer Immunol Immunother. 2017 Oct;66(10):1359-1366. doi: 10.1007/s00262-017-2030-y. Epub 2017 Jun 13.
Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m orally days 1-4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.
检查点阻断疗法彻底改变了黑色素瘤的治疗方式；然而，它仅使少数患者受益。几种药物已与免疫疗法联合使用，以改善T细胞的激活和持久性，包括生长因子、化疗和放疗。临床前数据表明，替莫唑胺代谢后产生的活性化合物与达卡巴嗪相同，可选择性地消耗调节性T细胞（Tregs）。替莫唑胺的这种潜在免疫调节作用为其与伊匹单抗联合使用提供了理论依据。我们开展了一项开放标签的单臂II期研究，评估伊匹单抗联合替莫唑胺一线治疗乳酸脱氢酶（LDH）≤2倍正常值上限的转移性黑色素瘤患者的疗效。伊匹单抗在第1天给予10mg/kg，替莫唑胺200mg/m²口服，第1 - 4天给药，每3周重复一次，共4个周期，随后每12周给予维持剂量的伊匹单抗，每4周给予维持剂量的替莫唑胺。该研究的主要目标是6个月的无进展生存期（PFS）。共纳入64例患者，6个月的PFS为45%，中位总生存期（OS）为24.5个月。有10例（15.6%）确认部分缓解，10例（15.6%）确认完全缓解。缓解者的缓解持续时间为35个月，在中位随访20个月时，有10例患者仍在持续缓解。研究过程中未出现死亡或意外毒性反应。最常见的胃肠道副作用是恶心和便秘，而非腹泻或结肠炎。这些结果表明，诱导期伊匹单抗联合替莫唑胺可能是一种有效的策略，可增强抗肿瘤活性，且毒性易于管理。这些发现值得在大型前瞻性研究中进一步评估。
