Department of Radiation Oncology, Ghent University Hospital, Belgium; Cancer Research Institute Ghent (CRIG), Belgium.
Department of Medical Oncology, Oncology Centre, University Hospital Brussels, Brussels, Belgium.
Int J Radiat Oncol Biol Phys. 2019 Jul 15;104(4):828-835. doi: 10.1016/j.ijrobp.2019.03.041. Epub 2019 Apr 3.
Nivolumab improves survival in patients with metastatic melanoma. Unfortunately, most patients do not respond to this treatment. Preclinical data indicate that radiation therapy could work synergistically with nivolumab and improve response rates.
We conducted a phase 2 trial in 20 patients with inoperable or metastatic melanoma with ≥2 measurable lesions (Response Evaluation Criteria in Solid Tumors v1.1). Stereotactic body radiation therapy (SBRT) of 3 × 8 Gy to the largest lesion was delivered before the second nivolumab cycle. The primary endpoint was overall response rate (ORR) in the nonirradiated lesions (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included toxicity. An exploratory endpoint was mutant BRAF and NRAS circulating tumor DNA (ctDNA) on serial blood samples.
An ORR of 45% was noted with 3 complete and 6 partial responses. Three patients experienced stable disease and 7 had progressive disease as best response. All patients with a complete response in the nonirradiated lesions exhibited a local complete response in the irradiated lesion. Grade 1 to 2 treatment-related adverse events (AEs) occurred in 17 patients; 3 patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred. ctDNA was detected in 8 patients, and changes corresponded to clinical response and suggested that a subset of patients with a low programmed death ligand-1 score only started responding after SBRT.
We conclude that the combination treatment was well tolerated and led to an ORR of 45% in patients with metastatic or inoperable melanoma, similar to historical response rates of nivolumab monotherapy. Although underpowered, our data therefore do not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT.
纳武利尤单抗可提高转移性黑色素瘤患者的生存率。然而，大多数患者对此治疗无反应。临床前数据表明，放射治疗与纳武利尤单抗联合使用可产生协同作用，提高反应率。
我们对 20 例有不可切除或转移性黑色素瘤且有≥2 个可测量病灶（实体瘤反应评价标准 1.1 版）的患者进行了一项 2 期试验。最大病灶接受立体定向体部放疗（SBRT），共 3 次，每次 8 Gy，于第二周期纳武利尤单抗前进行。主要终点是非照射病灶的总缓解率（ORR）（实体瘤反应评价标准 1.1 版）。次要终点包括毒性。探索性终点为连续血样中突变 BRAF 和 NRAS 循环肿瘤 DNA（ctDNA）。
非照射病灶的 ORR 为 45%，完全缓解 3 例，部分缓解 6 例。3 例患者病情稳定，7 例患者病情进展为最佳缓解。非照射病灶完全缓解的所有患者均在照射病灶中出现局部完全缓解。17 例患者出现 1 至 2 级治疗相关不良事件（AE）；3 例患者出现 3 级 AE（淋巴细胞减少症、胃肠炎和大疱性类天疱疮）。无 4 至 5 级 AE。8 例患者检测到 ctDNA，其变化与临床反应相对应，并提示仅一小部分程序性死亡配体-1 评分较低的患者在 SBRT 后才开始有反应。
我们的结论是，联合治疗耐受良好，可使转移性或不可切除性黑色素瘤患者的 ORR 达到 45%，与纳武利尤单抗单药治疗的历史缓解率相似。尽管效力不足，但我们的数据并未表明有明显的远隔效应。然而，连续的 ctDNA 分析表明，一小部分患者仅在添加 SBRT 后才有反应。
