The Angeles Clinic and Research Institute, Los Angeles, California.
Genentech, Inc., South San Francisco, California.
Clin Cancer Res. 2019 Oct 15;25(20):6061-6072. doi: 10.1158/1078-0432.CCR-18-3488. Epub 2019 Jul 29.
Atezolizumab [anti-programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842).
Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored.
Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35-not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9-66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival.
Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.
阿特珠单抗（抗程序性死亡配体 1[PD-L1]）选择性地靶向 PD-L1，以阻断其与程序性死亡 1 和 B7.1 受体的相互作用，从而重新激活抗肿瘤 T 细胞活性。我们在一项正在进行的 I 期研究（NCT01375842）中评估了阿特珠单抗在黑色素瘤患者中的长期安全性和活性，以及临床活性终点的生物学相关性。
招募不可切除或转移性黑色素瘤患者接受阿特珠单抗 0.1 至 20mg/kg 或每 3 周至少 10mg/kg 治疗。主要研究目标是安全性和耐受性。次要目标包括研究者评估的疗效措施；探索抗肿瘤活性的药效学和预测性生物标志物。
45 名患者入组并可评估安全性。大多数治疗相关不良事件（AE）为 1/2 级（60%）。最常见的任何级别治疗相关 AE 为疲劳（44%）、瘙痒（20%）、发热（18%）和皮疹（18%）。无治疗相关死亡。43 名可评估疗效的患者中，总体缓解率为 30%，中位缓解持续时间为 62 个月[95%可信区间（CI）：35-NE]。观察到具有临床意义的长期生存，中位总生存期为 23 个月（95%CI：9-66）。肿瘤免疫的基线生物标志物[免疫细胞上的 PD-L1 表达、T 效应（Teff）和抗原呈递基因特征]和肿瘤突变负担（TMB）与改善反应、无进展生存期和总生存期相关。
阿特珠单抗在黑色素瘤患者中具有良好的耐受性，可产生持久的反应和生存。PD-L1 表达、TMB 和 Teff 特征可能表明这些患者使用阿特珠单抗获益增加。
