Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
J Immunother Cancer. 2021 Feb;9(2). doi: 10.1136/jitc-2020-002092.
Although the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.
We performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.
The most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p<0.001) yet had significantly better PPS (HR 0.503, 95% CI 0.288 to 0.879, p=0.02).
Radiological dynamics were variable, yet significantly correlated with survival outcomes. SITC-defined primary and secondary resistance are distinct clinical manifestations in patients with melanoma, suggesting the possibility of resistance-type-based therapeutic decision-making and clinical trial design, once further validated by future prospective studies.
尽管癌症免疫治疗学会（SITC）免疫治疗耐药工作组最近定义了抗程序性细胞死亡蛋白 1（抗 PD-1）治疗的原发性和继发性耐药，但关于这些耐药亚型在影像学动态和临床表现方面的差异，缺乏真实世界的数据。
我们对在马萨诸塞州综合医院和北京大学肿瘤医院接受抗 PD-1 单药治疗的 254 例晚期黑色素瘤患者（中位随访 31 个月）的回顾性队列进行了独立放射科医生的放射学图像单盲重新评估。分析了多个关键时间点的影像学特征和时间，并相互关联，与生存相关。原发性和继发性耐药按照 SITC 免疫治疗耐药工作组的定义进行定义。
在抗 PD-1 治疗开始后 3 个月内，最显著的靶病变测量变化发生。在初始评估时表现为疾病稳定而无肿瘤缩小的患者具有明显不同的疾病轨迹，因为进一步升级为部分或完全缓解（CR/PR）的比例分别为 44%和 0%。11%的 PR 患者最终达到了 CR。在多变量分析中，更深的反应深度与更有限的进展模式、更少的受累器官、更低的肿瘤负担、疾病进展（PD）时更慢的生长速度（均 p≤0.001）和更长的后进展生存（PPS）（单变量分析，p=0.005）独立相关。与原发性耐药相比，继发性耐药与更广泛的 PD 模式、更低的肿瘤负担和更慢的肿瘤生长相关（均 p≤0.001）。继发性耐药患者接受进一步全身治疗的可能性较低（28%比 57%，p<0.001），但 PPS 显著更好（HR 0.503，95%CI 0.288 至 0.879，p=0.02）。
影像学动态变化多样，但与生存结果显著相关。SITC 定义的原发性和继发性耐药是黑色素瘤患者的不同临床表现，提示有可能根据耐药类型进行治疗决策和临床试验设计，一旦通过未来的前瞻性研究得到进一步验证。
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