Immune checkpoint blockade in the treatment of advanced non-small cell lung cancer – predictors of response and impact of previous radiotherapy

The implementation of immune checkpoint inhibitors (ICI) into the standard care of advanced non-small cell lung cancer (NSCLC) has improved prognosis for this group of patients. However, long-term survival is rare. The aim of the study was to identify predictors of response and, especially, to investigate the impact radiotherapy might have on duration of response. The association between pretreatment patient/tumor characteristics and progression-free survival (PFS), overall survival (OS), and lung cancer-specific survival was investigated in 78 patients receiving an ICI as ≥2nd line treatment for advanced NSCLC, using Cox regression analysis. Due to competing risk, cause-specific deaths were also examined with cumulative incidence plots. Median OS was 12.6 months (95% CI 7.8–18.2) and median PFS 4.1 months (95% CI 3.0–6.2), after median follow-up time of 49.7 months (range 20.9–51.5). Increasing CRP and neutrophil/lymphocyte ratio (NLR), were associated with poor PFS (CRP: HR 1.49, 95% CI 1.12–1.98; NLR: HR 1.59, 95% CI 1.22–1.85) and OS (CRP: HR 1.94, 95% CI 1.47–2.56; NLR: HR 1.54, 95% CI 1.27–1.87). Radiotherapy prior to immunotherapy was not significantly associated with patient outcome. However, when the dataset was split at 6 months of follow-up, to be able to identify early and late predictors of prognosis, we found that patients receiving radiotherapy <6 months prior to immunotherapy had better PFS (HR: 0.27, 95% CI 0.09–0.84) and lung cancer-specific survival (HR: 0.41, 95% CI 0.18–0.95) after the first 6 months of follow-up, while increasing CRP (PFS: HR1.61, 95% CI 1.21–2.14; OS: HR2.04, 95% CI 1.51–2.74) and NLR (PFS: HR 1.57, 95% CI 1.29–1.91; OS: HR 1.63, 95% CI 1.35–1.97) were predictors of poor short-term prognosis. Radiotherapy may be of importance to achieve a long-lasting response to immunotherapy, while indicators of systemic inflammation can help in identifying patients with poor short-term prognosis.

免疫检查点抑制剂（immune checkpoint inhibitors, ICI）纳入晚期非小细胞肺癌（advanced non-small cell lung cancer, NSCLC）的标准治疗方案后，显著改善了该类患者的预后，但长期生存仍属罕见。本研究旨在明确免疫治疗应答的预测因子，重点探讨放疗对应答持续时间的影响。研究纳入78例接受免疫检查点抑制剂作为晚期非小细胞肺癌二线及以上治疗的患者，采用Cox回归分析，探究治疗前患者/肿瘤特征与无进展生存期（progression-free survival, PFS）、总生存期（overall survival, OS）及肺癌特异性生存期的关联。鉴于存在竞争风险，研究同时通过累积发病率图分析了特异性死亡事件。中位随访时间为49.7个月（范围20.9~51.5个月），患者的中位OS为12.6个月（95%置信区间7.8~18.2），中位PFS为4.1个月（95%置信区间3.0~6.2）。血清C反应蛋白（CRP）水平升高与中性粒细胞/淋巴细胞比值（neutrophil/lymphocyte ratio, NLR）升高均与较差的PFS（CRP：风险比HR=1.49，95%CI 1.12~1.98；NLR：HR=1.59，95%CI 1.22~1.85）及OS（CRP：HR=1.94，95%CI 1.47~2.56；NLR：HR=1.54，95%CI 1.27~1.87）显著相关。免疫治疗前接受放疗与患者总体预后无显著关联。然而，当以随访6个月为界拆分数据集，以区分预后的早期与晚期预测因子时，研究发现：免疫治疗前6个月内接受放疗的患者，在随访前6个月后的PFS（HR=0.27，95%CI 0.09~0.84）与肺癌特异性生存期（HR=0.41，95%CI 0.18~0.95）显著更优；而升高的CRP（PFS：HR=1.61，95%CI 1.21~2.14；OS：HR=2.04，95%CI 1.51~2.74）与NLR（PFS：HR=1.57，95%CI 1.29~1.91；OS：HR=1.63，95%CI 1.35~1.97）则是短期预后不良的预测因子。本研究结果提示，放疗或可助力实现免疫治疗的持久应答，而全身炎症指标可辅助识别短期预后不良的患者。