Background and aim: A better understanding of resistance to checkpoint inhibitors is essential to define subsequent treatments in advanced non-small cell lung cancer. By characterizing clinical and radiological features of progression after anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1), we aimed to define therapeutic strategies in patients with initial durable clinical benefit. Patients and methods: This monocentric, retrospective study included patients who presented progressive disease (PD) according to RECIST 1.1 criteria after anti-PD-1/PD-L1 monotherapy. Patients were classified into two groups, “primary resistance” and “Progressive Disease (PD) after Durable Clinical Benefit (DCB)”, according to the Society of Immunotherapy of Cancer classification. We compared the post-progression survival (PPS) of both groups and analyzed the patterns of progression. An exploratory analysis was performed using the tumor growth rate (TGR) to assess the global growth kinetics of cancer and the persistent benefit of immunotherapy beyond PD after DCB. Results: A total of 148 patients were included; 105 of them presented “primary resistance” and 43 “PD after DCB”. The median PPS was 5.2 months (95% CI: 2.6–6.5) for primary resistance (p< 0.0001) vs. 21.3 months (95% CI: 18.5–36.3) for “PD after DCB”, and the multivariable hazard ratio was 0.14 (95% CI: 0.07–0.30). The oligoprogression pattern was frequent in the “PD after DCB” group (76.7%) and occurred mostly in pre-existing lesions (72.1%). TGR deceleration suggested a persistent benefit of PD-1/PD-L1 blockade in 44.2% of cases. Conclusions: PD after DCB is an independent factor of longer post-progression survival with specific patterns that prompt to contemplate loco-regional treatments. TGR is a promising tool to assess the residual benefit of immunotherapy and justify the continuation of immunotherapy in addition to radiotherapy or surgery.
背景与目的：深入理解免疫检查点抑制剂耐药机制对于确定晚期非小细胞肺癌的后续治疗方案至关重要。本研究通过分析抗程序性死亡受体-1/程序性死亡配体-1（抗PD-1/PD-L1）治疗后进展的临床及影像学特征，旨在为初始获得持久临床获益的患者制定治疗策略。 患者与方法：这项单中心回顾性研究纳入经RECIST 1.1标准评估在抗PD-1/PD-L1单药治疗后出现疾病进展的患者。根据癌症免疫治疗学会分类标准，将患者分为"原发性耐药"和"持久临床获益后疾病进展"两组。我们比较了两组的进展后生存期，并分析了疾病进展模式。采用肿瘤生长速率进行探索性分析，以评估癌症的整体生长动力学及免疫治疗在持久临床获益后疾病进展阶段的持续获益效应。 结果：共纳入148例患者，其中105例为"原发性耐药"，43例为"持久临床获益后疾病进展"。原发性耐药组中位进展后生存期为5.2个月（95%CI：2.6-6.5），而"持久临床获益后疾病进展"组为21.3个月（95%CI：18.5-36.3）（p<0.0001），多变量风险比为0.14（95%CI：0.07-0.30）。寡进展模式在"持久临床获益后疾病进展"组更为常见（76.7%），且主要发生于既存病灶（72.1%）。肿瘤生长速率减缓提示44.2%的病例仍持续获益于PD-1/PD-L1阻断治疗。 结论：持久临床获益后疾病进展是较长进展后生存期的独立影响因素，其特有的进展模式提示应考虑局部区域治疗。肿瘤生长速率是评估免疫治疗残余获益的有效工具，可为放疗或手术联合持续免疫治疗提供依据。
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