Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, P < 0.001, HR = 0.24; validation cohort: median PFS 11.0 vs 2.2 months, P < 0.001, HR = 0.17). Taken together, these results demonstrate that integrating early changes of ctDNA, normalized bTMB, and the first RECIST response can provide accurate, noninvasive, and early prediction of durable benefits for NSCLC patients treated with ICIs. Further prospective studies are warranted to validate these findings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.

免疫检查点抑制剂 （ICI） 改变了非小细胞肺癌 （NSCLC） 患者的治疗格局。尽管一些患者反应持久，但许多患者在 ICI 治疗期间出现早期疾病进展。因此，早期识别没有持久益处的患者将有助于这些患者的临床决策。在这项前瞻性、多中心研究中，在筛选了 328 例 III-IV 期 NSCLC 患者后，纳入了 101 例接受 ICI 治疗的非 EGFR/ALK 患者。在截止日期，83 例患者符合 ICI 疗效评价条件，其中 56 例患者在 6 个月内无进展生存期 （PFS），定义为持久临床获益 （DCB）。通过整合归一化 bTMB 、 ctDNA 的早期动态和第一个 RECIST 反应，建立了多模式模型。该模型可以稳健地预测 DCB，曲线下面积 （AUC） 为 0.878，敏感性为 79.2%，特异性为 86.4% （准确率 = 80.0%）。该模型在 DIREct-On 研究的独立队列中得到了进一步验证，AUC 为 0.887，灵敏度为 94.7%，特异性为 85.3% （准确率 = 90.3%）。预测评分较高的患者 PFS 明显长于评分较低的患者（训练队列：中位 PFS 13.6 vs 4.2 个月，P < 0.001，HR = 0.24;验证队列：中位 PFS 11.0 vs 2.2 个月，P < 0.001，HR = 0.17）。综上所述，这些结果表明，整合 ctDNA 的早期变化、正常化的 bTMB 和第一次 RECIST 反应可以为接受 ICIs 治疗的 NSCLC 患者提供准确、无创和早期的持久益处预测。 需要进一步的前瞻性研究来验证这些发现并指导 NSCLC 患者最佳免疫治疗的临床决策。