对于不可切除的局部晚期III期非小细胞肺癌（NSCLC），通常的治疗方法是联合放化疗（CRT），接着进行持续的durvalumab。本研究旨在评估新辅助性osimertinib作为替代疗法的优势，以期减少放疗范围。该调查是一项非随机、开放、单臂、II期前瞻性，概念证明研究。符合条件的患者为初次接受治疗的不可手术的第III期EGFR突变NSCLC患者。患者在进行明确的放疗（RT）和/或手术前12周内每天口服80毫克的osimertinib。响应在第6周和第12周被评估。对于响应者，计划进行顺序明确的RT和/或手术。非响应者则开始标准CRT。在RT±手术或CRT之后，患者无需接受辅助治疗进行两年的随访。主要终点是客观反应率（ORR），数据收集的截止时间为2022年9月20日。次要终点包括安全性以及在osimertinib之前与之后的粗病变体积（GTV）、计划病变体积（PTV）和除去GTV后超过20 Gy的总肺容积的百分比（V20%）。探索性分析包括对osimertinib治疗前、第6周和第12周、RT结束后以及术后6周循环游离肿瘤DNA（cfDNA）的检测。共有24名患者被纳入（19女性；中位年龄73岁，范围51-82岁）。其中19/24从未吸烟，20/24为腺癌，16/24为外显子19缺失，8/24为外显子21突变。参与者分别患有III A（10例），III B（9例）或III C（5例）的疾病。三名患者被排除在分析之外（一名退出研究，另外两名在截止日期仍在接受osimertinib治疗）。针对osimertinib诱导的ORR为95.2%（17例为部分反应（PR），3例为完全反应（CR）和1例为进展性疾病（PD））。在osimertinib诱导后，13/20患者明确接受了放疗，3/20接受了手术，5/20被排除在外。4例患者被重新分期为IV期（对侧的地面玻璃影经osimertinib治疗后有所改善），并且一名患者退出知情同意。三名患者接受了手术，其中一名患者接受了放疗。两名患者达到了pT1aN0，另一名达到了病理完全反应（pCR）。在osimertinib治疗前的中位GTV、PTV和V20%分别为47.4 ± 76.9 cm3（13.5-234.9），227.0 ± 258.8 cm3（77.8-929.2）和27.1 ± 16.4%（6.2-60.3）。治疗后的数值分别为27.5 ± 42.3 cm3（2.99-137.7；-48 ± 20%；p = 0.02），181.9 ±198.4 cm3（54-718.1；-31 ±20%；p = 0.01）和21.8 ± 11.7%（9.1-44.15；-24 ± 40%；p = 0.04）。PTV/GTV/V20%的减少与肿瘤大小和中央位置有关。中位随访时间为28.71（范围0.4-45.1）个月，中位无病生存期（DFS）尚未达到（平均30.59；标准误差3.94；（95%[22.86-38.31]））。在5名患者中检测到cfDNA；5例中有4例在基线时为cfDNA阳性，在osimertinib诱导期间变为阴性，但在osimertinib治疗终止后重新变为阳性。有趣的是，在基线时为cfDNA阴性的3名患者在放疗后变成了低水平阳性，然后在随访时又变成了阴性。在osimertinib或放疗阶段未报告任何重大不良事件。使用新辅助性osimertinib治疗对III期患者是可行的，接着进行明确的放疗和/或手术，其ORR为95.2%，并且具有出色的安全性。在明确的放疗前接受为期12周的osimertinib诱导治疗（不接受化疗）可以将放疗范围显著减少近50%，并且与肿瘤大小呈线性关联。在实践发生变化之前，需要进行进一步研究以测试这种无化疗药物治疗的长期结果。版权所有©2023，由Elsevier Inc.发表。

The treatment of unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT), followed by consolidation durvalumab. This study aims to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field.This investigation was a nonrandomized, open-label, single-arm, phase II prospective, proof-of-concept study. Eligible patients were treatment-naïve, nonoperable, stage III EGFR-mutant NSCLC patients. Patients received 80 mg oral osimertinib daily for 12 weeks prior to definitive radiotherapy (RT) and/or surgery. The response was assessed at week 6 and week 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT± surgery or CRT, patients were followed for two years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022 set as the cut-off for data collection. Secondary endpoints were safety and the gross tumour volume (GTV), planned tumour volume (PTV) and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before vs. after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumour-free DNA (cfDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT.Twenty-four patients were included (19 female; median age 73 years, range 51-82). Nineteen/24 had never smoked, 20/24 had adenocarcinoma, 16/24 had exon 19 deletions, and 8/24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (one dropped out, and two were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response (PR), 3 complete response (CR) & 1 progressive disease (PD)). After induction osimertinib, 13/20 patients were definitively radiated, 3/20 underwent surgery, and 5/20 were excluded. Four patients were restaged as stage IV (contralateral ground glass opacities responded to osimertinib), and one patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathological complete response (pCR). The median GTV, PTV & V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5-234.9), 227.0 ± 258.8 cm3 (77.8-929.2) and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99-137.7; -48 ± 20%; p=0.02), 181.9 ±198.4 cm3 (54-718.1; -31 ±20%; p=0.01) and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; p=0.04), respectively. PTV/GTV/V20% reduction was associated with tumour size and central location. The median follow-up time was 28.71(range 0.4-45.1) months and median disease-free survival (DFS) was not reached (mean 30.59; standard error 3.94; (95% [22.86-38.31])). cfDNA was detected in 5 patients; 4/5 were positive for cfDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were cfDNA negative at baseline became weakly positive after radiotherapy and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases.Neoadjuvant osimertinib therapy is feasible in stage III patients, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks prior to definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumour size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.Copyright © 2023. Published by Elsevier Inc.