Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem, Israel; The Hebrew University of Jerusalem, Jerusalem, Israel.
Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem, Israel; The Hebrew University of Jerusalem, Jerusalem, Israel.
Int J Radiat Oncol Biol Phys. 2023 Sep 1;117(1):105-114. doi: 10.1016/j.ijrobp.2023.03.042. Epub 2023 Mar 15.
The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed 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 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 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 2 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 tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT.
Twenty-four patients were included (19 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and V20% before osimertinib treatment were 47.4 ± 76.9 cm (13.5-234.9), 227.0 ± 258.8 cm (77.8-929.2), and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm (2.99-137.7; -48 ± 20%; P = .02), 181.9 ±198.4 cm (54-718.1; -31 ± 20%; P = .01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P = .04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT 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 patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.
无法切除的局部晚期 III 期非小细胞肺癌（NSCLC）的治疗方法是同步放化疗（CRT）后进行巩固性 durvalumab 治疗。本研究旨在评估新辅助 osimertinib 作为替代该方法的治疗方案的益处，目的是减少放射野。
这是一项非随机、开放标签、单臂、Ⅱ期、前瞻性、概念验证研究。符合条件的患者被归类为治疗初治、不可手术、III 期表皮生长因子受体突变 NSCLC 患者。患者在接受标准剂量的 RT（±手术）前，每天接受 80mg 口服 osimertinib 治疗 12 周。在第 6 周和第 12 周评估反应。对于有反应的患者，计划进行连续的标准剂量 RT（±手术）。无反应的患者开始接受标准 CRT。在 RT±手术或 CRT 后，患者在不接受辅助治疗的情况下随访 2 年。主要终点是客观缓解率（ORR），截止日期为 2022 年 9 月 20 日。次要终点是安全性和全肿瘤体积（GTV）、计划肿瘤体积（PTV）和全肺体积减去 GTV 超过 20Gy（V20%）在 osimertinib 治疗前后的变化。探索性分析包括评估治疗前、第 6 周和第 12 周、RT 结束时和 RT 后 6 周血浆游离循环肿瘤 DNA（ctDNA）的存在情况。
共纳入 24 例患者（19 例女性；中位年龄 73 岁；范围，51-82 岁）。24 例患者中有 19 例从不吸烟，24 例中有 20 例为腺癌，16 例有外显子 19 缺失，8 例有外显子 21 突变。患者的疾病分期为 IIIA（10 例）、IIIB（9 例）或 IIIC（5 例）。3 例患者被排除在分析之外（1 例退出，2 例在截止日期仍在接受 osimertinib 治疗）。诱导 osimertinib 的 ORR 为 95.2%（17 例部分缓解，3 例完全缓解，1 例进展）。在诱导 osimertinib 后，20 例患者中有 13 例接受了确定性放疗，3 例接受了手术，5 例被排除。4 例患者被重新分期为 IV 期（对侧磨玻璃影对 osimertinib 有反应），1 例患者撤回了知情同意书。3 例患者接受了手术，其中 1 例接受了 RT。2 例患者达到 pT1aN0，1 例达到病理完全缓解。在接受 osimertinib 治疗前，GTV、PTV 和 V20%的中位数分别为 47.4±76.9cm（13.5-234.9）、227.0±258.8cm（77.8-929.2）和 27.1±16.4%（6.2-60.3）。在接受 osimertinib 治疗后，相应的中位数分别为 27.5±42.3cm（2.99-137.7；-48±20%；P=0.02）、181.9±198.4cm（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 个月（范围，0.4-45.1 个月），中位无疾病生存期未达到（平均，30.59；标准误差，3.94；95%置信区间，22.86-38.31）。在 5 例患者中检测到 ctDNA；4 例患者在基线时 ctDNA 阳性，在诱导 osimertinib 期间转为阴性，但在 osimertinib 治疗结束后再次转为阳性。有趣的是，3 例基线时 ctDNA 阴性的患者在 RT 后出现弱阳性，然后在随访时转为阴性。在 osimertinib 或放射治疗期间均未报告显著的不良事件。
在 III 期肺癌 NSCLC 患者中，新辅助 osimertinib 治疗后进行确定性放疗（无化疗）联合/不联合手术是可行的，ORR 为 95.2%，安全性良好。在接受标准剂量 RT（±手术）前，进行 12 周的 osimertinib 诱导治疗可显著减少近 50%的放疗野，且与肿瘤大小呈线性相关。在改变实践之前，需要进一步的研究来测试这种无化疗的长期治疗效果。
