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题目 [NADIM研究]可切除的IIIA期NSCLC新辅助化疗联合免疫治疗
背景
IIIAN2非小细胞肺癌的预后差，5年生存约10%-15%。在未选择的转移性NSCLC患者中，化疗联合免疫可以有效提高客观缓解率，延长总生存。在新辅助治疗阶段，这一联合方案的疗效如何，目前未知。
新辅助两个剂量纳武利尤单抗（nivolumab）在早期肺癌病人中可以达到显著病理缓解(major pathologic response，mPR。定义是＜10%的肿瘤细胞)。
方案
NADIM研究(CA209-547 ， NCT03081689 ）是一项II期，单臂，开放的多中心研究，入组局部晚期可切除的IIIA N2期NSCLC 患者。患者接受化疗联合纳武利尤单抗治疗序贯附属治疗1年。新辅助治疗方案包括3个周期的纳武利尤单抗360mg IV Q3W 联合紫杉醇（paclitaxel）200mg/m2和卡铂（carboplatin）AUC6 IV Q3W化疗。在完成新辅助治疗后，手术前进行肿瘤评估。在完成3个周期的新辅助治疗后的第3或4周进行手术。辅助治疗方案为纳武利尤单抗240mg IV Q2W，4个月和纳武利尤单抗480mg IV Q4W，8个月，术后辅助治疗共12个月。研究计划招募46例患者。主要研究终点为从诊断计算起的24个月的无进展生存（progression-free survival，PFS率。太奇怪了吧，是手术的病人，为什么不是无疾病生存呢？）。采用客观病例缓解标准进行疗效探索性分析。本次报道完成了3个周期新辅助治疗后接受手术治疗患者的初步研究数据。
图1. NADIM: 研究设计和流程
结果
截至递交数据，研究共纳入46例患者，其中30例患者完成手术。化疗联合免疫治疗的耐受性良好，所有病例都能够依从方案，没有患者延长进行守护。没有患者因为基本进展或毒性在术前需要退出研究。共进行了20例手术，所有肿瘤均为可切除的。
具体的药物方案实施见： 纳武利尤单抗+紫杉醇+卡铂（NADIM方案）
疗效评价RECIST v1.1并以CT扫描评价。总体临床缓解率评估中，70%有效（21/30），3例CR（10%），18例PR（60%），9例（9/30，30%）SD稳定。90%出现降期。
术后病例缓解率评估中，13例(65.0%；95% CI 40.8-84.6%) 患者取得病理完成缓解，3例(3/30，10%)患者取得大的病理缓解，定义为切除标本中存活肿瘤细胞<10%。结合取得完全病理缓解和大PR的患者，总的ORR为80.0% (95% CI 56.3-94.3%)，CR率为60%。
毒性均可耐受。mPR在本研究中很高。
未报道术中并发症，但术后有7/30例术后并发症，但无术后死亡率。
结论
这是第一项多中心研究，在新辅助治疗阶段评估化疗联合免疫治疗，在局部晚期，潜在可切除的NSCLC患者中显示出卓越的抗肿瘤疗效，达到了超过预期的病理完全缓解率。
评论
在III期NSCLC中，这个mPR是前所未有的高！！！！！！但进入III期临床试验还要有3年才能等到结果NADIM II: Neo-Adjuvant Immunotherapy (NADIMII)。
存在的问题
待讨论。
相似的研究
NADIM II: Neo-Adjuvant Immunotherapy (NADIMII)
AFT-16 (NCT03102242) ：
单臂，II期研究。III期非小细胞肺癌。
治愈性化放疗前后atezolizumab治疗。预计入组63列。
Ross HJ, Kozono DE, Urbanic JJ, et al. Phase II trial of atezolizumab before and after definitive chemoradiation for unresectable stage III NSCLC. J Clin Oncol 2018;36:abstr TPS8585.
SAKK 16/14 (NCT02572843)：
单臂，II期研究。IIIA期 (N2) 非小细胞肺癌。
新辅助 顺铂+多西他赛3周期，加2周期durvalumab，手术后再加术后辅助durvalumab 12个月。入组68例。主要终点：无事件生存12个月。
25例手术，30天术后死亡率＜10%。
Rothschild SI, Zippelius A, Prince SS, et al. SAKK 16/14 - anti-PD-L1 antibody durvalumab (MEDI4736) in addition to neoadjuvant chemotherapy in patients with stage IIIA (N2) non-small cell lung cancer (NSCLC). A multicenter single-arm phase II trial. J Clin Oncol 2018;36:abstr TPS8584.
EA5142 (ANVIL; NCT02595944)：
ALCHEMIST的一部分，III期试验，随机入组714例，辅助nivolumab对比标准治疗。病理证实的IB–IIIA NSCLC。
Chaft JE, Dahlberg SE, Khullar OV, et al. EA5142 adjuvant nivolumab in resected lung cancers (ANVIL). J Clin Oncol 2018;36:abstr TPS8581.
Checkmate-816 (NCT02998528)：
III期试验。
新辅助nivolumab + ipilimumab 对比 新辅助含铂双药物化疗， IB–IIIA NSCLC. 入组326例。
主要终点：major pathological response rate。
Forde PM, Chaft JE, Felip E, et al. Checkmate 816: A phase 3, randomized, open-label trial of nivolumab plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. J Clin Oncol 2017;35:abstr TPS8577.
Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, Dómine M, Majem M, Rodríguez-Abreu D, Martínez-Martí A, De Castro Carpeño J, Cobo M, López Vivanco G, Del Barco E, Bernabé Caro R, Viñolas N, Barneto Aranda I, Viteri S, Pereira E, Royuela A, Casarrubios M, Salas Antón C, Parra ER, Wistuba I, Calvo V, Laza-Briviesca R, Romero A, Massuti B, Cruz-Bermúdez A. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1413-1422. doi: 10.1016/S1470-2045(20)30453-8. Epub 2020 Sep 24. PMID: 32979984.
Background: Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. Methods: This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients. Findings: Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4-28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9-87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]). Interpretation: Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable.
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