Neoadjuvant Durvalumab ± Tremelimumab in Combination With Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Muscle-Invasive Bladder Carcinoma: Results of the Phase I/II NEMIO Study.

Methods

NEMIO (ClinicalTrials.gov identifier: NCT03549715) is a multicenter, randomized, noncomparative phase II trial in cT2-T4a N0-1 cisplatin-eligible MIBC planned for radical cystectomy (RC).

NEMIO（ClinicalTrials.gov注册号：NCT03549715）是一项多中心、随机、非比较性II期临床试验，针对计划接受根治性膀胱切除术（RC）的cT2-T4a N0-1顺铂合格的MIBC患者。

Patients received ddMVAC (cisplatin 70 mg/m2, methotrexate 30 mg/m2, doxorubicin 30 mg/m2, and vinblastine 3 mg/m2 on days 1, and pegfilgrastim 6 mg on days 2) once every 2 weeks × four cycles plus durvalumab ± tremelimumab (durvalumab 1,500 mg and tremelimumab 75 mg) once every 4 weeks × two doses (C1D1 and C3D1) before RC.

患者接受ddMVAC治疗（顺铂70 mg/m2，甲氨蝶呤30 mg/m2，阿霉素30 mg/m2，长春碱3 mg/m2在第1天，以及聚乙二醇化重组人粒细胞刺激因子6 mg在第2天），每两周一次，共四个周期，加上durvalumab ± tremelimumab（durvalumab 1,500 mg和tremelimumab 75 mg）每四周一次，共两次剂量（C1D1和C3D1），在根治性膀胱切除术（RC）之前。

Coprimary end points (local assessment) were pathologic complete response (pCR; ypT0N0) and grade ≥3 treatment-related adverse events (TRAEs).

共同主要终点（局部评估）是病理完全缓解（pCR；ypT0N0）和3级或以上治疗相关不良事件（TRAEs）。

The study was considered positive if the pCR rate was ≥45% and the rate of grade ≥3 TRAEs was ≤30%.

如果病理完全缓解（pCR）率≥45%且3级或以上治疗相关不良事件（TRAEs）发生率≤30%，则研究结果被认为是积极的。

Results

From 2018 to 2022, 119 patients received ddMVAC + durvalumab (n = 60) or ddMVAC + durvalumab + tremelimumab (n = 59); 113 underwent RC.

从2018年到2022年，共有119名患者接受了去甲长春花碱、多柔比星、顺铂和紫杉醇（ddMVAC）联合durvalumab治疗（n=60）或ddMVAC联合durvalumab和tremelimumab治疗（n=59）；其中113人进行了根治性膀胱切除术（RC）。

The overall Bayesian posterior mean pCR rate was 48.70% (95% CI, 35.93 to 61.56) with doublet and 46.27% (95% CI, 33.92 to 58.85) with triplet.

整体贝叶斯后验平均pCR率为48.70%（95%置信区间，35.93至61.56）使用双重疗法，以及46.27%（95%置信区间，33.92至58.85）使用三重疗法。

Among 103 patients with PD-L1 data (exploratory), Bayesian posterior mean pCR was 68.25% (95% CI, 54.57 to 80.49) in PD-L1-high tumors versus 33.49% (95% CI, 22.13 to 45.91) in PD-L1-low/negative tumors.

在103名有PD-L1数据的患者（探索性）中，PD-L1高表达肿瘤的贝叶斯后验平均pCR率为68.25%（95%置信区间，54.57至80.49），而在PD-L1低表达/阴性肿瘤中为33.49%（95%置信区间，22.13至45.91）。

Bayesian posterior mean grade ≥3 TRAEs occurred in 40.95% (95% CI, 32.50 to 49.69) overall (30.48% [95% CI, 20.00 to 42.08] doublet; 49.63% [95% CI, 37.55 to 61.73] triplet); immune-related adverse events occurred in 26.9% (grade ≥3 4.2%).

贝叶斯后验均值3级或更高级别的不良事件发生率为40.95%（95%置信区间，32.50至49.69），总体而言（双药组合为30.48% [95%置信区间，20.00至42.08]；三药组合为49.63% [95%置信区间，37.55至61.73]）；免疫相关不良事件发生率为26.9%（3级或更高级别为4.2%）。

Two-year event-free survival and overall survivalrates were 75% and 85% in the doublet arm, and 77% and 88% in the triplet arm, respectively.

双药组合组两年无事件生存率和总生存率分别为75%和85%，三药组合组分别为77%和88%。

Conclusions

Neoadjuvant ddMVAC plus durvalumab demonstrated encouraging pCR rates, favorable early survival outcomes, and manageable safety profile.

新辅助ddMVAC联合durvalumab显示出令人鼓舞的病理完全缓解(pCR)率、良好的早期生存结果和可控的安全性。

Adding tremelimumab provides similar pCR but worse toxicity.

添加tremelimumab可以提供类似的pCR率，但毒性更差。

These results support further study of ddMVAC plus durvalumab as a neoadjuvant chemoimmunotherapy strategy for localized MIBC, to be evaluated in comparative trials within an evolving perioperative treatment landscape.

这些结果支持进一步研究ddMVAC联合durvalumab作为局部MIBC的新辅助化疗免疫治疗策略，并在不断发展的围手术期治疗领域内，通过比较性试验进行评估。