de Castro Gilberto, Rizvi Naiyer A, Schmid Peter, Syrigos Konstantinos, Martin Claudio, Yamamoto Nobuyuki, Cheng Ying, Moiseyenko Vladimir, Summers Yvonne, Vynnychenko Ihor, Lee Sung Yong, Bryl Maciej, Zer Alona, Erman Mustafa, Timcheva Constanta, Raja Rajiv, Naicker Kirsha, Scheuring Urban, Walker Jill, Mann Helen, Chand Vikram, Mok Tony
Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
Columbia University Medical Center, New York, New York.
J Thorac Oncol. 2023 Jan;18(1):106-119. doi: 10.1016/j.jtho.2022.09.223. Epub 2022 Oct 12.
NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC).
Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients.
As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy).
NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.
NEPTUNE是一项3期开放标签研究，评估了一线度伐利尤单抗联合曲美木单抗与化疗治疗转移性非小细胞肺癌（mNSCLC）的疗效。
符合条件的表皮生长因子受体（EGFR）和间变性淋巴瘤激酶（ALK）野生型mNSCLC患者被随机分组（1:1），接受一线度伐利尤单抗（每4周20mg/kg，直至疾病进展）联合曲美木单抗（每4周1mg/kg，最多4剂）或标准化疗。随机分组根据肿瘤程序性死亡配体1表达（≥25%对<25%）、肿瘤组织学类型和吸烟史进行分层。修订后的主要终点是血液肿瘤突变负荷（bTMB）大于或等于每兆碱基20个突变（mut/Mb）的患者的总生存期（OS）。次要终点包括bTMB大于或等于20 mut/Mb的患者的无进展生存期（PFS）以及所有接受治疗患者的安全性和耐受性。
截至2019年6月24日，823例患者被随机分组（意向性分析[ITT]）；512例（62%）可评估bTMB，其中512例中的129例（25%）bTMB大于或等于20 mut/Mb（度伐利尤单抗联合曲美木单抗组[n = 69]；化疗组[n = 60]）。意向性分析中基线特征均衡。在bTMB大于或等于20 mut/Mb的患者中，度伐利尤单抗联合曲美木单抗与化疗相比，OS改善未达到统计学意义（风险比0.71[95%置信区间：0.49 - 1.05；p = 0.081]；中位OS，11.7个月对9.1个月）；PFS的风险比为0.77（95%置信区间，0.51 - 1.15；中位PFS，4.2个月对5.1个月）。在总体安全性人群中，3级或4级治疗相关不良事件的发生率分别为20.7%（度伐利尤单抗联合曲美木单抗）和33.6%（化疗）。
对于bTMB大于或等于20 mut/Mb的mNSCLC患者，NEPTUNE研究未达到度伐利尤单抗联合曲美木单抗对比化疗改善OS的主要终点。尽管研究设计进行了修订，导致主要分析人群较小，但治疗活性与基于机制生物学和既往研究的预期一致。
