背景：在 3 期隨機 CheckMate 9LA 試驗（NCT03215706）中，一線 NIVO + IPI 聯合2 周期化療與單藥化療 4 周期相比，顯著改延長了總生存期 （OS）， 無進展生存期 （PFS）和客觀應答率 （ORR）。無論 PD-L1 表達水平和組織學分型如何，我們都觀察到臨床療效。我們將在此彙報至少 2 年的跟蹤隨訪數據。

Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study.

方法：我們將 IV 期或複發 NSCLC、ECOG 評分≤1 分 和已知無明確 EGFR/ALK 突變的成人患者（pts）按 PD-L1（< 1% 與 ≥1%），性別，和組織學表型 （鱗癌 VS 非鱗癌）分層，並被 1：1 隨機分組到 NIVO 360 mg Q3W + IPI 1 mg / kg Q6W + 化療 （2 周期; n = 361） 或單藥化療 （4 周期; n = 358）。在化療組中非鱗 NSCLC 的 pts 可以接受培美曲塞維持。主要終點是 OS。次要終點包括通過獨立中心盲審的 PFS 和 ORR，以及 PD-L1 不同等級的療效。此研究的安全性是得以保證的。

Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory.

結果：OS 至少隨訪 24.4 個月（數據庫於 2021 年 2 月 18 日鎖定），經 NIVO + IPI + chemo 治療的 pts 與單藥化療相比得到了 OS 獲益，中位 OS 分別為 15.8 個月與 11.0 個月（HR， 0.72 [95% CI， 0.61–0.86]）;2 年 OS 率分別為 38%和 26%。經 NIVO + IPI + chemo 治療與單藥化療的中位 PFS 分別為 6.7 個月與 5.3 個月 （HR，0.67 [95% CI，0.56-0.79]）；分別有 8%和 37%的有疾病進展的患者接受了後續免疫治療。NIVO+IPI+chemo ORR 38% VS 單藥化療 ORR 25%。在所有隨機分組的 pts 和大多數子分組都觀察到了類似於 NIVO+ IPI + chemo VS 單藥化療的臨床獲益，包括不同的 PD-L1 表達水平或組織學分型。與治療相關的任何等級和 3-4 級不良事件在 NIVO + IPI + chemo 組分別為 92% 和 48% VS 化療組為 88% 和 38%。

Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively.

Summary of efficacy outcomes by PD-L1 expression.
	PD-L1 < 1%	PD-L1 < 1%	PD-L1 ≥ 1%	PD-L1 ≥ 1%	PD-L1 ≥ 50%	PD-L1 ≥ 50%	All randomized	All randomized
	NIVO + IPI + chemo n = 135	Chemo n = 129	NIVO + IPI +chemo n = 204	Chemo n = 204	NIVO + IPI +chemo n = 76	Chemo n = 98	NIVO + IPI +chemo n = 361	Chemo n = 358
Median OS, months	17.7	9.8	15.8	10.9	18.9	12.9	15.8	11.0
OS HR (95% CI) vs chemo	0.67(0.51–0.88)	-	0.70(0.56–.89)	-	0.67(0.46–.97)	-	0.72(0.61–0.86)	-
2-year OS rate, %	37	22	41	28	45	32	38	26
2-year PFS rate, %	20	5	20	9	28	10	20	8
ORR, n (%)	42 (31)	26 (20)	87 (43)	57 (28)	38 (50)	31 (32)	137 (38)	91 (25)
Median duration of response, months	17.5	4.3	11.8	5.6	26.0	5.4	13.0	5.6
Responders with ongoing response ≥ 2 years, %	45	0	33	13	52	16	34	12

結論：在晚期 Nsclc 的 pts 治療中，至少２年的隨訪、一線 NIVO + IPI + chemo 方案具有持久生存和臨床獲益；未發現新的安全信號。

Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified.