背景：PD-L1/PD-1 抑製劑改變了晚期 NSCLC 的治療方案（tx）。有證據表明免疫治療中 irAEs 的發生可能改善腫瘤（如 NSCLC）的預後。目前已獲批用於 NSCLC 的一線及二線之後的 Atezolizumab (atezo; anti–PD-L1) 在治療中已顯示出療效及安全性。3 期臨床試驗IM-power130、IMpower132 和 IMpower150 試驗評估 Atezolizumab (atezo; anti–PD-L1) 在 NSCLSC 的 1L tx。我們探索了這些試驗中 irAEs 與療效之間是否存在關聯。

Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials.

方法：每個試驗都招募了未經治療（pts）的非鱗 IV 期 NSCLC 患者。Pts 被隨機分組到：arboplatin (carbo) + nab-paclitaxel 單藥或聯合 atezo 在 Impower130；carbo 或 cisplatin 單藥或聯合 atezo 在 IMpower132：atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP 在 Impower 150。數據彙集（數據截止時間：2018 年 3 月 15 日 [IMpower130]；2018 年 5 月 22 日[IMpower132]；2019 年 9 月 13 日 [IMpower150]）， 並按 tx （atezo 維持治療或控製治療） 和 irae 狀態進行分析。在 1，3，6 和 12 個月時間時進行依賴的 cox 模型和生存分析，用來控製永恒時間偏倚。研究協議要求當出現≥3 級 irAEs 時中斷或停止 atezo tx。

Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs.

結果：本分析包括 2503 pts（atezo，n =1577;對照組，n=926）。兩組的基線特征一般都在有 irAEs（atezo， n = 753; 控製， n = 289） 和無 irAEs（atezo， n = 824; con - trol， n = 637）中保持平衡。48% （atezo）和 32% （對照組）發生了任何等級的 irAEs；11% （atezo）和 5% （對照組）發生了 3-5 級的 irAEs 。最常見的 irAEs （atezo vs 對照組）是皮疹 （28% VS 18%）， 肝炎 （實驗室異常; 15% vs 10%），甲狀腺功能減退（12% VS 4%）。第一次出現 irAEs 的中位時間是 1.7 個月 （atezo） 與 1.4 個月（對照組）。時間依賴 cox 模型中有 irAEs 與無 irAEs 的 OS HRs （95% CI）在 atezo 組是 0.69 （0.60， 0.78）， 在對照組中是 0.82 （0.68， 0.99）；剔除皮疹（被認為是最不特異的 irAE）後，OS HR （95% CI）分別為 0.75 （0.65， 0.87） 和 0.90 （0.71， 1.12）。OS 生存分析如下表。

Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table.

Landmark	Atezo with irAE	Atezo with Gr 1/2 irAE	Atezo with Gr 3-5 irAE	Atezo without irAE	Control with irAE	Control without irAE
	n mOS, mo	n mOS, mo	n mOS, mo	n mOS, mo	n mOS, mo	n mOS, mo
1 mo	305 22.2	247 23.8	58 11.3	1210 18.9	116 19.3	764 14.3
3 mo	451 23.1	370 24.8	81 16.6	963 19.6	180 19.1	625 16.0
6 mo	532 25.6	431 26.6	101 21.5	736 22.4	197 21.8	498 19.3
12 mo	519 32.7	428 33.4	91 29.9	455 27.5	175 31.8	329 25.5

結論：在本探索性彙集分析中，atezo 和對照組中根據時間依賴 cox 模型和生存分析，與無 irAE 的 pts 相比，有 irAEs 的 pts 具有更長的 OS；atezo 組排除皮疹後這種趨勢仍然存在。生存分析表明，在 atezo 組中，1/2 級 irAEs 的 pts 具有最長的 OS，而出現≥３級 irAEs 的pts 具有最短的 OS，可能是由於 tx 中斷/停止。

Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation.