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.

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.