背景：CheckMate816(NCT02998528)是對可切除的 NSCLC 中新輔助劑 NIVO 化療與化療的隨機 3 期研究。該研究達到了第一個主要終點，證明新輔助 NIVO 化療顯著改善了病理完全反應(PCR)。這裏我們報告了研究的關鍵手術結果。
Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significantly improved pathological complete response (pCR) with neoadjuvant NIVO + chemo. Here we report key surgical outcomes from the study.
方法：將 IB 期（≥4cm）-IIIA（按 AJCC 第 7 版）可切除 NSCLC、ECOG PS≤1 且未發生已知 EGFR/ALK 改變的成人隨機分配到 NIVO 360mg 鉑雙態化療 Q3W 或化療 Q3W 進行 3個周期（分別 n=179）。最終的手術將在治療後的 6 周內進行。主要終點為 pCR（定義為肺和淋巴結中 0%可行的腫瘤細胞）和無事件生存率；兩者均通過盲法獨立審查進行評估。手術和手術相關不良事件(AE)的可行性是探索性終點。
Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ALK alterations were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Definitive surgery was to be performed within 6 weeks of treatment. Primary endpoints are pCR (defined as 0% viable tumor cells in lung and lymph nodes) and event-free survival; both are evaluated by blinded independent review. Feasibility of surgery and surgery-related adverse events (AEs) are exploratory endpoints.
結果：兩組間的基線特征相似，64%的患者(患者)為 IIIA 期。NIVO 化療時（n=149）的最終手術率為 83%，而化療時為 75%（n=135）。導致手術取消的原因是疾病進展（分別為12 和 17 患者）、不良事件（2 患者/arm）或其他情況（分別為 14 和 19 患者；包括患者拒絕、不可切除、肺功能差）。微創手術率分別為 30%和 22%，NIVO 化療和化療從微創手術率轉換到開放手術率分別為 11%和 16%。77%和 61%的患者分別進行了肺切除術，NIVO 化療的肺切除術分別為 17%和 25%的肺切除術。不良事件導致 NIVO 化療組 6 例和化療組 9 例的手術延遲。83%對 78%的患者進行 R0 切除，NIVO 化療組的中位剩餘存活腫瘤(RVT)細胞為 10%和 74%。NIVO 化療與化療期間的中位數（Q1、Q3）手術時間和住院時間沒有增加（184vs217min；分別為 10.0vs10.0 天）。NIVO 化療和 4 級手術相關不良事件和 11%分別為 41%和 47%和 15%。在 NIVO 化療組和化療組中，有 2vs0 患者報告了 5 級手術相關不良事件；0vs3 患者分別死於治療相關不良事件。
Results: Baseline characteristics were comparable between arms; 64% of patients (pts) were stage IIIA. Definitive surgery rates were 83% with NIVO + chemo (n = 149) vs 75% with chemo (n = 135). Reasons for cancelled surgery were disease progression (12 and 17 pts, respectively), AEs (2 pts/arm), or other scenarios (14 and 19 pts, respectively; including pt refusal, unresectability, poor lung function). Minimally invasive surgery rates were 30% and 22%, and conversion from minimally invasive to open surgery rates were 11% and 16% for NIVO + chemo and chemo, respectively. Lobectomy was performed in 77% vs 61% of pts, and pneumonectomy in 17% and 25% for NIVO + chemo vs chemo, respectively. AEs were responsible for delays of surgery in 6 pts in the NIVO + chemo arm and 9 pts in the chemo arm. An R0 resection was achieved in 83% vs 78% of pts and median residual viable tumor (RVT) cells in the primary tumor bed were 10% vs 74% for NIVO + chemo vs chemo. There was no increase in median (Q1, Q3) duration of surgery and length of hospitalization between NIVO + chemo vs chemo (184 [130, 252] vs 217 [150, 283] min; and 10.0 [7, 14] vs 10.0 [7, 14] days, respectively). Any-grade and grade 3–4 surgery-related AEs were reported in 41% vs 47% and 11% vs 15% of the NIVO + chemo vs chemo arms, respectively. Grade 5 surgery-related AEs were reported in 2 vs 0 pts in the NIVO + chemo vs chemo arms; 0 vs 3 pts died due to treatment-related AEs, respectively.
結論：在CheckMate816 中，新輔助 NIVO 化療不妨礙手術的可行性和時間，以及切除與單獨化療的程度或完整性，治療可接受，不增加手術並發症。NIVO 化療導致了病理反應的深度的增加。CheckMate816 的手術結果數據，作為 IB-IIIA 切除 NSCLC 患者的潛在新輔助選擇。
Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo did not impede the feasibility and timing of surgery, nor the extent or completeness of resection vs chemo alone; treatment was tolerable and did not increase surgical complications. NIVO + chemo led to increased depth of pathological response. The surgical outcome data from CheckMate 816 along with significant improvement in pCR support NIVO + chemo as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC.
