1.First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA
進展期NSCLC和腦轉移患者的一線Nivolumab + Ipilimumab +化療:來自CheckMate 9LA的結果
Introduction
介紹
Patients with advanced non-small cell lung cancer (NSCLC) and brain metastases have high unmet needs and could benefit from checkpoint inhibitors. In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line nivolumab (NIVO) + ipilimumab (IPI) combined with chemotherapy (chemo) significantly improved overall survival (OS; primary endpoint) versus chemo alone in patients with advanced NSCLC. Clinical benefit was observed regardless of programmed death ligand 1 expression or histology. Here we report a post hoc analysis of efficacy and safety outcomes in patients with and without baseline (BL) brain metastases.
進展期非小細胞肺癌(NSCLC)和腦轉移患者有很高的未滿足需求，檢查點抑製劑可以獲益。在隨機3期CheckMate 9LA試驗(NCT03215706)中，一線nivolumab (NIVO) + ipilimumab (IPI)聯合化療(chemi)顯著改善了總生存期(OS;主要終點)與進展期NSCLC患者單獨化療比較。無論程序性死亡配體1表達或組織學如何，臨床獲益均可觀察到。在這裏，我們報告了一項關於基線(BL)腦轉移和非基線(BL)腦轉移患者療效和安全性結果的事後分析。
Methods
研究方法
Eligible patients were adults with stage IV/recurrent NSCLC, ECOG performance status ≤1, and no known sensitizingEGFR/ALKalterations. Patients with adequately treated brain metastases who were asymptomatic for ≥2 weeks prior to first treatment were eligible; corticosteroids were permitted if the dose was stable or decreasing at ≤10 mg daily prednisone (or equivalent) for ≥2 weeks prior to first study treatment. Patients were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) or chemo alone (4 cycles); treatment was until disease progression, unacceptable toxicity, or 2 years for immunotherapy. Brain MRI/CT was performed in all patients at BL, and in patients with history/symptoms of brain metastases during treatment, at 2 follow-up visits, and every 3 months thereafter until disease progression. Radiographic assessment of intracranial tumor response was performed per modified RECIST (adapted for brain metastases) by blinded independent central review.
符合條件的患者為成年IV期/複發NSCLC, ECOG性能狀態≤1，且無已知致敏EGFR/ALK改變。第一次治療前無症狀≥2周的充分治療腦轉移的患者是合格的;在第一次研究治療前，如果劑量穩定或以每日≤10 mg強的鬆(或等效)的劑量減少≥2周，則允許使用皮質類固醇。將患者1:1隨機分為NIVO 360 mg Q3W + IPI 1 mg/kg Q6W +化療(2個周期)或單獨化療(4個周期);治療直到疾病進展，不可接受的毒性，或2年的免疫治療。所有患者在BL時進行腦MRI/CT檢查，治療期間有腦轉移病史/症狀的患者在2次隨訪時進行腦MRI/CT檢查，此後每3個月進行一次，直到疾病進展。采用盲法獨立中央審查，按照改良的RECIST(適用於腦轉移)對顱內腫瘤反應進行影像學評估。
Types of Analysis and Data Reporting
分析和數據報告的類型
Baseline and disease characteristics; efficacy and safety outcomes including OS, progression-free survival, and response; and treatment-related adverse events for patients with and without baseline brain metastases in CheckMate 9LA are reported.
基線和疾病特征;療效和安全性結果，包括OS、無進展生存期和應答;報告了CheckMate 9LA基線腦轉移和基線腦轉移患者的治療相關不良事件。
Results
結果
Of 719 randomized patients, 101 (14%) had BL brain metastases. BL characteristics were generally similar between patients with and without BL brain metastases and between treatment arms, except for a slightly greater proportion of patients who had never smoked (NIVO + IPI + chemo arm) and patients with liver metastases (chemo arm) in the BL brain metastases subgroup. Survival and systemic efficacy outcomes were improved with NIVO + IPI + chemo versus chemo in patients with and without brain metastases (Table). Intracranial efficacy data will be reported in the presentation. In patients with BL brain metastases, any-grade neurological treatment-related adverse events occurred in 22% and 10% of the NIVO + IPI + chemo and chemo arms, respectively; most were grade 1/2.
在719例隨機患者中，101例(14%)有BL腦轉移。除了在BL腦轉移亞組中從未吸煙(NIVO + IPI +化療組)和有肝轉移(化療組)的患者比例稍高外，有無BL腦轉移的患者和治療組之間的BL特征基本相似。NIVO + IPI +化療與化療相比，有腦轉移和無腦轉移患者的生存和全身療效結果均得到改善(見表)。顱內療效數據將在報告中報告。在BL腦轉移患者中，NIVO + IPI +化療組和化療組中發生任何級別神經治療相關不良事件的比例分別為22%和10%;大多數是1/2級。
Table. Efficacy by BL brain metastases in CheckMate 9LA |
||||
Patients with BL brain metastases |
Patients without BL brain metastases |
|||
NIVO + IPI + chemo n = 51 |
Chemo n = 50 |
NIVO + IPI + chemo n = 310 |
Chemo n = 308 |
|
OS, median (95% CI), months |
19.3 (12.3–23.9) |
6.8 (4.7–9.7) |
15.6 (13.8–19.4) |
12.1 (10.2–13.7) |
HR vs chemo (95% CI) |
0.43 (0.27–0.67) |
–– |
0.79 (0.65–0.95) |
–– |
1-year rate, % (95% CI) |
67 (52.0–77.8) |
26 (14.9–38.6) |
62 (56.6–67.4) |
50 (44.6–55.8) |
2-year rate, % (95% CI) |
35 (22.6–48.2) |
12 (4.9–22.6) |
39 (33.3–44.1) |
29 (23.9–34.0) |
Systemic PFS,amedian (95% CI),months |
10.6 (6.7–12.6) |
4.1 (2.8–5.4) |
5.8 (5.2–7.3) |
5.4 (4.5–5.6) |
HR vs chemo (95% CI) |
0.40 (0.25–0.64) |
–– |
0.74 (0.62–0.89) |
–– |
1-year rate, % (95% CI) |
36 (22.4–50.2) |
8 (2.2–19.5) |
33 (27.2–38.0) |
21 (15.8–25.8) |
2-year rate, % (95% CI) |
19 (9.1–32.3) |
6 (1.0–15.9) |
20 (15.5–24.9) |
8 (5.3–12.6) |
Systemic ORR,an (%) |
22 (43) |
12 (24) |
115 (37) |
79 (26) |
95% CI |
29.3–57.8 |
13.1–38.2 |
31.7–42.7 |
20.9–30.9 |
Systemic DOR,amedian (95% CI), months |
15.5 (5.6–NR) |
4.4 (2.8–7.1) |
13.0 (8.6–20.2) |
5.7 (4.4–8.0) |
1-year rate, % (95% CI) |
51 (28–70) |
21 (3–49) |
52 (42–60) |
25 (16–35) |
2-year rate, % (95% CI) |
38 (17–59) |
0 |
34 (24–44) |
11 (5–19) |
aPer blinded independent central review. CI, confidence interval; DOR, duration of response; HR, hazard ratio; NR, not reached; ORR, objective response rate; PFS, progression-free survival. |
||||
Conclusion
結論
In patients with advanced NSCLC and BL brain metastases NIVO + IPI + chemo provided durable survival benefit versus chemo, consistent with benefits observed in all randomized patients from CheckMate 9LA. No new safety signals were identified.
在晚期NSCLC和BL腦轉移患者中，NIVO + IPI +化療比化療提供了持久的生存獲益，這與CheckMate 9LA所有隨機患者觀察到的獲益一致。沒有發現新的安全信號。
