进展期NSCLC和脑转移患者的一线Nivolumab + Ipilimumab +化疗和脑转移患者的一线Nivolumab + Ipilimumab +化疗
1.First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA 进展期NSCLC和脑转移患者的一线Nivolumab + Ipilimumab +化疗:来自CheckMate 9LA的结果 Introductio
1. First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA
进展期NSCLC和脑转移患者的一线Nivolumab + Ipilimumab +化疗:来自CheckMate 9LA的结果
Introduction
介绍
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.
进展期非小细胞肺癌(NSCLC)和脑转移患者有很高的未满足需求，检查点抑制剂可以获益。在随机3期CheckMate 9LA试验(NCT03215706)中，一线nivolumab (NIVO) + ipilimumab (IPI)联合化疗(chemi)显著改善了总生存期(OS;主要终点)与进展期NSCLC患者单独化疗比较。无论程序性死亡配体1表达或组织学如何，临床获益均可观察到。在这里，我们报告了一项关于基线(BL)脑转移和非基线(BL)脑转移患者疗效和安全性结果的事后分析。
Methods
研究方法
Eligible patients were adults with stage IV/recurrent NSCLC, ECOG performance status ≤1, and no known sensitizing EGFR/ALK alterations. 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.
符合条件的患者为成年IV期/复发NSCLC, ECOG性能状态≤1，且无已知致敏EGFR/ALK改变。第一次治疗前无症状≥2周的充分治疗脑转移的患者是合格的;在第一次研究治疗前，如果剂量稳定或以每日≤10 mg强的松(或等效)的剂量减少≥2周，则允许使用皮质类固醇。将患者1:1随机分为NIVO 360 mg Q3W + IPI 1 mg/kg Q6W +化疗(2个周期)或单独化疗(4个周期);治疗直到疾病进展，不可接受的毒性，或2年的免疫治疗。所有患者在BL时进行脑MRI/CT检查，治疗期间有脑转移病史/症状的患者在2次随访时进行脑MRI/CT检查，此后每3个月进行一次，直到疾病进展。采用盲法独立中央审查，按照改良的RECIST(适用于脑转移)对颅内肿瘤反应进行影像学评估。
Types of Analysis and Data Reporting
分析和数据报告的类型
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.
基线和疾病特征;疗效和安全性结果，包括OS、无进展生存期和应答;报告了CheckMate 9LA基线脑转移和基线脑转移患者的治疗相关不良事件。
Results
结果
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例随机患者中，101例(14%)有BL脑转移。除了在BL脑转移亚组中从未吸烟(NIVO + IPI +化疗组)和有肝转移(化疗组)的患者比例稍高外，有无BL脑转移的患者和治疗组之间的BL特征基本相似。NIVO + IPI +化疗与化疗相比，有脑转移和无脑转移患者的生存和全身疗效结果均得到改善(见表)。颅内疗效数据将在报告中报告。在BL脑转移患者中，NIVO + IPI +化疗组和化疗组中发生任何级别神经治疗相关不良事件的比例分别为22%和10%;大多数是1/2级。
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Table. Efficacy by BL brain metastases in CheckMate 9LA |
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Patients with BL brain metastases |
Patients without BL brain metastases |
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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,a median (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) |
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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) |
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Systemic ORR,a n (%) |
22 (43) |
12 (24) |
115 (37) |
79 (26) |
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95% CI |
29.3–57.8 |
13.1–38.2 |
31.7–42.7 |
20.9–30.9 |
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Systemic DOR,a median (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) |
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1-year rate, % (95% CI) |
51 (28–70) |
21 (3–49) |
52 (42–60) |
25 (16–35) |
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2-year rate, % (95% CI) |
38 (17–59) |
0 |
34 (24–44) |
11 (5–19) |
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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. |
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Conclusion
结论
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脑转移患者中，NIVO + IPI +化疗比化疗提供了持久的生存获益，这与CheckMate 9LA所有随机患者观察到的获益一致。没有发现新的安全信号。
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