Background

Black patients were severely under-represented in the clinical trials that led to the approval of immune checkpoint inhibitors (ICIs) for all cancers. The aim of this study was to characterise the effectiveness and safety of ICIs in Black patients.

Methods

We did a retrospective cohort study of patients in the US Veterans Health Administration (VHA) system's Corporate Data Warehouse containing electronic medical records for all patients who self-identified as non-Hispanic Black or African American (referred to as Black) or non-Hispanic White (referred to as White) and received PD-1, PD-L1, CTLA-4, or LAG-3 inhibitors between Jan 1, 2010, and Dec 31, 2023. Effectiveness outcomes were overall survival, time to treatment discontinuation, and time to next treatment. The safety outcome was the frequency of immune-related adverse events; assessed among a random sample of 1000 Black patients and 1000 White patients, 892 pairs were matched on the basis of baseline characteristics using 1:1 exact matching without replacement. After manual chart review, patients who did not receive ICI therapy or who had inadequate follow-up were excluded. The adjusted effect of race on each effectiveness outcome was assessed in the whole ICI-treated cohort with propensity-weighted Cox regression with robust standard errors. Immune-related adverse events outcomes were analysed in the random matched sample with multivariable Cox regression, adjusting for baseline characteristics.

Findings

We identified 26 398 patients, of whom 4943 (18·7%) patients were Black, 21 455 (81·3%) were White, 895 (3·4%) were female, 25 503 (96·6%) were male, 11 859 (45%) had non-small-cell lung cancer, and 26 045 (98·7%) received PD-1 or PD-L1 inhibitors. As of data cutoff (Aug 28, 2024), median follow-up was 40·3 months (95% CI 38·3–42·3) for Black patients and 43·9 months (43·0–45·1) for White patients. Compared with White patients, Black patients had longer time to treatment discontinuation (2-year unadjusted rates 10·7% [95% CI 9·8–11·7] for Black patients vs 8·6% [8·2–9·0] for White patients; adjusted hazard ratio [HR] 0·91, 95% CI 0·87–0·95, p<0·0001), similar time to next treatment (23·5% [22·3–24·8] for Black patients vs 25·6% [25·0–26·2] for White patients; 1·00, 0·95–1·05, p=0·96), and slightly improved overall survival (36·5% [35·2–38·1] for Black patients vs 36·5% [35·8–37·1]; 0·95, 0·90–0·99, p=0·036). 1710 patients (n=862 Black and n=848 White) were analysed for safety outcomes. Compared with White patients, Black patients had a reduced risk of all-grade immune-related adverse events (unadjusted 2-year rate 33·1% [95% CI 28·9–37·1] vs 44·1% [95% CI 39·1–48·7]; adjusted HR 0·75, 95% CI 0·62–0·90, p=0·0026), immune-related adverse events requiring treatment with systemic steroids (0·61, 0·46–0·81, p=0·00051), and immune-related adverse events resulting in permanent ICI discontinuation (0·58, 0·44–0·78, p=0·00024). In exploratory analyses of irAE subtypes, a significant risk reduction in Black patients was found for colitis (0·46, 0·27–0·76, p=0·0026) and hyperthyroidism or hypothyroidism (0·63, 0·44–0·90, p=0·011), and no significant differences were found for any other immune-related adverse event subtypes analysed. Similar results were found in analyses using a steroid-based definition of immune-related adverse events among the entire ICI-treated cohort.

Interpretation

Compared with White patients, Black patients had similar ICI effectiveness and lower toxicities among those treated in the national VHA system, potentially reflecting an important difference in the therapeutic ratio (ratio of benefit to harm) of ICIs. Our findings of decreased toxicity among Black patients require further investigation to assess their generalisability.

Funding

Million Veteran Program, Office of Research and Development, Veterans Health Administration and the LUNGevity foundation.

中文翻译：

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美国国家卫生系统中免疫检查点抑制剂在黑人患者与白人患者中的有效性和安全性：一项回顾性队列研究

 背景

黑人患者在导致免疫检查点抑制剂 （ICI） 获批用于所有癌症的临床试验中代表性严重不足。本研究的目的是描述 ICIs 在黑人患者中的有效性和安全性。

 方法

我们对美国退伍军人健康管理局 （VHA） 系统企业数据仓库中的患者进行了回顾性队列研究，其中包含所有自我认定为非西班牙裔黑人或非裔美国人（称为黑人）或非西班牙裔白人（称为白人）并在 1 月 1 日期间接受 PD-1、PD-L1、CTLA-4 或 LAG-3 抑制剂的患者的电子病历， 2010 年和 2023 年 12 月 31 日。有效性结局是总生存期、停止治疗时间和下一次治疗时间。安全性结果是免疫相关不良事件的频率;在 1000 名黑人患者和 1000 名白人患者的随机样本中进行评估，使用 1：1 精确匹配（无替换）根据基线特征匹配 892 对。在手动图表审查后，未接受 ICI 治疗或随访不充分的患者被排除在外。在整个 ICI 治疗的队列中，使用具有稳健标准误差的倾向加权 Cox 回归评估种族对每个有效性结果的调整后影响。在随机匹配样本中通过多变量 Cox 回归分析免疫相关不良事件结果，并调整基线特征。

 发现

我们确定了 26 398 例患者，其中 4943 例 （18·7%） 患者为黑人，21 455 例 （81·3%） 为白人，895 例 （3·4%） 为女性，25 503 例 （96·6%） 为男性，11 859 例 （45%） 为非小细胞肺癌，26 045 例 （98·7%） 接受 PD-1 或 PD-L1 抑制剂治疗。截至数据截止日期（2024 年 8 月 28 日），黑人患者的中位随访时间为 40·3 个月 （95% CI 38·3–42·3），白人患者的中位随访时间为 43·9 个月 （43·0–45·1）。与白人患者相比，黑人患者停止治疗的时间更长（黑人患者 2 年未调整率为 10·7% [95% CI 9·8–11·7]，白人患者为 8·6% [8·2–9·0];调整后风险比 [HR] 0·91,95% CI 0·87–0·95，p<0·0001），与下一次治疗相似的时间（黑人患者为 23·5% [22·3–24·8]，白人患者为 25·6% [25·0–26·2];病人;1·00， 0·95–1·05， p=0·96），总生存期略有提高（黑人患者为 36·5% [35·2–38·1] vs 36·5% [35·8–37·1];0·95， 0·90–0·99，p=0·036）。对 1710 例患者 （n=862 Black 和 n=848 White） 进行了安全性结局分析。与白人患者相比，黑人患者发生所有级别免疫相关不良事件的风险降低（未经调整的 2 年率 33·1% [95% CI 28·9–37·1] vs 44·1% [95% CI 39·1–48·7];调整后的 HR 0·75,95% CI 0·62–0·90，p=0·0026），需要全身性类固醇治疗的免疫相关不良事件（0·61，” 0·46–0·81，p=0·00051），以及导致永久性 ICI 停药的免疫相关不良事件（0·58,0·44–0·78，p=0·00024）。在对 irAE 亚型的探索性分析中，发现黑人患者患结肠炎 （0·46， 0·27–0·76， p=0·0026） 和甲状腺功能亢进症或甲状腺功能减退症 （0·63， 0·44–0·90， p=0·011） 的风险显著降低，并且未发现任何其他免疫相关不良事件亚型分析的显著差异。 在整个 ICI 治疗队列中使用基于类固醇的免疫相关不良事件定义的分析中发现了类似的结果。

 解释

与白人患者相比，黑人患者在国家 VHA 系统中接受治疗的患者具有相似的 ICI 有效性和较低的毒性，这可能反映了 ICI 治疗比率（利弊比）的重要差异。我们关于黑人患者毒性降低的发现需要进一步调查以评估其普遍性。

 资金

百万退伍军人计划、研究与发展办公室、退伍军人健康管理局和 LUNGevity 基金会。