Effectiveness and safety of immune checkpoint inhibitors in Black patients versus White patients in a US national health system: a retrospective cohort study

Sean Miller, Ralph Jiang, Matthew Schipper, Lars G Fritsche, Garth Strohbehn, Beth Wallace, Daria Brinzevich, Virginia Falvello, Benjamin H McMahon, Rafael Zamora-Resendiz, Nithya Ramnath, Xin Dai, Kamya Sankar, Donna M Edwards, Steven G Allen, Shinjae Yoo, Silvia Crivelli, Michael D Green, Alex K Bryant
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The aim of this study was to characterise the effectiveness and safety of ICIs in Black patients.<h3>Methods</h3>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.<h3>Findings</h3>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 <em>vs</em> 8·6% [8·2–9·0] for White patients; adjusted hazard ratio [HR] 0·91, 95% CI 0·87–0·95, p&lt;0·0001), similar time to next treatment (23·5% [22·3–24·8] for Black patients <em>vs</em> 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 <em>vs</em> 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] <em>vs</em> 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.<h3>Interpretation</h3>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.<h3>Funding</h3>Million Veteran Program, Office of Research and Development, Veterans Health Administration and the LUNGevity foundation.","PeriodicalId":22865,"journal":{"name":"The Lancet Oncology","volume":"1 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Lancet Oncology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/s1470-2045(24)00528-x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract

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.
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美国国家医疗系统中黑人患者与白人患者使用免疫检查点抑制剂的有效性和安全性: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(ICIs)获准用于所有癌症的临床试验中代表性严重不足。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一项回顾性队列研究,该数据库包含所有自称为非西班牙裔黑人或非裔美国人(简称黑人)或非西班牙裔白人(简称白人),并在2010年1月1日至2023年12月31日期间接受过PD-1、PD-L1、CTLA-4或LAG-3抑制剂治疗的患者的电子病历。疗效指标为总生存期、终止治疗时间和下次治疗时间。安全性结果是免疫相关不良事件的发生频率;在随机抽取的 1000 名黑人患者和 1000 名白人患者中进行评估,根据基线特征采用 1:1 精确配对法对 892 对患者进行配对,不进行替换。经过人工病历审查,未接受 ICI 治疗或随访不足的患者被排除在外。采用带有稳健标准误差的倾向加权 Cox 回归法评估了整个 ICI 治疗队列中种族对每种疗效结果的调整效应。我们发现了26 398名患者,其中4943人(18-7%)为黑人,21 455人(81-3%)为白人,895人(3-4%)为女性,25 503人(96-6%)为男性,11 859人(45%)患有非小细胞肺癌,26 045人(98-7%)接受了PD-1或PD-L1抑制剂治疗。截至数据截止日(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,黑人患者中断治疗的时间更长(2 年未调整率黑人患者为 10-7% [95% CI 9-8-11-7] ,白人患者为 8-6% [8-2-9-0];调整后危险比 [HR] 0-91,95% CI 0-87-0-95,p<;0-0001),下次治疗时间相似(黑人患者为23-5% [22-3-24-8] vs 白人患者为25-6% [25-0-26-2]; 1-00, 0-95-1-05, p=0-96),总生存期略有改善(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名患者(黑人患者862人,白人患者848人)进行了安全性结果分析。与白人患者相比,黑人患者发生所有等级免疫相关不良事件的风险较低(未经调整的 2 年不良事件发生率为 33-1% [95% CI 28-9-37-1] vs 44-1% [95% CI 39-1-48-7];调整后 HR 0-75,95% CI 0-62-0-90,p=0-0026)、需要使用全身类固醇治疗的免疫相关不良事件(0-61,0-46-0-81,p=0-00051)和导致永久停用 ICI 的免疫相关不良事件(0-58,0-44-0-78,p=0-00024)。在对免疫相关不良事件亚型的探索性分析中发现,黑人患者发生结肠炎(0-46,0-27-0-76,p=0-0026)和甲状腺功能亢进或甲状腺功能减退(0-63,0-44-0-90,p=0-011)的风险显著降低,而在分析的其他免疫相关不良事件亚型中未发现显著差异。在使用基于类固醇的免疫相关不良事件定义对整个ICI治疗队列进行分析时,也发现了类似的结果。与白人患者相比,黑人患者的ICI疗效相似,而在全国VHA系统中接受治疗的患者的毒性较低,这可能反映出ICI的治疗比(获益与伤害之比)存在重要差异。我们关于黑人患者毒性降低的研究结果需要进一步调查,以评估其普遍性。
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