Miller Sean, Jiang Ralph, Schipper Matthew, Fritsche Lars G, Strohbehn Garth, Wallace Beth, Brinzevich Daria, Falvello Virginia, McMahon Benjamin H, Zamora-Resendiz Rafael, Ramnath Nithya, Dai Xin, Sankar Kamya, Edwards Donna M, Allen Steven G, Yoo Shinjae, Crivelli Silvia, Green Michael D, Bryant Alex K
Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Lancet Oncol. 2024 Dec;25(12):1666-1676. doi: 10.1016/S1470-2045(24)00528-X. Epub 2024 Nov 14.
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.
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.
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.
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.
Million Veteran Program, Office of Research and Development, Veterans Health Administration and the LUNGevity foundation.
在导致免疫检查点抑制剂（ICIs）被批准用于所有癌症的临床试验中，黑人患者的代表性严重不足。本研究的目的是描述ICIs在黑人患者中的有效性和安全性。
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，该仓库包含所有自我认定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）且在2010年1月1日至2023年12月31日期间接受PD - 1、PD - L1、CTLA - 4或LAG - 3抑制剂治疗的患者的电子病历。有效性结局包括总生存期、治疗中断时间和下次治疗时间。安全性结局是免疫相关不良事件的发生率；在1000名黑人患者和1000名白人患者的随机样本中进行评估，基于基线特征使用1:1精确匹配且无放回的方式匹配了892对。经过人工病历审查，未接受ICI治疗或随访不充分的患者被排除。在整个接受ICI治疗的队列中，使用倾向加权Cox回归和稳健标准误评估种族对每个有效性结局的调整效应。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局，并对基线特征进行调整。
我们识别出26398名患者，其中4943名（18.7%）为黑人，21455名（81.3%）为白人，895名（3.4%）为女性，25503名（96.6%）为男性，11859名（45%）患有非小细胞肺癌，26045名（98.7%）接受了PD - 1或PD - L1抑制剂治疗。截至数据截止（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），白人患者为43.9个月（43.0 - 45.1）。与白人患者相比，黑人患者的治疗中断时间更长（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]；调整后的风险比[HR]为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]，白人患者为25.6%[25.0 - 26.2]；HR为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]，白人患者为36.5%[35.8 - 37.1]；HR为0.95，0.90 - 0.99，p = 0.036）。对1710名患者（862名黑人患者和848名白人患者）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的免疫相关不良事件的风险降低（未调整的2年发生率为33.1%[95%CI 28.9 - 37.1]，白人患者为44.1%[95%CI 39.1 - 48.7]；调整后的HR为0.75，95%CI 0.62 - 0.90，p = 0.0026），需要使用全身性类固醇治疗的免疫相关不良事件（HR为0.61，0.46 - 0.81，p = 0.00051），以及导致永久性停用ICI的免疫相关不良事件（HR为0.58，0.44 - 0.78，p = 0.00024）。在免疫相关不良事件亚型的探索性分析中，发现黑人患者患结肠炎（HR为0.46，0.27 - 0.76，p = 0.0026）和甲状腺功能亢进或减退（HR为0.63，0.44 - 0.90，p = 0.011）的风险显著降低，而在分析的任何其他免疫相关不良事件亚型中未发现显著差异。在整个接受ICI治疗的队列中，使用基于类固醇的免疫相关不良事件定义进行分析也得到了类似结果。
与白人患者相比，在国家VHA系统接受治疗的黑人患者ICI有效性相似，但毒性较低，这可能反映了ICI治疗获益 - 风险比的重要差异。我们关于黑人患者毒性降低的发现需要进一步研究以评估其普遍性。
百万退伍军人计划、研发办公室、退伍军人健康管理局和长寿基金会。
