Heyward James, Lesko Catherine R, Murray Joseph C, Mehta Hemalkumar B, Segal Jodi B
Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
JAMA Oncol. 2025 May 8. doi: 10.1001/jamaoncol.2025.0985.
The benefits and harms of immune checkpoint inhibitor (ICI) therapy for lung cancer vary across groups, including those typically underrepresented in randomized clinical trials.
To quantify the harms and benefits of ICI-containing regimens in individuals with non-small cell lung cancer and assess heterogeneity across priority subgroups.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted in 2024 used 2013 to 2019 Surveillance, Epidemiology, and End Results (SEER) Medicare data of individuals 66 years or older with non-small cell lung cancer who were exposed to any ICI.
ICI + chemotherapy, single ICI (reference group).
Severe immune-related adverse events (irAE; harm) and mortality (when delayed mortality was the benefit). Severe irAEs were defined using validated diagnosis and medication codes. Mortality was ascertained from Medicare data. Hazard ratios (HRs) were estimated and 95% CIs were stratified by whether an ICI was used as the first or second or later systemic anticancer treatment (SACT) and in subgroups defined by preexisting autoimmune disease, sex, and age. The harm-benefit tradeoff was described as excess severe irAEs per year of life gained in which the gain in survival time was assessed using restricted mean survival time.
Of 17 681 Medicare beneficiaries, 8797 (49.5%) were female, and the mean (SD) age was 74 (6.0) years. Compared with a single ICI (14 249 [80.6%]), individuals treated with ICI + chemotherapy (3432 [19.4%]) had an elevated risk of severe irAE in the first SACT setting (hazard ratio [HR], 1.18; 95% CI, 1.06-1.30) but not in the second or later SACT setting (HR, 1.04; 95% CI, 0.92-1.19); there was a decreased risk of mortality in the first SACT setting (HR, 0.66; 95% CI, 0.62-0.72) but not in the second or later SACT setting (HR, 0.94; 95% CI, 0.68-1.03). In the first SACT setting, ICI + chemotherapy delayed mortality more among patients with (vs without) autoimmune disease at baseline. For each 1 year of life gained, the risk of severe irAEs was 0.31 (95% CI, 0.09-0.53) and the tradeoff was also statistically significant in men and patients without autoimmune disease.
The results of this cohort study suggest that given both treatment-related harms and benefits, ICI + chemotherapy use in the first SACT setting requires informed decision-making; the potential benefits of ICI + chemotherapy vs single ICI in high-risk subgroups is encouraging.
免疫检查点抑制剂（ICI）疗法对肺癌的益处和危害因群体而异，包括那些在随机临床试验中代表性通常不足的群体。
量化含ICI方案对非小细胞肺癌患者的危害和益处，并评估优先亚组之间的异质性。
设计、地点和参与者：这项于2024年进行的回顾性队列研究使用了2013年至2019年监测、流行病学和最终结果（SEER）医疗保险数据，这些数据来自66岁及以上接受过任何ICI治疗的非小细胞肺癌患者。
ICI + 化疗、单药ICI（参照组）。
严重免疫相关不良事件（irAE；危害）和死亡率（当延迟死亡为益处时）。严重irAE使用经过验证的诊断和用药代码进行定义。死亡率从医疗保险数据中确定。估计风险比（HR），并根据ICI是用作首次还是第二次或后续全身抗癌治疗（SACT）以及根据既往自身免疫性疾病、性别和年龄定义的亚组对95%置信区间进行分层。危害-益处权衡被描述为每获得一年生命所增加的严重irAE数量，其中使用受限平均生存时间评估生存时间的增加。
在17681名医疗保险受益人中，8797名（49.5%）为女性，平均（标准差）年龄为74（6.0）岁。与单药ICI（14249名[80.6%]）相比，接受ICI + 化疗的患者（3432名[19.4%]）在首次SACT治疗时发生严重irAE的风险升高（风险比[HR]，1.18；95%置信区间，1.06 - 1.30），但在第二次或后续SACT治疗时未升高（HR，1.04；95%置信区间，0.92 - 1.19）；在首次SACT治疗时死亡风险降低（HR = 0.66；95%置信区间，0.62 - 0.72），但在第二次或后续SACT治疗时未降低（HR = 0.94；95%置信区间，0.68 - 1.03）。在首次SACT治疗时，基线时有（相对于无）自身免疫性疾病的患者中，ICI + 化疗使死亡延迟更多。每获得1年生命，严重irAE的风险为0.31（95%置信区间，0.09 - 0.53），并且这种权衡在男性和无自身免疫性疾病的患者中也具有统计学意义。
这项队列研究的结果表明，考虑到治疗相关的危害和益处后，在首次SACT治疗时使用ICI + 化疗需要进行知情决策；在高危亚组中，ICI + 化疗相对于单药ICI的潜在益处令人鼓舞。
