各位好！今天与大家分享一篇近期发表在JITC上的一篇文献，该研究回顾了使用atezolizumab的临床试验数据，作者尝试阐明不同器官免疫副反应及副反应程度与总生存的关系。究竟有没有哪些器官的副反应预示着更好的预后，一起来看看？
Correlation of safety and efficacy of atezolizumab therapy across indications
Gonzalo Durán-Pacheco,1 G Scott Chandler ,1,2 Vidya Maiya,3 Mark A Socinski,4 Guru Sonpavde ,4,5 Javier Puente,6 Laurent Essioux,7 Corey Carter,3 Jose Vicente Cardona,1 Rajat Mohindra,2 Jarushka Naidoo8,9
Journal for ImmunoTherapy of Cancer 18 October 2024
Background: The association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer outcomes is poorly understood. Most irAEs are mild-to-moderate but severe irAEs may pose clinical management challenges and affect patient outcomes.
背景：免疫检查点抑制剂的安全性和有效性之间的关联是已知的，但免疫相关不良事件（irAE）对特定器官影响的严重程度和影响与癌症结局之间的相关性知之甚少。大多数irAE为轻至中度，但严重irAE可能会带来临床管理挑战并影响患者结果。
Methods: We assessed the association between irAE grade (G) and specific organ involvement with overall survival (OS) in 9,521 patients across 14 studies involving atezolizumab as mono (IO) or with chemo/targeted (C-IO) therapy as compared with chemo/targeted therapy (C) in advanced non-small cell lung, small-cell lung, renal cell, urothelial, and triple-negative breast cancers. We used a mixed-effect Cox proportional hazard model for time-varying covariates to address immortal-time bias; adjusted for baseline factors associated with irAEs and OS to control for confounding bias; and focused on five common irAEs (dermatologic, thyroid dysfunction, hepatitis, pneumonitis, and colitis) to avoid low statistical power for rare events.
方法：我们在14项涉及atezolumab单药（IO）或与化疗/靶向（C-IO）治疗的研究中评估了irAE分级（G）和特定器官受累与总生存期（OS）之间的关系，并与化疗/靶向治疗（C）进行了比较晚期非小细胞肺癌、小细胞肺癌、肾细胞癌、尿路内皮癌和三阴性乳腺癌。我们使用时变协变量的混合效应Cox比例风险模型来解决永恒时间偏差;调整与irAE和OS相关的基线因素以控制混杂偏差;并重点关注五种常见irAE（皮肤病、甲状腺功能障碍、肝炎、肺炎和结肠炎），以避免罕见事件的统计功效较低。
Results: For patients treated with IO or C-IO, G1-2 irAEs were associated with improved OS (HR=0.65, p<0.01) and G3-4 irAEs showed a slight increased risk of death (HR=1.18, p=0.10) versus patients without irAEs. By specific irAE, G1-2 cutaneous irAEs, thyroid dysfunction, or pneumonitis were associated with improved OS (p<0.05), while G3-4 pneumonitis and colitis were associated with worse OS (p<0.01). There was no association between hepatitis and OS by any grade. Findings were consistent across indications.
结果：对于接受IO或C-IO治疗的患者，G1-2 irAE与OS改善相关（HR=0.65，p<0.01），G3-4 irAE显示死亡风险略有增加（HR=1.18，p=0.10）。通过特定irAE，G1-2皮肤irAE、甲状腺功能障碍或肺炎与OS改善相关（p<0.05），而G3-4肺炎和结肠炎与OS恶化相关（p<0.01）。肝炎与OS之间没有任何等级的关联。各适应症的结果一致。
Conclusions: This analysis demonstrates a correlation between irAEs and improved OS with atezolizumab by severity grade and the most common irAEs by organ involvement. Low-grade irAEs are significantly associated with improved OS, while specific high-grade irAEs are associated with poorer OS, underscoring the importance of early recognition and management of toxicity to optimize benefit/risk balance.
结论：该分析表明，irAE与atezolumab治疗后的OS改善之间存在相关性，并按器官受累程度显示，irAE与atezolumab治疗后的OS改善之间存在相关性。低级别irAE与OS改善显着相关，而特定的高级别irAE与OS较差相关，这凸显了早期识别和管理毒性以优化获益/风险平衡的重要性。
1. 随着免疫治疗在抗肿瘤治疗中的广泛应用，首先我们还是得先系统学习下免疫副反应的诊疗。
2.上细节：
首先本文是基于有atezolizumab的14个临床试验的数据进行的二次分析。研究主要分析了5个主要的免疫副反应（皮肤、肝、甲状腺、肺、直肠副反应）与OS的相关性。研究结论很清晰，G1- 2皮肤副反应、甲状腺、肺炎可能与OS更好相关。G3-4 的直肠副反应、肺炎与更差的OS相关。免疫性肝炎程度与OS并无显著相关。
其次，文章方法算是两个亮点，第一是呈现了不同类型副反应在用药后出现的大概时间。第二是使用了mixed- effect Cox proportional hazard model来解决永恒时间偏倚的问题。并详细的在文中提供了进行分析的R包，有兴趣的可以学习模仿。
第三，文章在讨论部分也详细针对每个副反应分析中可能存在的系统性误差进行了详细分析。甚至在更大视角下，副反应与OS间还存在许多治疗，如激素的应用及对抗肿瘤免疫、OS的影响。仅以现有数据进行的分析可能也只是管中窥豹，但这篇文献为我们呈现了大规模开展前瞻性免疫副反应研究可能面临的技术问题和基础数据。
3.对于免疫副反应，目前仍然缺乏更广泛和更深入的研究，借着JITC这个ppt一起来学下如何开展这方面的研究吧。
目录
1. INTRODUCTION
2. Methods
2.1 Patients and outcomes (figure S1)(supplemental table S1)
2.2 Statistical methods (Table 1)(supplemental table S3)
3. Results (table 1, online supplemental table S2)(online supplemental figure S2-3)
3.1 Timing of irAEs (online supplemental figure S4)
3.2 Overall survival (Figure 1-2)(Table 2)(Figure 3)(supplemental table S4)
4. Discussion
— 图表汇总—
2.1 Patients and outcomes
Figure S1. Patients disposition
IO = atezolizumab as monotherapy, C-IO = atezolizumab in combination with chemotherapy and/or bevacizumab.
* Other therapies = Sunitinib (advanced renal cell carcinoma studies) .
supplemental table S1. Studies, indications, therapy arm description and number of eligible patients (N)
irAEs = immune-related adverse events were reported in all study arms, including Standard of Care without atezolizumab, given the blinded nature of the controlled trials.
2.2 Statistical methods
Table 1. Incidence proportion and incidence rate of irAEs in patients treated with atezolizumab (alone or in combination) and chemotherapy
supplemental table S3. List of baseline covariates adjusted in the statistical models
3. Results
Supplemental table S2. Incidence proportion and incidence rate of irAEs by indication
a) NSCLC/SCLC
b) Advanced Renal Cell Carcinoma
c) Urothelial Bladder Cancer
d) Triple negative breast cancer
Supplemental figure S2. Proportion of irAEs, by toxicity grade and cancer indication
irAEs = immune-related adverse events were reported in all study arms, including Standard of Care without atezolizumab, given the blinded nature of the controlled trials. IO = atezolizumab monotherapy, C-IO = atezolizumab in combination with chemotherapy or bevacizumab, chemotherapy = Chemotherapy regime or chemotherapy with bevacizumab. Skin = immune-related rash, immune-related severe cutaneous reactions. Hepatitis = immune-related hepatitis (clinical diagnosis), immune-related hepatitis (lab abnormalities). Thyroid = immune-related hypothyroidism, immune-related hyperthyroidism, immune-related thyroiditis.
Supplemental figure S3. Incidence rates (incidence densities) of irAE per 100 patients-years at risk
irAEs = immune-related adverse events were reported in all study arms, including Standard of Care without atezolizumab, given the blinded nature of the controlled trials.
3.1 Timing of irAEs
Supplemental figure S4. Estimation of the hazard function of the top 5 irAEs for patients treated with IO | C IO and C, using: the piecewise exponential hazard function (gray) and kernel-based methods (black)
irAEs = immune-related adverse events were reported in all study arms, including Standard of Care without atezolizumab, given the blinded nature of the controlled trials.
IO = atezolizumab monotherapy, C-IO = atezolizumab in combination with chemotherapy or bevacizumab, chemotherapy = Chemotherapy regime or chemotherapy with bevacizumab.
Skin = immune-related rash, immune-related severe cutaneous reactions.
Hepatitis = immune-related hepatitis (clinical diagnosis), immune-related hepatitis (lab abnormalities).
Thyroid = immune-related hypothyroidism, immune-related hyperthyroidism, immune-related thyroiditis.
3.2 Overall survival
Figure 1. Study-specific and individual-patient level meta-analysis HR estimates for the effect of any irAE on OS in patients treated with IO/C-IO. irAE is treated as a time-varying covariate.
(a) Effect of any grade 1–2 irAE (whichever occurred first) on OS in study arms where patients were treated with IO/C-IO.
(b) Effect of any grade 1–2 irAE (whichever occurred first) on OS in study arms where patients were treated with chemotherapy.
(c) Effect of any grade 3–4 irAE (whichever occurred first) on OS in study arms where patients were treated with IO/C-IO.
(d) Effect of any grade 3–4 irAE (whichever occurred first) on OS in study arms where patients were treated with chemotherapy.
(e) Individual-patient level data meta-analytic HR estimates of the mixed-effect cox regression analysis for the effect of any irAE on OS by toxicity grade.
TRT: Chemotherapy=treatment with chemotherapy regimen or chemotherapy with bevacizumab; TRT: C-IO=treatment with atezolizumab in combination with chemotherapy or bevacizumab; FDR, false discovery rate; TRT: IO=treatment with atezolizumab monotherapy; irAEsimmune-related adverse events were reported in all study arms, including standard of care without atezolizumab, given the blinded nature of the controlled trials; lower, lower confidence limit, OS, overall survival; upper, upper confidence limit, *both confidence limits have been adjusted using the FDR principle.
Figure 2. Overall survival of patients under atezolizumab (IO/C-IO) and chemotherapy (C) when available, who experienced grade 1–2, 3–4 (time-varying) irAEs in four cancer indications: non-small cell lung cancer and small cell lung cancer (a); renal cell carcinoma (b); urothelial bladder cancer (c); and triple-negative breast cancer (d).
TRT=treatment regimen as follows: C=chemotherapy regimen or chemotherapy with bevacizumab; C-IO=treatment with atezolizumab in combination with chemotherapy or bevacizumab; IO=treatment with atezolizumab monotherapy. irAEs, immune-related adverse events were reported in all study arms, including standard of care without atezolizumab, given the blinded nature of the controlled trials; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; TNBC, triple-negative breast cancer.
Table 2. Median OS, 95% CIs, number of irAE and OS events by cancer indication, therapy group and irAE grade
Figure 3. Individual-patient level data meta-analytic HRs for the effect of any irAE, dermatologic, hepatitis, thyroid, pneumonitis and colitis irAEs on overall survival in patients treated with atezolizumab (mono or in combination) and with chemotherapy.
TRT: C=chemotherapy, chemotherapy regimen or chemotherapy with bevacizumab; TRT: C-IO=treatment with atezolizumab in combination with chemotherapy or bevacizumab; FDR, false discovery rate; hepatitis, immune-related hepatitis (clinical diagnosis), immune-related hepatitis (laboratory abnormalities); TRT: IO= treatment with atezolizumab monotherapy; irAEs, immune-related adverse events were reported in all study arms, including standard of care without atezolizumab, given the blinded nature of the controlled trials; skin, immune-related rash, immune-related severe cutaneous reactions; thyroid, immune-related hypothyroidism, immune-related hyperthyroidism, immune-related thyroiditis.
supplemental table S4. Individual-patient level meta-analysis Hazard Ratio estimates, confidence intervals, p-values for the association of onset of irAE with Overall Survival in patients treated with atezolizumab (alone or in combination) and with chemotherapy.
* Confidence intervals using FDR corrections
irAEs = immune-related adverse events were reported in all study arms, including Standard of Care without atezolizumab, given the blinded nature of the controlled trials.
IO = atezolizumab monotherapy, C-IO = atezolizumab in combination with chemotherapy or bevacizumab, chemotherapy = Chemotherapy regime or chemotherapy with bevacizumab.
Skin = immune-related rash, immune-related severe cutaneous reactions.
Hepatitis = immune-related hepatitis (clinical diagnosis), immune-related hepatitis (lab abnormalities).
Thyroid = immune-related hypothyroidism, immune-related hyperthyroidism, immune-related thyroiditis.
