Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3–4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.     

Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer

Tobacco is a known risk factor for lung cancer, and continued tobacco use is associated with poorer outcomes across multiple lung cancer treatment modalities including surgery, chemotherapy and radiation therapy. Less is known about the association of tobacco use and outcomes with immune checkpoint inhibitors (ICIs), which are becoming an important part of the treatment landscape in lung cancer, both in metastatic and curative settings. We reviewed the literature on the association of tobacco and tumor biology as it relates to immunotherapy. We also reviewed the association of tobacco use on outcomes among phase III randomized clinical trials involving ICIs in non-small cell lung cancer (NSCLC). We identified that patients with a smoking history may have a greater benefit with ICI treatment compared to never smokers in both treatment-naïve (HR 0.82, 95% CI 0.69–0.97, vs. HR 1.06, 95% CI 0.81–1.38) and pre-treated (HR 0.79, 95% CI 0.70–0.90 vs. 1.03, 95% CI 0.74–1.43) settings. In trials where smoking status was further defined, ex-smokers appear to demonstrate greater benefit with ICI therapy compared to current smokers (HR 0.78, 95% CI 0.59–1.01 vs. 0.91, 95% CI 0.72–1.14). We conclude by offering our perspective on future directions in this area of research, including implementation of standardized collection and analysis of tobacco use in clinical trials involving ICI therapy in lung cancer and other disease sites, and also evaluating how tobacco may affect toxicities related to ICI therapy. Based on our review, we believe that a patient’s history of tobacco smoking does have a role to play in guiding treatment decision making in patients with lung cancer.     

Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer

Introduction

Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described.

Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings

BackgroundImmune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited.Patients and MethodsThis was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases.ResultsThe PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS.ConclusionsThe 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.     

癌症患者表皮生长因子抑制剂皮肤毒性的处理

靶向药物导致不同的副作用,最常见的是皮肤毒性,如毛囊炎、皮疹、瘙痒、皮肤干燥和毛发异常,而且持续时间长,常需要仔细的临床处理,使患者顺利完成治疗。     

Immune Checkpoint Inhibitor Rechallenge Safety and Efficacy in Stage IV Non-Small Cell Lung Cancer Patients After Immune-Related Adverse Events

BackgroundDespite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥ 2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging.MethodsWe retrospectively studied 1051 adult patients with stage IV non-small cell lung cancer (NSCLC) treated with ICIs at a single institution between January 2015 and December 2020, and identified 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption. Forty patients underwent retreatment (rechallenged group), while 59 discontinued the treatment (discontinued group).ResultsBaseline characteristics of patients in the 2 groups were similar. Initial irAEs were less severe in the rechallenged group. After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. Twenty (50%) developed second grade≥ 2 irAEs. No grade 4 irAE or irAE-related death occurred after rechallenging. Using multivariate analysis, no statistically significant differences in overall survival (OS) (HR: 1.10, 95% CI: 0.57-2.15, P = .77) or progression-free survival (PFS) (HR: 0.87, 95% CI: 0.45-1.71, P = .69) were noted between the 2 groups, while the best objective response prior to the initial irAEs was the only variable affecting OS and PFS.ConclusionsRechallenge was associated with a relative high risk of second grade≥ 2 irAEs. The risk was less if the initial irAEs were resolved. No differences were seen in survival outcomes of patients who had ICI rechallenge and those who did not. Permanent ICI discontinuation is an appropriate strategy after grade≥ 2 irAEs, especially severe irAEs.     

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.     

免疫检测点在宫颈癌中的研究进展

摘 要：T细胞是杀伤表达肿瘤特异性抗原的肿瘤细胞的重要成分。众所周知,肿瘤免疫逃逸是肿瘤发生发展的一个重要机制。免疫检测点治疗是以T细胞的调节通路为靶点来提高抗肿瘤效应的治疗方法。近年来,免疫检测点参与肿瘤免疫逃逸而受到极大的关注,并在肿瘤免疫治疗方面取得了有效进展。全文就免疫检测点与宫颈癌治疗的应用研究进展作一综述。     

影像组学在晚期非小细胞肺癌免疫检查点抑制剂治疗中的应用研究进展

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)越来越多地应用于晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床治疗中,给患者带来显著的生存获益.影像组学在晚期NSCLC患者ICIs治疗中的研究主要集中在疗效评估相关的三个方面,包括...     

恶性肿瘤免疫检查点治疗的未来发展方向

2011年,FDA批准了第一个免疫检查点抑制剂（ICIs）——CTLA-4抑制剂Ipilimumab,以ICIs为代表的免疫检查点治疗（ICT）取得了突破进展。ICIs可诱导某些肿瘤患者亚群产生持久的抗肿瘤反应,但目前仍存在较多问题,比如获益人群的选择、严重免疫毒性的管理,以及如何通过合理的组合策略克服原发和适应性耐药机制来改善治疗反应等。本综述全面分析了当前对 ICIs 的反应和抵抗机制,并提出了通过更好的患者选择和合理组合来实现疗效最大化和毒性最小化的途径。     

Immune Checkpoint Inhibitor Toxicity

Purpose of review

Immune checkpoint inhibitors have revolutionised the treatment of multiple malignancies and have a growing list of indications. As our familiarity with these agents grows, so does our understanding of their unique spectrum of toxicities. Here, we will review the literature regarding the toxicities of checkpoint inhibitors and address challenges encountered in day-to-day clinical practice.

Recent findings

Inhibitors of the PD-1/PD-L1 axis are considerably less toxic than the anti-CTLA-4 antibody ipilimumab. The combination of ipilimumab and anti-PD-1 agents is being trialled in multiple malignancies and is associated with increased toxicity. There is accumulating evidence suggesting a potential correlation between a subset of toxicities and clinical benefit in several tumour types, although conflicting data exists. Retrospective series have shown that anti-PD-1 can be safely administered to patients with prior high-grade toxicity from ipilimumab or combination immunotherapy.

Summary

The management of checkpoint inhibitor toxicity is complex and requires collaboration with our subspecialty colleagues. Identifying predictive biomarkers of both efficacy and toxicity would likely help guide treatment decisions, and should be a research priority in the years ahead.

     

Impact of Checkpoint Inhibitor Pneumonitis on Survival in NSCLC Patients Receiving Immune Checkpoint Immunotherapy

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.     

免疫检查点抑制剂在小细胞肺癌中的临床研究进展

小细胞肺癌(small cell lung cancer,SCLC)是分化较差的高级别肺神经内分泌肿瘤,尽管仅占所有肺癌的14％左右,但生长迅速、较早出现转移,复发后缺少有效的治疗手段,改善SCLC治疗迫在眉睫.近年来,肿瘤免疫治疗展现了良好的前景,尤其程序性死亡受体1(programmed death1,PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte-associated antigen 4,CTLA-4)抑制剂的研究正在改变多种实体瘤的临床实践.SCLC与吸烟密切相关,具有较高的肿瘤突变负荷,是免疫治疗潜在理想的肿瘤类型.本文将总结免疫治疗在SCLC的临床研究进展,探讨SCLC免疫治疗中存在的问题、面临的挑战以及未来的应用前景.     

免疫检测点抑制剂治疗后"超进展"的晚期肺腺癌患者2例及文献复习

目的:免疫检测点抑制剂治疗在多种肿瘤中都表现出了很好的疗效。然而,约10%的患者在治疗中出现肿瘤加速生长的情况,临床上将其称为超进展。对于在接受免疫检测点抑制剂治疗中发生“超进展”的非小细胞肺癌患者来说,仍然需要对其临床病理特征进行更多的研究。方法:我们报导2例分别使用帕博利珠单抗和阿特珠单抗二线治疗的晚期肺腺癌患者。这两例患者均在治疗后出现肿瘤快速进展,根据目前的诊断标准评价为“超进展”。另外,我们通过复习相关文献,探讨“超进展”的定义、风险因素及患者预后。结果:本文中报导的2例“超进展”的患者具有相应的临床特点,但与既往研究中所报导的不完全一致。结论:在接受免疫检测点抑制剂治疗后发生的“超进展”现象具有复杂性,研究“超进展”相关的临床病理特征很有必要。