Clinical Outcomes of Patients with Metastatic Cancer Receiving Immune Checkpoint Inhibitors in the Inpatient Setting

BackgroundAs indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials.Material and MethodsWe conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality.ResultsDuring the 4‐year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty‐two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non‐small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy.ConclusionThe poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality.Implications for PracticeImmunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.     

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.     

Predictive Value of Combining Biomarkers for Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

IntroductionA high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC.MethodsWe retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR <5, and combined biomarkers.ResultsData from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio [HR], 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP.ConclusionsTMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.     

Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection

BackgroundThe safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).Materials and MethodsThis was a single‐institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.ResultsWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1–2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).ConclusionAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.Implications for PracticeThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors’ institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.     

Genomic and Clinical Prognostic Factors in Patients With Advanced Urothelial Carcinoma Receiving Immune Checkpoint Inhibitors

BackgroundRecently data suggest that telomerase reverse transcripatase (TERT) promoter mutations portend superior outcomes with immune checkpoint inhibitor (ICI) therapy in mUC. In our retrospective analysis from 2 tertiary cancer centers, we assessed the predictive role of TERT mutations along with other parameters.MethodsPatient registries were queried for patients treated with ICI for mUC with available genomic and clinical data. Select clinical and laboratory parameters, in addition to primary tumor site, histology, treatment modality, and setting were recorded. Tumor mutational burden (TMB), and mutational status of TERT, CDKN2A, CDKN2B, TMB, TP53, RB1, KMT2D, ARID1A, ERBB2, KDM6A, PIK3CA, FGFR3, and ATM were noted. Univariate analysis of significance concerning overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) was conducted.ResultsIn total, 113 patients were found to meet inclusion criteria. In our study, ORR was 55%, median PFS was 5.1 months (0.2-71.8), and median OS was 13.4 months (0.2-84.8). On univariate analysis, female sex, NLR>5, and ATM mutation were associated with inferior PFS and OS, whereas upper tract primary disease and ECOG score ≥ 2 were associated with worse OS. On multivariate analysis, NLR >5 was associated with worse PFS and OS whereas upper tract primary disease, albumin <3.4 g/dL, hemoglobin <10 g/dL and ATM mutation were significantly associated with worse OS on multivariate analysis. No significant differences were seen in ORR, PFS, or OS regarding TERT promoter mutations.ConclusionTERT promoter mutations were not significantly associated with any difference in outcome in patients treated with ICI.     

放疗联合免疫检查点抑制剂在食管癌中的应用

摘 要：近年来以免疫检查点抑制剂为代表的免疫治疗作为一种新兴的治疗方法,使食管癌的治疗步入了新的阶段。既往研究表明免疫治疗可以提高晚期转移性食管癌患者的生存率,且免疫检查点抑制剂与放射治疗相结合可更好地发挥局部治疗作用,放疗联合免疫检查点抑制剂应用于围手术期、局部晚期和晚期食管癌的各项临床研究取得了可观的成效。全文对近年来放疗联合免疫检查点抑制剂在食管癌中的应用进行综述。     

免疫检查点抑制剂在结直肠癌中的研究进展CSCD

免疫治疗是当前实体肿瘤治疗研究的新方向,而在免疫系统中发挥负性调节分子的免疫检查点在限制抗肿瘤免疫反应中起着关键作用。针对PD-1及PD-L1、CTLA-4的免疫检查点抑制剂已被开发为抗肿瘤药物进行临床研究,dMMR/MSI-H型结直肠癌对免疫检查点抑制剂具有客观反应。本文基于结直肠癌免疫分型,对免疫检查点抑制剂在结直肠癌中的治疗方案进行综述。     

The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment

Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells (“immune surveillance”), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development.

Implications for Practice:

Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient’s own immune system, immunotherapies have the potential to be a powerful weapon against cancer.     

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.     

免疫检查点阻断剂在肝癌治疗中的研究进展

近年来,免疫检查点阻断剂在众多实体瘤和恶性血液病的临床应用中均取得了值得肯定的效果,但是与肝癌相关的免疫靶向药物却仅限于索拉菲尼（Sorafenib）。随着2014年美国FDA连续通过了两个PD-1/PD-L1通路阻断剂,研究者们对免疫检查点阻断剂治疗肝癌能否取得良好的抗癌效果产生了浓厚兴趣。目前程序性细胞死亡蛋白（programmed cell death-1, PD-1）及其配体（programmed cell death ligand 1, PD-L1）、细胞毒性T淋巴细胞相关抗原-4（cytotoxic T lymphocyte associated antigen 4, CTLA-4）等分子阻断剂均在肝癌中开展了相关研究。其中检查点阻断剂Nivolumab和Tremelimumab在肝癌的临床试验初步研究结果乐观,前景值得期待。     

Immune Checkpoint Inhibitors: Therapeutic Tools for Breast Cancer

Breast cancer is one of the major threats to female health, and its incidence is rapidly increasing in many countries. Currently, breast cancer is treated with surgery, followed by chemotherapy or radiation therapy, or both. However, a substantial proportion of breast cancer patients might have a risk for local relapse that leads to recurrence of their disease and/or metastatic breast cancer. Therefore searching for new and potential strategies for breast cancer treatment remains necessary. Immunotherapy is an attractive and promising approach that can exploit the ability of the immune system to identify and destroy tumors and thus prevent recurrence and metastatic lesions. The most promising and attractive approach of immunotherapeutic research in cancer is the blockade of immune checkpoints. In this review, we discuss the potential of certain inhibitors of immune checkpoints, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), in breast cancer therapeutics. Immune checkpoint inhibitors may represent future standards of care for breast cancer as monotherapy or combined with standard therapies.     

Immune Checkpoint Inhibitors in Gliomas

Purpose of Review

Malignant gliomas result in disproportionately high morbidity and mortality compared with other primary tumors, and progression of disease is inevitable. Novel therapies to improve outcomes are needed and immune checkpoint inhibitors hold significant promise.

Recent Findings

A limited body of preclinical evidence suggests that checkpoint inhibitors may be effective treatment for gliomas. Biomarkers to identify characteristics of gliomas responsive to these therapies will be essential. These may include mismatch repair deficiency and high mutational load that might be germline, somatic, or acquired after therapy. Evidence on the use of immune checkpoint inhibitors in gliomas is evolving. Clinical trials are underway and results are eagerly awaited.

Summary

Understanding the role of immune checkpoint inhibitors in combination with other treatment modalities for gliomas is crucial to the improvement of outcomes. The design and conduct of future clinical trials need to account for increasingly complex treatment options.

     

Overview of Microsatellite Instability and Immune Checkpoint Inhibitors in Colorectal Cancer

Purpose of Review

This review examines the pathophysiological features of microsatellite instability (MSI) high colorectal cancer and discusses recent clinical studies of immune checkpoint inhibitors for MSI high colorectal cancer.

Recent Findings

Emerging clinical data demonstrated durable clinical activity and safety of PD-1 blockade agents in diverse cancers, and PD-1 blockade agents have led to a paradigm shift in the cancer therapy. Although initial clinical data showed disappointing result of anti-PD-1 therapy in unselected metastatic colorectal cancer, recent data demonstrated promising results with significant anticancer activity of PD-1 blockade in colorectal cancers with microsatellite instability which have highly immunogenic tumor microenvironment.

Summary

Anti-PD-1 therapy demonstrated durable clinical activity and safety, and it has changed the landscape of cancer therapy in MSI high colorectal cancer. Further studies with better understanding of tumor microenvironment will improve clinical outcomes of colorectal cancer.