Immune Checkpoint Inhibitors In Clinical Practice Research Articles

Long-Term Survival in Patients With Advanced Melanoma

Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data

BackgroundThe impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood.MethodsWe screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsA total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not.ConclusionsPatients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Nomograms confirm serum IL-6 and CRP as predictors of immune checkpoint inhibitor efficacy in unresectable hepatocellular carcinoma.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has become the first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, only a small portion of patients are responsive to ICIs. It is important to identify the patients who are likely to benefit from ICIs in clinical practice. We aimed to examine the significance of serum IL-6 and CRP levels in predicting the effectiveness of ICIs for uHCC. We retrospectively recruited 222 uHCC patients who received ICIs treatment (training cohort: 124 patients, validation cohort: 98 patients). In the training cohort, patients are categorized into the response group (R) and no-response group (NR). The levels of serum IL-6 and CRP were compared between the two groups. Internal validation was performed in the validation cohort. Survival analysis was carried out using the Kaplan-Meier method and Cox proportional hazard regression model. The nomograms were developed and assessed using the consistency index (C-index) and calibration curve. Serum levels of IL-6 and CRP were significantly lower in the R group than in the NR group (9.94 vs. 36.85 pg/ml, p< 0.001; 9.90 vs. 24.50 mg/L, p< 0.001, respectively). An ROC curve was employed to identify the optimal cut-off values for IL-6 and CRP in both groups, resulting in values of 19.82 pg/ml and 15.50 mg/L, respectively. Multivariate Cox regression analysis revealed that MVI (HR 1.751, 95%CI 1.059-2.894, p=0.029; HR 1.530, 95%CI 0.955-2.451, p=0.077), elevated IL-6 (HR 1.624, 95%CI 1.016-2.596, p=0.043; HR 2.146, 95%CI 1.361-3.383, p =0.001) and high CRP (HR 1.709, 95%CI 1.041-2.807, p=0.034; HR 1.846, 95%CI 1.128-3.022, p = 0.015) were independent risk factors for PFS and OS, even after various confounders adjustments. Nomograms are well-structured and validated prognostic maps constructed from three variables, as MVI, IL6 and CRP. Low levels of IL-6 and CRP have a positive correlation with efficacy for uHCC patients receiving ICIs.

Proteomic profiling of a patient with cutaneous melanoma metastasis regression following topical contact sensitizer diphencyprone and immune checkpoint inhibitor treatment

Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of advanced melanoma, but many patients do not respond to ICIs alone, and thus there is need for additional treatment options. Topical immunomodulators such as diphencyprone (DPCP) also have clinical use in advanced melanoma, particularly in the treatment of cutaneous metastases. In a previous report, we characterized the enhanced clinical response to dual agent immunotherapy with pembrolizumab and DPCP in a patient with cutaneous melanoma metastases. To improve mechanistic understanding of this response, we analyzed proteomic data using the Olink immuno-oncology panel of 96 biomarkers from tissue and serum samples of this patient throughout his treatment course. Particular attention was paid to programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) given they are all targeted by ICIs in clinical practice. These proteins were upregulated during the period of DPCP monotherapy, then downregulated during pembrolizumab monotherapy, and then robustly upregulated again during dual therapy. Although not exclusively, the induction of checkpoint inhibitor proteins in the presence of DPCP suggests potential synergy between this agent and ICIs in the treatment of cutaneous melanoma metastases. Large-scale investigation is warranted to further evaluate this potential novel combination therapeutic approach.

Chinese expert consensus on the multidisciplinary management of pneumonitis associated with immune checkpoint inhibitor.

Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

Vaccination against Cancer or Infectious Agents during Checkpoint Inhibitor Therapy.

The use of immune checkpoint inhibitors (ICI) has substantially increased the overall survival of cancer patients and has revolutionized the therapeutic situation in oncology. However, not all patients and cancer types respond to ICI, or become resistant over time. Combining ICIs with therapeutic cancer vaccines is a promising option as vaccination may help to overcome resistance to immunotherapies while immunotherapies may increase immune responses to the particular cancer vaccine by reinvigorating exhausted T cells. Thus, it would be possible to reprogram a response with appropriate vaccines, using a particular cancer antigen and a corresponding ICI. Target populations include currently untreatable cancer patients or those who receive treatment regimens with high risk of serious side effects. In addition, with the increased use of ICI in clinical practice, questions arise regarding safety and efficacy of administration of conventional vaccines, such as influenza or COVID-19 vaccines, during active ICI treatment. This review discusses the main principles of prophylactic and therapeutic cancer vaccines, the potential impact on combining therapeutic cancer vaccines with ICI, and briefly summarizes the current knowledge of safety and effectiveness of influenza and COVID-19 vaccines in ICI-treated patients.

1322P Development and external validation of a novel four-gene-pair signature for predicting clinical response to anti-PD-1 immunotherapy of non-small cell lung cancer

Immune-checkpoint inhibitors (ICIs) are characterised by durable responses and improved survival in patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only certain patients can benefit from immunotherapy, therefore a feasible tool is urgently needed to predict the patients who might benefit from ICIs in clinical practice.

Immune-related adverse events associated with immune checkpoint inhibitors: a call to action for collecting and sharing clinical trial and real-world data

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI clinical...

Incidence, risk factors and clinical outcome of venous thromboembolism in non-small cell lung cancer patients receiving immune checkpoint inhibition

BackgroundBesides the cancer itself, venous thromboembolism (VTE) is the leading cause of death in cancer patients receiving outpatient chemotherapy (CT). Data on VTE development and impact on treatment course and outcome in real-life NSCLC patients receiving immune check-point inhibitors (ICI) is currently sparse. More knowledge within this area is warranted due to the emerging use of ICI in clinical practice. ObjectivesTo quantify risk of VTE and recurrent VTE in NSCLC patients receiving ICI. Explore the clinical impact of VTE on ICI course and survival and explore potential risk factors for VTE. Patients/methodsPatients with advanced/metastatic NSCLC treated with an immune checkpoint inhibitor (ICI) at the University Hospital of Odense, Denmark during 2015–2018 were identified and data gathered retrospectively from electronic medical records (n = 118). All patients had finished ICI at the time of data-cut off. Baseline Khorana Score (KRS) was calculated within one week prior to ICI initiation. Based on follow-up data cumulative incidence of VTE and its impact on outcome and survival was performed using Kaplan Meier and cox-regression hazard estimation. ResultsRisk of VTE was 8% during ICI and 15% at any time point after ICI initiation. Cumulative incidence rates of VTE at 1, 3, 6 and 18 months after first ICI was 1.7%, 5.2%, 6.9% and 13.8% respectively. Median time to VTE during ICI was 2.3 months [IQR 0.6–5.4]. Having VTE during ICI lead to discontinuation of ICI in 78% of cases, most due to fatal PE. History of VTE before onset of ICI was a significant risk factor for recurrent VTE during ICI (24% within this subgroup) despite use of anticoagulant therapy. ConclusionsThe incidence and impact of VTE during ICI for real-life NSCLC patients is not negligible with almost 10% developing VTE leading to termination of further ICI in the majority of cases - many due to fatal PE. The risk of recurrent anticoagulant resistant VTE in patients with known VTE during ICI is also considerable, which calls for better management and prevention of VTE including development of treatment specific VTE risk assessment models.

Neurological Adverse Events Induced by Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Current Perspectives and New Development.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple malignancies, especially in non-small cell lung cancer (NSCLC). With the extensive application of ICIs in clinical practice, clinicians have to manage their toxicities, which are often termed immune-related adverse events (irAEs). Several ICIs, such as nivolumab, pembrolizumab, atezolizumab, and durvalumab, have been approved by the US Food and Drug Administration (FDA) to treat advanced NSCLC, accompanied by a broad spectrum of toxicity reactions. However, ICIs-associated neurological toxicities, regarding polyneuropathy, Bell palsy, encephalopathy, and myasthenia gravis, as uncommon emerging toxicities have not been well recognized, present a challenge for clinicians to improve awareness of supervision, recognition, and management before death from them. Herein, we have summarized the incidence, diagnosis, clinical manifestations, potential mechanisms, treatments, and outcomes of ICIs-related neurotoxicity and optimized the management approach for NSCLC patients. Prompt recognition and proper management are indispensable to reduce the morbidity of these patients with immune-related neurological toxicities.

1939P Potential role of longitudinal plasma next generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) patients (pts) experiencing hyperprogression (HPD) and early death (ED) during treatment with immune checkpoint inhibitors (ICIs)

The introduction of ICIs in clinical practice has revolutionized aNSCLC treatment but a proportion of pts does not benefit from ICIs and could even derive detrimental effects. No predictive markers are currently available for their early detection. Aim of the study was to characterize pts experiencing HPD and ED with plasma NGS to analyze their modification at an early time-point during treatment.

DNA damage and repair gene panel as a biomarker of immune checkpoint inhibitor response.

e15052 Background: Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although predictive biomarkers for efficacy still remain largely unknown. Methods: This study aims to develop a novel gene panel by selecting DNA damage and repair (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) database and perform validation using publicly available cohorts. Association between the DDR gene panel and tumor mutation burden or microsatellite status were analyzed from The Cancer Genome Atlas (TCGA) database. To further improve the clinical accessibility of the DDR gene panel, we analyzed the feasibility of its predictive value using cell free DNA in from 64 patients receiving ICIs. Results: The 193 mutated DDR genes in various cancers were chosen from the COSMIC databank, and the DDR genes found to individually predict a response rate &gt; 50% in publicly melanoma cohort (Van Allen, et al) were selected. Eighteen DDR genes were selected as the DDR gene panel. The prevalence of the DDR gene mutations and predicted response rate of ICIs were validated in other three publicly available cohorts (Hugo et al, Synder et al, and Rizvi et al.). Tumor mutational burden and high microsatellite instability were positively associated with mutations of the 18 DDR genes for most cancers. Further validation was performed using cell-free DNA from cancer patients receiving ICIs. This DDR gene panel was detected in approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients receiving ICIs. Conclusions: Our developed DDR gene panel can serve as a novel and reliable biomarker that can provide critical information for predicting the response to ICIs in cancer patients and guide the appropriate administration of ICIs in clinical practice.

Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies.

Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38°C within 24h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001). We found that the use of ipilimumab and the presence of fever within 24h of initial ICI administration were predictive factors for immune-related liver injury.

The Identification of Immunological Biomarkers in Kidney Cancers.

The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.