Efficacy and immune-related adverse event associations in avelumab-treated patients

BackgroundAdverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order.MethodsWe analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity.Results295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions.ConclusionsPatients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab.Trial registration numbersNCT01772004 and NCT02155647.

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The quality of reporting general safety parameters and immune-related adverse events in clinical trials of FDA-approved immune checkpoint inhibitors

BMC Cancer ◽

10.1186/s12885-020-07518-5 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zahra Karimian ◽

Sandra Mavoungou ◽

Joe-Elie Salem ◽

Florence Tubach ◽

Agnès Dechartres

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Safety Information ◽

Safety Data ◽

Phase Iii ◽

Quality Of Reporting ◽

Link Type

Abstract Background While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. Methods PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. Results Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov. Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8 and 8.8% of publications respectively, compared to 11.8 and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. Conclusions The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

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Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

Cancers ◽

10.3390/cancers13050989 ◽

2021 ◽

Vol 13 (5) ◽

pp. 989

Author(s):

Heidar J. Albandar ◽

Jacob Fuqua ◽

Jasim M. Albandar ◽

Salahuddin Safi ◽

Samuel A. Merrill ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Survival Outcomes ◽

Limited Data ◽

Risk Of Death ◽

Survival Difference ◽

Histopathologic Diagnosis ◽

Cancer Types

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

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540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.540 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A570-A570

Author(s):

Chen Zhao ◽

Matthew Mule ◽

Andrew Martins ◽

Iago Pinal Fernandez ◽

Renee Donahue ◽

...

Keyword(s):

T Cells ◽

Adverse Events ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Effector Memory ◽

Link Type ◽

Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

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522 Transcriptomic changes in cancer patients treated with immune-checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.522 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A552-A552

Author(s):

Dmitrii Shek ◽

Bo Gao ◽

Joey Lai ◽

Won-Hee Yoon ◽

Tania Moujaber ◽

...

Keyword(s):

Cancer Patients ◽

Differentially Expressed Genes ◽

Immune Checkpoint ◽

Functional Annotation ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Link Type ◽

Pre Treatment ◽

Grade 3 ◽

Transcriptomic Changes

BackgroundImmune-checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitory CTLA-4/PD-1 signalling pathways and thus boost cytotoxic T cell antitumor activity. ICIs have been proven effective in various malignancies, but there is a lack of knowledge regarding factors associated with ICI efficacy and safety. This study aims to examine transcriptomic changes in cancer patients treated with ICIs and their potential association with related clinical outcomes.MethodsThis is a prospective multicentre cohort study (NCT04631731) recruiting cancer patients treated with (1) ICI monotherapy; (2) ICI dual therapy; (3) ICI + kinase inhibitor; (4) ICI + platinum-doublet chemotherapy. Peripheral blood is collected at baseline and 6–8 weeks after first ICI treatment as well as after the development of immune-related adverse events (irAEs, grade 2 and higher). Whole transcriptome sequencing (Novaseq S4 300 cycle lane, Illumina) was performed and followed by functional annotation using the ConsensusPath-DB platform.Results22 patients were recruited to the study and had paired blood taken. Two patients had developed grade 3–4 irAEs. RNA sequencing analysis identified 3,000 genes that were significantly dysregulated at week 6–8 after ICI commencement as compared to pre-treatment in n=20 recruited patients without irAEs (figure 1). Functional annotation established that 132 pathways were associated with the identified set of dysregulated genes. Among them: (1) pre-NOTCH processing in Golgi, (2) Interleukin-15 signalling; (3) STAT5 activation, and (4) RORA activation of gene expression possessed a gene set enrichment of at least 80% and p<0.01. In 2 patients with grade 3 immune-mediated hepatitis, both treated with combination of CTLA-4/PD-1 inhibitors, analysis revealed that 360 and 325 were 2-fold up- and downregulated respectively upon onset of toxicity as compared to both pre-treatment and 1-week post-steroid treatment. Interestingly, this gene set possessed minimal overlap when compared to genes dysregulated in patients without irAEs. Moreover, functional annotation established different pathways that were associated with toxicity. The highest enrichment scores belonged to pathways regulating cell cycle and apoptotic pathways driven by CDC25A, p53 and BCL-2, among others.Abstract 522 Figure 1Volcano plot representing the differentially expressed genesThe figure representing differentially expressed genes elucidated in this pilot study. N=3000 genes were significantly dysregulated between pre- and week 6–8 post-IO commencement.ConclusionsThe preliminary analysis of the first 22 patients recruited to NCT04631731 confirms that ICI treatment interferes with expression of coding and non-coding RNAs. Importantly, patients with and without irAEs show different patterns of transcriptomic changes as well as variability among activated cellular pathways. This data emphasises the need for further exploration and validation of transcriptomic changes in a larger cohort. In the near future, RNA signatures may be utilised as biomarkers to rapidly and accurately diagnose irAEs.AcknowledgementsN/ATrial RegistrationClinicalTrials.Gov identification number: NCT04631731ReferencesN/AEthics ApprovalThis study has been approved by the Western Sydney Local Health District (WSLHD) Human Research Ethics Committee on the November 9th, 2020 to be conducted at Blacktown and Westmead Public Hospitals of the WSLHD, Sydney, NSW, Australia.ConsentEach participant recruited to this translational study has provided written consent approved on the November 6th, 2020 (MASTER version) by the WSLHD HREC.

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Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_237967 ◽

2019 ◽

pp. e126-e140 ◽

Cited By ~ 8

Author(s):

Kimberly Levinson ◽

Oliver Dorigo ◽

Krista Rubin ◽

Kathleen Moore

Keyword(s):

Solid Tumors ◽

Solid Tumor ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gynecologic Cancer ◽

Hematologic Malignancies ◽

Next Generation ◽

Gynecologic Cancers ◽

Clinical Benefits

Immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs), has been transformative in both solid tumor and hematologic malignancies. Patients with previously terminal illnesses have experienced profound responses of great durability with these agents, fueling excitement among patients and providers regarding their use. Unfortunately, the gains seen in some solid tumors have not been replicated in a large percentage of patients with gynecologic cancer. This review focuses on the clinical benefits seen to date, toxicities and management when using ICIs, ways to improve prediction of who should receive immunotherapy, and a discussion of next-generation immunotherapy with cellular therapeutics and how these might relate to gynecologic cancers.

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Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2554 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2554-2554 ◽

Cited By ~ 1

Author(s):

Jermaine Coward ◽

Vinod Ganju ◽

Ramin Behzadigohar ◽

Kenneth Kwong ◽

June Xu ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Human Study ◽

Safety Data ◽

Advanced Solid Tumors ◽

Duration Of Treatment ◽

Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

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Immune Checkpoint Inhibitors and Cardiotoxicity: Reverse Translational Research by Using Real World Safety Data from the European Spontaneous Reporting System

SSRN Electronic Journal ◽

10.2139/ssrn.3756856 ◽

2020 ◽

Author(s):

Annamaria Mascolo ◽

Cristina Scavone ◽

Carmen Ferrajolo ◽

Concetta Rafaniello ◽

Romano Danesi ◽

...

Keyword(s):

Translational Research ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Spontaneous Reporting ◽

Reporting System ◽

Spontaneous Reporting System ◽

Checkpoint Inhibitors ◽

Safety Data

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Association of systemic anticancer therapy with an increased risk of death in hospitalized COVID-19 positive oncology patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18594 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18594-e18594

Author(s):

David Jacob Hermel ◽

Samantha R. Spierling Bagsic ◽

Munveer Singh Bhangoo ◽

Kathryn Blount Bollin ◽

James R. Mason ◽

...

Keyword(s):

Solid Tumors ◽

Metastatic Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hematologic Malignancy ◽

Anticancer Therapy ◽

Cytotoxic Chemotherapy ◽

Lung Involvement ◽

Risk Of Death

e18594 Background: Malignancy is thought to be an independent risk factor for increased COVID-19 morbidity and mortality. However, neoplastic diseases encompass a heterogenous group of pathologic processes, and further stratification of those patients prone to severe disease is necessary. We sought to identify predictors of poor COVID-19 outcomes among hospitalized patients with malignancy. Methods: We retrospectively reviewed all patients with a diagnosis of hematologic and solid tumor malignancy within the regional Scripps Health hospital system in San Diego County from March 1, 2020 to January 5, 2021 with a PCR confirmed diagnosis of COVID-19. Cancer diagnoses were confirmed via manual chart review; in situ non-melanoma skin cancers were excluded. Only hospitalizations greater than one day were included in the analysis and readmissions were excluded. Outcomes of interest included admission to the ICU, intubation during hospitalization, and death. Associations between outcomes of interest and tumor types, metastatic disease (with or without lung involvement) and those receiving active systemic anticancer therapy (treatment within 3 months of admission) were determined using univariable logistic regression analyses. The study was approved by the Scripps Health Institutional Review Board. Systemic anticancer therapy included cytotoxic chemotherapy, immunomodulators, immune checkpoint inhibitors, and other targeted therapies. Results: Among a total of 2,771 hospitalized patients, 204 (7.36%) met inclusion criteria. The average age was 72.7 years, 48.5% were male, 33.3% were Hispanic and the average BMI was 27.5. The majority of patients (82.8%) had solid tumors, with the most prevalent being breast carcinoma (17.6%) and prostate carcinoma (17.2%). Overall, 21.9% had metastatic disease and 16% had lung involvement. 17.2% had been receiving active cancer systemic treatment. On univariate analysis, patients who were actively receiving treatment had an increased rate of death (37.1% vs 18.9%, OR: 2.5 (1.1-5.5) p= .021). Among patients receiving systemic anticancer therapy, 48.6% received cytotoxic chemotherapy, 5.7% immune checkpoint inhibitors, 22.9% immunomodulators, 17.1% molecularly targeted agents and 2.7% other agents. Moreover, there was a trend towards increased mortality in those with lung involvement (33.3% vs 17.6%, OR: 2.3 (0.9-5.7) p= .067) and those with hematologic malignancy (31.4% vs 20.1%, OR: 0.5 (0.2-1.3) p = 0.146). Conclusions: Among patients hospitalized with a diagnosis of cancer, systemic anticancer therapy was associated with a significantly increased odds of death. Other factors potentially increasing risk of death include hematologic malignancy and solid tumors with lung involvement. Further validation of these findings in a larger sample could impact therapeutic decision making during the COVID-19 pandemic.

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