bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of immune checkpoint blockade biomarkers in elderly patients using large-scale cancer genomics data.
Authors: Erbe Rossin , Wang Zheyu , Wu Sharon , Xiu Joanne , Zaidi Neeha , Lippman Marc E. , Isaacs Claudine , Basho Reva K , Lenz Heinz-Josef , Astsaturov Igor A. , Marshall John , Baylin Stephen , Jaffee Elizabeth M. , Roussos Torres Evanthia T. , Weeraratna Ashani , Easwaran Hariharan , Fertig Elana J.
Published: June 2021

2543

Background: Immune checkpoint blockade (ICB) immunotherapy in some cases elicits striking patient responses, but its efficacy appears to be dependent on several incompletely understood factors. Most studies of ICB therapies in elderly patients have concluded that they received no reduced benefit or even increased benefit compared to the younger patients analyzed, despite the systemic age-related immune changes that might be expected to produce a less effective immune response, such as loss of the capacity to generate new naive T cells. To understand and apply these results, it is necessary to investigate the relationship of age and the immune tumor microenvironment. Methods: We apply bioinformatics methods to genomic, transcriptomic, and clinical data from 9,523 patients across 31 cancer types from TCGA, 15,557 patients with breast, colon, or head and neck cancers from Caris Life Sciences, and 37,961 patients across 8 cancer types collected by GENIE. From these data we apply multivariate linear models across and within individual tumor types to estimate age-related associations to tumor mutational burden (TMB), T cell receptor diversity (miTCR), differential gene expression (edgeR), pathway enrichment (mSigDB and fgsea), and immune cell type infiltration (Quantiseq and MIXTURE). Results: Our analysis of large-scale molecular and clinical databases associates patient age with changes in several major biomarkers of ICB response. Notably, a robust correlation between increased tumor mutational burden and age was found across three different large cohorts (TCGA, Caris Life Sciences, and GENIE) in most ICB-approved cancer types. In the TCGA data, TMB increased with age pan-cancer (p < 1x10-16) and in 7 of 9 ICB-approved cancer types. These associations were validated in the larger cohort of patient samples in GENIE, which demonstrated correlations between increased TMB levels and patient age in all eight ICB-approved cancer types assayed (Table), as well as in the Caris colorectal (q < 0.001) and breast (q < 0.001) cancer cohorts. Significant associations of age to other biomarkers of ICB response (checkpoint gene expression, immune infiltration, and immune related pathway signaling) will be presented. Conclusions: These results provide context for the efficacy of ICB in elderly patients, highlight potential biomarkers for the treatment of elderly patients with immunotherapies, and strongly suggest the value of large-scale prospective study of elderly cancer patients treated with ICB.[Table: see text]
Using the tumor microenvironment to identify predictors of immunotoxicity to checkpoint inhibitors.
Authors: Alexander William , Attwood Kristopher , Catalfamo Kayla , Dy Grace K. , George Saby , Ernstoff Marc S. , Abdou Yara
Published: June 2021

2545

Background: While Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, the benefits have come at the cost of serious side effects known as immune-related adverse events (irAEs). Approaches that can predict patients’ susceptibility to irAEs are key to their early detection and management. In the present study, we investigate the association between irAEs reported during ICI therapy across multiple cancer types and markers of tumor immune response. Our primary objective is to explore potential biomarkers for assessing patients’ risk of irAEs. Methods: 472 patients were evaluated who had tumor immune profiling performed paraffin embedded formalin fixed archival tumor biopsy samples using Omniseq Immune Report Card (IRC) and subsequently underwent ICI therapy. The IRC consisted of enumeration of tumor infiltrating lymphocytes (TILs) by immunohistochemistry (IHC) and TIL-associated genes by RNA-Seq, PD-L1 expression by IHC, and tumor mutational burden (TMB) by DNA-Seq. irAE type and grade were determined based on retrospective chart review. Fisher’s exact test was used to determined statistically significant associations between immune markers and irAE development. Results: Patients with lung (55%), ovarian (9%), and melanoma (5%) cancers constituted the majority of the cases. The median age of patients was 61, with 56% being female and 44% male. Most patients underwent treatment with (94%). irAEs developed in 36% of patients, with 2% of patients developing high-grade irAEs (Grade 3 or 4). Skin (11%), thyroid (10%), and GI (9%), were the most commonly affected organ systems. Increased TILs were associated with increased risk for any irAE (p = 0.04). A stronger association was noted in patients who underwent anti-PD-1/L1 monotherapy (p = 0.01) and/or in cases of lung cancer (p = 0.01). Interestingly, subanalyses by gender showed a statistically significant correlation between increased TILs and risk for any irAE in males (p = 0.006) but not in females (p = 0.63). High PD-L1 (defined as > 70% by IHC) was also significantly associated with increased risk for any irAE (p = 0.03). Subanalyses by gender and age again showed a similar association in females (p = 0.0002) and/or patients < 65 years (p = 0.04). high TMB and any irAE in female patients (p = 0.01) and in breast cancer cases (p = 0.03). On multivariate analysis, TILs by IHC appeared to be the strongest predictor of irAEs (p = 0.03). Conclusions: The tumor immune microenvironment (TME) has been shown to influence response to ICI, yet its association with irAEs has not been well studied. Our analysis sheds light on potential TME predictors for irAE in patients receiving ICI therapy. Further studies are needed to deepen our understanding of immune toxicity and to develop tools for identifying patients who are at risk.
Association of KMT2C/D loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.
Authors: Liu Ruiqi , Niu Yanling , Zhang Xin , Ma Tonghui
Published: June 2021

2587

Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.
A phase 1b study of personalized neoantigen vaccine plus pembrolizumab in adults with advanced cancer.
Authors: Miller Aaron , Kosaloglu-Yalcin Zeynep , Westernberg Luise , Montero Leslie , Bahmanof Milad , Frentzen Angela , Logandha Ramamoorthy Premlal Ashmitaa , Greenbaum Jason , Seumois Gregory , Habbaba Roxanne , Natsuhara Amanda , McConnell Kim , Eng Elaine , Sette Alessandro , Peters Bjoern , Schoenberger Stephen Philip , Cohen Ezra E.W.
Published: June 2021

2615

Background: Neoantigens (NeoAg) are key targets for personalized immunotherapy but efficient methods for their systematic identification and therapeutic targeting remain elusive. We developed a methodology to reliably identify and verify somatic alteration-derived neoantigens based on natural T cell responses against them which formed the basis of an individualized therapeutic vaccine strategy. Methods: This is a phase Ib study to assess the immunogenicity, safety and early clinical activity of personalized synthetic long peptides (PSLP) cancer vaccines in combination with pembrolizumab for patients with treatment refractory metastatic solid tumors or PSLP vaccine alone as an adjuvant treatment with patients with no evidence of disease (NED) that incorporates patient-specific NeoAg identified by an HLA-agnostic, functional T-cell assay (see table). Results: At the time of data cutoff, a total of 5 patients had been treated on ARM-A, 5 patients on ARM-C and 2 patients on ARM-D. AES possibly attributed to personalized vaccine (PSLP), or pembrolizumab, or both include: Grade 1: Arthralgia (1); Diarrhea (1); Fever (4); Fatigue (7); Generalized muscle weakness (1); Headache (2); Nausea (1); Confusion (1); Injection site reaction (5); Rash maculo-papular (3); Flu like symptoms (5); Myalgia (1); and Grade 2: Diarrhea (1); Fatigue (1); Hyperhidrosis (1); Hypothyroidism (1); Injection site reaction (1); Proteinuria (1); Renal and Urinary – other (1); and Grade 3: Colitis (1). For the 9 patients with at least 1 radiographic assessment at the time of analysis 6 had a best response of stable disease (SD) and 3 had progressive disease (PD). Immune monitoring of peripheral blood specimens consistently demonstrated that NeoAg-specific T cell responses were enhanced following administration of PSLP vaccine. On-treatment biopsies demonstrated immune-editing with the variant allele frequency of targeted mutations decreasing following administration of the PSLP vaccine. Conclusions: Taken together, these data meet the trial primary endpoint by demonstrating PSLP vaccines targeting NeoAg identified using the HLA-agnostic pipeline augment effector T cell function against these targets. Clinical trial information: NCT02287428. [Table: see text]
Age affects the efficacy of immune checkpoint inhibitors in patients with advanced cancer.
Authors: Wang Yongjie , Yang Ronghua , Wang Dong , Zhao Donghua , Li Peng , Li Mengjun , Qi Yingxue , Luo Ningning , Wu Yaqing , Zhang Qin
Published: June 2021

2638

Background: Immune checkpoint inhibitors (ICIs), such as programmed death(ligand)1 (PD-(L)1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, have dramatic effects on treatment in patients with various malignancies. High tumor mutation burden (TMB) is predictive of clinical response to ICI in multiple cancer types. Although age-related immune dysfunction might induce difference on the efficacy of ICIs between younger and older patients, the potential effect of age on the efficacy of ICIs remains little known and controversial. Herein, we aimed to analysis the association between age and the efficacy of ICIs based on MSKCC cohort. Methods: We screened out 1661 patients having complete information with advanced cancer, whose tumors underwent next-generation sequencing (NGS) detection and who were treated with at least one dose of ICI in MSKCC cohort. All patients were divided into two groups according to age, the younger group (age ≤50-year old) and the older group (age > 50-year old). We further analyzed the differences in overall survival (OS) and TMB between the two groups. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated via Cox regression model for OS and P-values were calculated via the Wilcoxon sign test for TMB. We analyzed the effect of age on ICI in lung cancer using the same way. Results: In 1661 patients with cancer in our study, 312 (19%) younger and 1349 (81%) older patients were found. The pooled HRs for OS was 1.28 (95% CI: 1.09-1.52) in younger group compared with older group. In 1661 patients with cancer, there was 350 (21%) patients with lung cancer, including 30 (9%) younger and 320 (91%) older patients. The pooled HRs for OS was 1.45 (95% CI: 0.95-2.23) in younger group compared with older group in lung cancer. In addition, TMB in older group was higher than in younger group and significant difference of TMB was found via the Wilcoxon sign test (p = 2.6e-10) between the two groups, especially in lung cancer (p = 1e-4). Conclusions: Our study assessed the impact of age on the efficacy of ICIs using the threshold of 50 years old for the first time and we founded that patients in older group had higher TMB and longer OS than younger group.
Improving tolerability of pembrolizumab with weight based dosing: A meta-analysis.
Authors: Patail Nabeela Khan , Sher Amna Falak , Wu Shenhong
Published: June 2021

2639

Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI), has demonstrated significant clinical activity in various cancers. Despite a favorable toxicity profile, discontinuation due to adverse events including immune related adverse events (irAE) has been reported. We conducted a meta-analysis of published clinical trials to evaluate the tolerability of pembrolizumab in cancer patients. Methods: A systematic review was conducted of relevant studies from the databases of PubMed and abstracts presented at American Society of Clinical Oncology (ASCO) from June 2015 until September 2020. Eligible studies included prospective clinical trials that reported a discontinuation rate due to adverse effects. Incidence, relative risk and 95% confidence intervals (CI) were calculated by employing fixed or random effects models. Results: A total of 6,380 patients with a variety of hematologic and solid malignancies from 20 studies of pembrolizumab were included for analysis. The overall rate of pembrolizumab discontinuation due to adverse events was 8.2% (95% CI: 6.4-10.4%). The discontinuation rate of pembrolizumab was not significantly lower than the chemotherapy controls, with RR of 0.84 (95% CI: 0.58-1.12, p = 0.33). However, the discontinuation rate of pembrolizumab was significantly higher compared to placebo control with RR of 2.20 (95% CI: 1.36-3.54, p < 0.001), and significantly lower compared to ipilimumab with RR of 0.58 (95% CI: 0.34-0.99, p = 0.04) respectively. The discontinuation rate varied widely among different tumor types with the lowest rate of 0.8% (95% CI: 0.2-3%) in gastric cancer, and the highest of 13.5% (95% CI: 10.8-16.8%) in head and neck squamous cell carcinoma. Interestingly, the discontinuation rate varied with pembrolizumab dosing, with the fixed dosing of 200mg being 9.2% (95% CI: 6.9-12%) and the weight-based dosing being 6.5% (95% CI: 4.8-8.8%). The weight-based dosing was associated with a significantly lower discontinuation rate compared to controls with RR of 0.62 (95% CI: 0.47-0.81, p < 0.0001), while the fixed dosing had similar discontinuation rate with RR of 1.03 (95% CI: 0.89-1.20, p = 0.67). Conclusions: The tolerability of pembrolizumab may be comparable to chemotherapy in cancer patients and may vary with its dosing. Future studies are warranted to evaluate the impact of different dosing.
A risk stratification model for toxicities in phase 1 immuno-oncology (P1-IO) trials.
Authors: Hernando-Calvo Alberto , Salawu Abdulazeez , Oliva Bernal Marc , Araujo Daniel Vilarim , Liu Zhihui (Amy) , Chen Rachel , Siu Lillian L.
Published: June 2021

2648

Background: Despite an exponential increase in the number of potential targets in the immuno-oncology (IO) field, lack of risk models to predict toxicities remains a challenge in early drug development. We proposed a risk stratification strategy and investigated whether different IO classes may be associated with incremental risk of toxicities. Methods: A systematic search for IO studies from 01/2014 to 10/2020 was conducted. Among the 12053 abstracts screened, 254 reporting phase I-IO trials were selected. Type of IO treatment (IO monotherapy [mono] vs IO combination [comb]), therapeutic class (e.g. IO, molecularly targeted agents [MTA]), and dose escalation method (rule-based, model-based and model-assisted) were collected. A risk scoring model was developed after expert consensus: treatment-related deaths (1:yes, 0:no), incidence of G3/G4 treatment related adverse events (TRAE) or treatment emergent adverse events (TEAE) (0 if 1-29%,1 if ≥30-49%, 2 if ≥50%), incidence of ≥G2 cytokine release syndrome (1:yes, 0:no), incidence of ≥G2 encephalopathy (1:yes 0:no) and incidence of dose-limiting toxicity (DLT) (0:no, 1:lab, 2:clinical). Risk categories were defined by summing all points (0 = low, 1-2 = intermediate, 3+ = high) and were correlated with type of IO treatment, therapeutic class and dose escalation method. Results: Of 254 P1-IO trials reviewed, 228 (90%) were scorable, 26 were not (25 due to lack of AE data). Up to 10/26 (38%) of non-scorable studies were cell therapies. Among the 228 scorable studies, 120 (53%) scored 0, 65 (28%) scored 1-2, 43 (19%) scored 3+; 24 (11%) and 125 (55%) did not provide no. of pts with G3/G4 TRAEs or TEAEs respectively. A significant association was observed between risk categories and therapeutic class (p<0.001) (see table). Additionally, IO-MTA and IO-IO were both associated with an increased risk of toxicity as compared to IO-mono (OR=3.91 (95%CI 1.7-9.2), p=0.002) and (OR=2.79 (95%CI 1.2-6.5), p=0.02) respectively. There was no association between dose escalation method and risk of toxicity (p=0.95), but 182 (92%) used rule-based methods. Conclusions: Our results suggest that different IO classes are associated with different risks of toxicity. This risk classification strategy may guide future clinical trial design. Additionally, standards for reporting toxicities in P1-IO trials are urgently needed.[Table: see text]
Pembrolizumab patient reported benefits: A perspective based on multiple tumors.
Authors: Wu Elise , Miskala Paivi H , Siddiqui Mohd Kashif , Rai Pankaj , Hajdukova Eva , Erpelding Nathalie , Vanderpuye-Orgle Jacqueline
Published: June 2021

2650

Background: Pembrolizumab is a programmed death ligand receptor-1 (PD-L1) treatment indicated for multiple tumors. Patient-reported outcomes (PRO) benefit has only been reported at the tumor level, while a holistic review of PRO effects across tumor types has been missing. We performed a systematic review of PRO to assess the overall health-related quality of life (HRQoL) among cancer patients treated with pembrolizumab across multiple tumors. Methods: We systematically searched PRO evidence published from January 2014 to April 2020 across approved pembrolizumab indications using Embase, MEDLINE, and CENTRAL. Eligible studies were required to assess cancer patients treated with pembrolizumab (200 mg or 2mg/kg Q3W) and report PROs and/or HRQoL. The PRO evidence was summarized into three categories: short-term (≤Week 12), mid-term (Week 13-Week 24), and long-term (Week 25-Week 52). A clinically meaningful difference in HRQoL is defined as at least a 10 points improvement or deterioration relative to baseline; a change between ± 10 points is defined as stable. Results: We screened 1,262 citations, of which 16 publications reported EORTC QLQ-C30 data; 10 (9 trial-based studies; 1 observational study) of 16 publications reported global health status (GHS) mean change from baseline (CFB) across six indications. Within trial based studies in first-line setting (n=3 studies), the short-term, mid-term, and long-term GHS changes from baseline vary from 0.5 to 2.1, 1.2 to 8.4, and 1.6 to 2.5, respectively. For second-line plus setting (n=6 studies), GHS changes vary from -3.3 to 8.6, -1.0 to 10.9, and -0.9 to 9.2, respectively. Eight trial-based publications reported EORTC QLQ-C30 domain data as CFB. Short- or mid-term mean changes in functioning domain data showed improvement or stability in emotional, cognitive, role, and social functioning. Short-term deterioration in physical functioning was observed for 1 study, whereas physical functioning remained stable for other studies. For symptom domains, deterioration was not observed in any studies; mid-term improvement was reported by one study each in fatigue, dyspnea, and appetite loss; 2 studies reported mid-term improvement in pain. Conclusions: This is the first study that presented pembrolizumab PRO evidence at the product level. This study suggests that most pembrolizumab-treated patients maintained or improved HRQoL relative to baseline at pre-defined timepoints. This review's limitations include potential publication bias and lack of meta-analytic methods in reporting results. Nevertheless, these findings provide additional information about pembrolizumab's benefits to physicians and patients from a patient-centric perspective.
Impact of multidisciplinary severe immunotherapy complication service on outcomes for cancer patients receiving immune checkpoint inhibition.
Authors: Zubiri Leyre , Molina Gabriel E. , Mooradian Meghan , Durbin Sienna , Dougan Michael , Thomas Molly , Faje Alexander , Rengarajan Michelle , Guidon Amanda C , Chen Steven T. , Nasrallah Mazen , Kohler Minna , Sise Meghan , Neilan Tomas G , Zlotoff Daniel A , Bardia Aditya , Sullivan Ryan J. , Semenov Yevgeniy R. , Villani Alexandra C , Reynolds Kerry Lynn
Published: June 2021

2654

Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.
Concordancy of immunocytochemistry profiling of circulating tumor cells with immunohistochemistry for analysis of therapeutically relevant biomarkers.
Authors: Akolkar Dadasaheb B , Patil Darshana , Murthy Sudha S , Bendale Kiran , Patil Revati , Datta Vineet , Fulmali Pradip , Fulmali Pooja , Adhav Archana , Patel Shoeb , Chougule Rohit , Ranjan Vishal , Khan Shabista , Dhasarathan Raja , Apurwa Sachin , Schuster Stefan , Srinivasan Ajay , Datar Rajan
Published: June 2021

3047

Background: Immunohistochemistry (IHC) profiling of tumor tissue is the present standard for evaluation of therapeutically relevant biomarkers such as ER, PR, HER2, AR, ARv7, PD-L1 and MMR for selection of targeted, endocrine and checkpoint inhibitor therapy selection. However, this critical analysis is dependent on availability of tumor tissue obtained by an invasive biopsy. Challenges to this analysis include insufficient tumor tissue and inability to perform a repeat biopsy to obtain fresh tumor tissue. We have previously described an approach for negative enrichment of Circulating Tumor Cells (CTCs) from peripheral blood and for Immunocytochemistry (ICC) profiling of these CTCs for detection of diagnostically relevant tissue of origin and subtype specific markers, concordant with tumor tissue analysis. Methods: In the present study, we determined concordance between tumor tissue (HPE) and CTCs (ICC) for ascertaining the status of therapeutically relevant markers ER, PR, HER2, AR, ARv7 PD-L1 and MMR. We evaluated 201 matched pairs of tumor tissue (FFPE blocks) and CTCs obtained from peripheral blood. Results: Among the 743 paired assays on matched tumor tissue and CTCs, concordance (positive or negative) was observed in 651 matched pairs (87.6%). The concordance was 82.9% for ER, 100% for PR, 90.2 % for Her2, 93.8% for AR, 90% for Arv7, 85.1% and 87.6% for PD-L1 clones 22c3 and 28-8, and 85.6% for MMR (MLH1, MSH2, MSH6, and PMS2). Conclusions: The study findings indicate that ICC analysis of CTCs may be able to substitute IHC analysis of tumor tissue for profiling of therapeutically relevant markers. This approach may have application in cases where tumor tissue may be limiting and / or where an invasive biopsy to obtain tumor tissue may be unviable.
Development of extracellular vesicles-based classifier for detection of early-stage bladder, ovarian, and pancreatic cancer.
Authors: Hinestrosa Juan Pablo , Kurzrock Razelle , Lewis Jean , Schork Nick , Kamat Ashish M. , Lowy Andrew M. , Eskander Ramez Nassef , Perrera Orlando , Searson David , Clark Iryna , Balcer Heath , Adler Mark J. , Lippman Scott Michael , Krishnan Rajaram
Published: June 2021

3048

Background: Many cancers are lethal because they present with metastatic disease. Because localized/resectable tumors produce vague symptoms, diagnosis is delayed. In pancreatic cancer, only ̃10% of patients survive five years, and it will soon become the second leading cause of cancer-related deaths in the USA. For patients with metastatic disease, the 2- and 5-year survival is < 10% and ̃3%, respectively. For the few patients with local disease, 5-year survival is ̃40%. Many other cancers have comparable differences between early- and late-stage disease. It is apparent a diagnostic assay for early-stage cancers would transform the field by minimizing the need for aggressive surgeries and other harsh interventions, and by its potential to increase survival. Identifying cancer-specific aberrations in blood-based “liquid” biopsies offers a prospect for a non-invasive cancer detection tool. In the bloodstream, there are extracellular vesicles (EVs) with cargoes including membrane and cytosolic proteins, as well as RNA and lipids derived from their parent cells. Methods: We used an alternating current electrokinetics (ACE) microarray to isolate EVs from the plasma of stage I and II bladder (N = 48), ovarian (N = 42), and pancreatic cancer patients (N = 44), and healthy volunteers (N = 110). EVs were analyzed using multiplex protein immunoassays for 54 cancer-related proteins. EV protein expression patterns were analyzed using stepwise logistic regression followed by a split between training and test sets (67%/33% respectively). This process enabled biomarker selection and generation of a classifier to discriminate between cancer and healthy donors. Results: The EV protein-based classifier had an overall area under curve (AUC) of 0.95 with a sensitivity of 71.2% (69.4% – 73.0%, at 95% confidence interval) at > 99% specificity. The classifier’s performance for the pancreatic cancer cohort was very strong, with overall sensitivity of 95.7% (94.6% – 96.9%, at 95% confidence interval) at > 99% specificity. Conclusions: EV-associated proteins may enable early cancer detection where surgical resection is most likely to improve outcomes. The classifier’s performance for the initial three cancers studied showed encouraging results. Future efforts will include examining additional cancer types and evaluating the classifier performance using samples from donors with related benign conditions with the aim of a pan-cancer early detection assay.
Dermatologic adverse events of brentuximab vedotin: Characteristics, management, and their relationship with dose regimen.
Authors: Oh Yuna , Bang Alexander , Kurtansky Nicholas , Khan Niloufer , Pulitzer Melissa , Noor Sarah
Published: June 2021

3049

Background: Owing to its high efficacy and tolerability, brentuximab vedotin (BV) is increasingly being favored over other aggressive systemic therapies for the treatment of various CD30+ Hodgkin and non-Hodgkin lymphomas, including peripheral T-cell lymphoma and cutaneous T-cell lymphomas. Dermatologic adverse events (dAE) are one of the most common toxicities associated with BV but data regarding their characteristics including correlation to dose, time to occurrence, and management is scarce. We aim to describe the clinical and pathologic characteristics of dAEs associated with BV, their relationship with administered dose regimen, and available management strategies. Methods: An IRB-approved retrospective analysis was conducted for all patients who had received at least one cycle of BV from Memorial Sloan Kettering Cancer Center in 2009-2020. Logistic regression, χ2, student’s t-test were performed for univariate analyses. Kaplan-Meier survival and multivariate Cox proportional hazard model evaluated dAE occurrence stratified by 5 major dose regimens (single cycle, 1.2mg q1w, 1.2mg q2w, 1.2mg q3w, 1.8mg q3w). Results: Of 611 patients, 201 experienced dAE with median time-to-event of 24 days and 29% experiencing > 1 dAEs. Rash was the most common (62%; 142/230), followed by alopecia (20%) and xerosis (13%). For rash, 50% reported involvement of only the extremities and/or acral sites compared to 25% who had generalized rash. Of those reported (111), 68 patients had grade 1 dAE (61%), 38 grade 2 (34%), and 5 grade 3 (5%)-all grade 3 were rash (maculopapular/morbilliform). 14 cases (7%) resulted in treatment interruptions and 6 in discontinuations due to dAEs (3%). Pathology were often nonspecific consistent with a hypersensitivity reaction: spongiotic/psoriasiform dermatitis with perivascular lymphocytic infiltrates . Patients undergoing weekly regimen were at a statistically and clinically significantly higher risk of dAE during the first 100 days of BV treatment (p = 0.001). Between the two most frequently administered dose regimens (1.8mg vs. 1.2mg, q3w), the higher dose carried 105% higher risk for dAE (HR: 2.047, p = 0.053). Those who had received a single cycle of BV had the lowest risk compared to all other regimen (1/42, p = 0.001). Topical and/or systemic steroids were most frequently prescribed (43%) with 12% of patients requiring systemic steroids. Other treatments varied ranging from antihistamines to moisturizers. Conclusions: Understanding of the detailed characteristics, management strategies, dose-dependent effects associated with BV is critical to provide clinical guidance for primary providers and minimize treatment interruptions or discontinuations. The results overall suggest that the risk for dAEs is dose-dependent with those undergoing frequent dosing regimens having a greater risk, although most dAEs remain mild or low-grade.
Sputum supernatant as a viable alternative for liquid biopsy in advanced non-small cell lung cancer.
Authors: Zhou Cheng-Zhi , Xie Xiaohong , Wu Jianhui , Guo Bingpeng , Qin Yinyin , Lin Xinqing , Liu Ming , Qiu Luting , Zou Xiao , Chen Zhange
Published: June 2021

3053

Background: Sputum has previously attracted attention as a potential medium for detecting genetic and epigenetic alterations in early-stage lung cancer. Recent progress in advanced non-small cell lung cancer (aNSCLC) has highlighted plasma as an option in scenarios where tissue specimens are unavailable. In this study, we investigated the feasibility of mutation profiling with sputum from aNSCLC patients. Methods: Matched tissue (TIS), whole blood, and either induced or spontaneous sputum were collected from 42 prospectively enrolled, previously untreated patients with stage IIIB-IV NSCLC. Eight and two milliliters of whole blood and sputum were respectively used for preparation of plasma (PLA) and sputum supernatant (SPU). Capture-based targeted sequencing of TIS, PLA and SPU samples was performed with a panel of 520 cancer-related genes. Results: The cohort had a median age of 59 (range 26-79) with a majority of men (31/42). Thirty-five patients were diagnosed with lung adenocarcinoma (LUAD) and the remaining seven with squamous cell carcinoma (LUSC). There were more non-smokers (26/42) than smokers. Most patients (34/42) had metastatic disease. First, we assessed the performance of three sample types in terms of key quality control indices. PLA and SPU showed maximum allelic fraction that were both significantly smaller than that of TIS. Subsequently compared was positive detection rate, TIS, PLA, and SPU achieved respective rates of 92.9%, 71.4%, and 59.5%, revealing comparable levels between PLA and SPU samples (p = 0.36). Rates of detection were highly similar between induced (54.6%) and spontaneous sputum (61.3%), but were higher in LUSC (85.7%) than in LUAD patients (54.3%) although this difference was not statistically significant (p = 0.21). Furthermore, detection rates rose in smokers (81.3% for PLA and SPU, 100% for TIS). Next, using TIS as the gold standard, we compared the sensitivity of detecting eight established driver alterations in NSCLC with the two liquid biopsies. SPU and TIS achieved respective levels of 50.0% and 70.0%, which, similar to detection rate, improved to 88.9% (8/9) and 77.8% (7/9) in the smokers subgroup. Importantly, detection of altered KRAS and ALK was more sensitive with SPU (6/6, 2/3, entire cohort) than with PLA (5/6, 1/3). For EGFR mutation, which occurred mainly in nonsmokers, the sensitivity was considerably lower in SPU (4/14, entire cohort) than in PLA (12/14). Detection of mutant MET, however, appeared difficult for both biopsies (0/4). In addition, there was a high level of correlation between estimates of tumor mutational burden based on PLA and on SPU (Pearson r2 = 0.58). Conclusions: Our study demonstrated that for aNSCLC patients, sputum supernatant demonstrates comparable performance as plasma. Sputum is therefore a viable alternative for profiling for established driver alterations in aNSCLC, especially in smokers.
A phase II study investigating biological effects of maintenance usage of hydroxychloroquine on Par-4 levels in patients with resected tumors.
Authors: Wang Peng , Burikhanov Ravshan , Weiss Heidi , Jayswal Rani , Arnold Susanne M. , Villano John L. , Rangnekar Vivek
Published: June 2021

3085

Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.
Anticancer drugs associated with venous thromboembolic event: Analysis of the WHO pharmacovigilance database.
Authors: DA Silva Angélique , Alexandre Joachim , Laneelle Damien , Sassier Marion , Chrétien Basile , Fedrizzi Sophie , Joly Florence , Emile George , Bertoletti Laurent , Mery Benoite , Plane Anne Flore , Legallois Damien , Dolladille Charles
Published: June 2021

3094

Background: Venous thromboembolic event (VTE) is a frequent complication of cancer, as of some classical cancer therapy, like chemotherapy and surgery. The advent of new therapies such as immunotherapy and targeted therapies has meant that new therapies may be associated with VTE. Reliable data concerning the association between ADs and VTE are scarce. Methods: On March 1st, 2020 we utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) to determine the association between the 206 FDA- or EMA-labeled ADs and VTE, defined as deep vein thrombosis and pulmonary embolism. RORs were adjusted (aRORs) on population characteristics including the cancer risk of VTE with the primary tumor site according to Khorana classification and metastatic status. Results: A total of 50,438 VTE cases associated with at least one AD were identified. Thirteen ADs were associated with higher reporting of VTE of which 2 represented new VTE associations not previously confirmed in the summary of product characteristics or literature including sipuleucel-t and megestrol. ADs more reported with VTE were lenalidomide (n:5,796), bevacizumab (n:2,780) and thalidomide (n:1,700). ADs associated-VTE occurred mainly during the first 6 months after AD initiation. Conclusions: Although cancer itself may generate VTE, we identified 13 ADs associated with VTE overreporting. Recognition of AD most likely to cause VTE can help raise practitioner awareness and lead to earlier diagnosis and treatment. Futures studies should include ADs in VTE risk evaluation and evaluate the management of VTE when recurrences occur under AD favoring VTE. ClinicalTrial registration number: NCT04696250.
Phase 1/2 first-in-human (FIH) study of CPI-0209, a novel small molecule inhibitor of enhancer of zeste homolog 2 (EZH2) in patients with advanced tumors.
Authors: Lakhani Nehal J. , Gutierrez Martin , Duska Linda R. , Do Khanh Tu , Sharma Manish , Gandhi Leena , Papadopoulos Kyriakos P. , Truong Jennifer , Fan Xiaolin , Lee Ji Hyun , Bobba Suresh , Rippley Ronda , Wu Rentian , Cui Jike , Sun Kaiming , Wang Jing Y. , Trojer Patrick , Rasco Drew W.
Published: June 2021

3104

Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.
First-in-human dose-finding study of venadaparib (IDX-1197), a potent and selective PARP inhibitor, in patients with advanced solid tumors.
Authors: Kim Yong Man , Bae Kyun-Seop , Baek Nam Seok , Kim Kyungun , Lee Won Sik , Roh Eun-Jihn , Ock Chan-Young , Kim Sung-Bae
Published: June 2021

3107

Background: Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for ovary, breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or homologous recombinant repair mutation (g/sHRRmt). In this phase 1 dose finding study of venadaparib, we determined the maximum tolerated dose for venadaparib monotherapy and explored the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib in patients with advanced solid tumor which progressed after an attempt of standard-of-care therapy and for which effective therapy does not exist. Methods: Subjects who satisfied all of the inclusion/exclusion criteria and provided written informed consent were enrolled in this study. The investigational product was administered orally once daily continuously in a 3 weekly cycle. Enrolled subjects were assessed for safety and evaluated on tumor response using RECIST 1.1. The study was carried out in a conventional 3+3 design, starting from 2 mg up to 240 mg. Dose limiting toxicities (DLTs) and pharmacokinetics were assessed during the first cycle. Results: As of 08 Feb 2021, enrollment is completed with 32 patients enrolled. Most common tumor types enrolled are breast cancer (16 patients) and ovarian cancer (11 patients). Other tumor types include cancers of endometrium, fallopian tube, uterus and prostate. No DLTs were observed up to the maximum tested dose of 240 mg. Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). Overall objective response rate (ORR) was 16% and clinical benefit rate (CBR) was 47%. Partial response was observed starting from 40 mg and clinical benefit was observed from the lowest dose of 2 mg. From optional tumor tissue samples, venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg. For patients with known germline or somatic BRCA status either from local lab results or examined at a central lab retrospectively, ORR and CBR was 22% and 44% respectively for BRCAm(+) (9) patients. Interestingly, clinical efficacy was observed in BRCAm(-) (18) patients also, with ORR and CBR of 17% and 50% respectively. Conclusions: Safety and tolerability of the venadaparib monotherapy was confirmed with preliminary efficacy signals observed, even in BRCAm(-) patients. Clinical benefit was observed from the lowest tested dose, suggesting the potential to combine with other chemotherapeutic agents. Further studies to explore efficacy and safety of venadaparib in other tumor types and combinations, as well as to explore adequate biomarkers are warranted. Clinical trial information: NCT03317743.