bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I clinical trial investigating the telomerase vaccine UV1 in combination with pembrolizumab in patients with advanced melanoma.
Authors: Zakharia Yousef , O'Day Steven , Rasch Wenche , Milhem Mohammed M. 
Published: June 2021

2620 Background: UV1, a telomerase peptide-based vaccine, consists of 3 long peptides (15-30 aa) representing a 54 aa sequence in the catalytic unit of the reverse transcriptase subunit of telomerase (hTERT). UV1 contains both CD4 and CD8 epitopes, and immunogenicity is shown in 78% of HLA unselected patients (pts.) in prior studies. UV1 induced expansion of hTERT specific CD4+ T cells that might be relevant in tumors expressing telomerase, theoretically enabling enhanced checkpoint efficacy in pts. with insufficient spontaneously primed T cells. Reciprocally, checkpoint inhibitor may support the UV1-induced T cells and provide increased effector activity, as these cells may be restricted by intrinsic and tumor-induced suppressor mechanisms. Methods: UV1 was combined with standard of care pembrolizumab in pts. with advanced melanoma. The primary objective of this phase I, multicenter study (NCT03538314), was to evaluate safety and tolerability of UV1 in combination with standard pembrolizumab. Secondary objective was evaluation of response rate (RR) according to iRECIST. Pts. received, in a serial manner, adjuvant GM-CSF and UV1 (300μg) intradermally followed by pembrolizumab. The first 3 UV1/GM-CSF doses were given during week 1, and from week 2 in combination with pembrolizumab (Q3W). Two different doses of GM-CSF were investigated: 37.5μg (20 pts. cohort 1) and 75μg (10 pts. cohort 2). Totally 8 UV1/GM-CSF vaccinations per pt. were planned (14 weeks). Results: In total 30 pts. were enrolled; cohort 1 (N = 20); cohort 2 (N = 10). The abstract reports cohort 1 results. The majority of adverse events (AEs) reported was grade 1 or 2 (48%, 41%). Main AEs were fatigue (8%), injection site reaction (5%), diarrhea (4%) and pyrexia (3%). 18% and 30% of AEs were possibly/definitely related to UV1 or pembrolizumab, respectively. Three patients experienced SAE, one (inflammatory arthritis) was considered possibly related to UV1. No severe allergic reactions were observed. Pembrolizumab was continued after completion of UV1 treatment in 14 pts. for a mean of 8.2 months (range 3-21). Four pts. discontinued pembrolizumab due to PD, one for irAE and one for unknown reason. The RR was 60%, with 5 CRs, and the 1-year survival rate 85 %. Conclusions: Results from cohort 1 (N = 20) show that the treatment of UV1 together with pembrolizumab was safe and well tolerated in patients with advanced melanoma. Updated data with minimum 18 months follow-up will be presented at the conference. Cohort 2 results will be presented at a later stage. Clinical trial information: NCT03538314. [Table: see text]
Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.
Authors: Shah Neil J. , Wang Shuo , Williams Aquino , Weber Melinda , Sinclaire Brittany , Gourna Paleoudis Elli , Alaoui Adil , lev-Ari Shaked , Adams Shari , Kaufman Jordan , Parikh Sahil B. , Tonti Emily , Muller Eric , Serzan Michael T , Cheruku Divya , Ahn Jaeil , Pecora Andrew , Ip Andrew , Atkins Michael B. 
Published: June 2021

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P <0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age >75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]
Incidence of hepatitis associated with addition of immune checkpoint blockade to conventional solid tumor therapy: A meta-analysis of phase 3 randomized clinical trials.
Authors: Fujiwara Yu , Horita Nobuyuki , Namkoong Ho , Miyashita Hirotaka , Harrington Matthew , Galsky Matt D. 
Published: June 2021

2645 Background: Immune checkpoint blockade (ICB) has emerged as a promising treatment strategy for many solid tumors. Although safe for many patients, ICB causes immune-related adverse events (irAEs) including hepatitis, which may result in morbidity and treatment disruption. Severe hepatitis requires immunosuppression, including corticosteroids and mycophenolate mofetil. We conducted a meta-analysis of clinical trials to investigate the effect of adding ICB to conventional solid tumor therapy on the incidence of hepatitis. Methods: Phase 3 randomized clinical trials (RCTs) comparing ICB and conventional therapy to conventional therapy alone were chosen by database search on PubMed, Embase, Web of Science, and Cochrane Library. The odds ratios [OR] of any-grade and grade ≥3 hepatitis, elevated aspartate aminotransferase (AST), and elevated alanine aminotransferase (ALT) were calculated. Meta-analysis was conducted to determine the incidence of hepatitis, elevated AST, and elevated ALT among patients receiving ICB and those receiving conventional therapy alone. Subgroup analysis based on the mechanism of ICB (Cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor, programmed cell death protein 1 [PD-1] inhibitor, and programmed death-ligand 1 [PD-L1] inhibitor) was also conducted. Results: A total of 29 randomized controlled trials (RCTs) enrolling 18,829 participants were analyzed. Incidence of hepatitis was derived from 24 RCTs enrolling 15,183 patients, and incidence of grade ≥3 hepatitis was derived from 22 RCTs enrolling 13,846 patients. Incidence of elevated AST was extracted from 18 RCTs, and incidence of elevated ALT was extracted from 20 RCTs. Addition of ICB to conventional therapy was associated with an increase in incidence of any-grade hepatitis (OR 2.54, 95% confidence interval [CI] 1.82-3.55) and grade ≥3 hepatitis (OR 4.22, 95% CI 2.51-7.11). The addition of ICB was also associated with an increase in incidence of elevated AST (any grade: OR 2.19, 95% CI 1.59-3.03; grade ≥3: OR 3.18, 95% CI 1.85-5.48) and elevated ALT (any grade: OR 2.08, 95% CI 1.47-2.92; grade ≥3: OR 2.41, 95% CI 1.40-4.14). Subgroup analysis based on the mechanism of ICB demonstrated increased incidence of grade ≥3 hepatitis associated with CTLA-4 inhibitor, PD-1 inhibitor, and PD-L1 inhibitor therapy (OR 2.78, 95% CI 1.26-6.14; OR 6.30, 95% CI 2.23-17.78; OR 4.73, 95% CI 1.83-12.23, respectively). No significant difference of heterogeneity was observed among subgroups ( I2= 0%, p = 0.43). Conclusions: Addition of ICB to conventional solid tumor therapy was associated with increased incidence of any-grade and severe hepatitis, and elevations of AST and ALT, regardless of the mechanism of ICB. Clinicians should weigh the risk of liver toxicity when considering addition of ICB therapy in patients with solid tumors.
Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.
Authors: Hua Gang , Chen Xiaoxi , Yu Ruoying , Bao Hua , Wu Xue , Shao Yang 
Published: June 2021

3011 Background: Sequential treatment with first-, second-generation ALK TKI followed by third-generation TKI (lorlatinib) have been widely applied to ALK-positive lung cancer. However, acquired resistance is often driven by secondary ALK mutations, which are needed to be further explored. Circulating tumor DNA, a non-invasive approach, can detect tumor-derived DNA from multiple metastatic sites and has become a promising strategy for assessing the genetic evolution of tumors and analyzing TKI resistance. Methods: Post-progression plasma specimens were collected and sequenced with a targeted gene panel from a total of 116 patients underwent ALK TKI treatment with from February 2014 to April 2020. The ALK TKIs administrated in this cohort included crizotinib (first-generation), ceritinib (second-generation), alectinib (second-generation), brigatinib (second-generation), ensartinib (second-generation) and lorlatinib (third-generation). Results: In this ALK-positive lung adenocarcinoma cohort, 49.1% were female and the rest were male with a median age of 52 (range 20 to 79). More than half of patients received more than one line of ALK TKI treatment. The most frequent ALK fusion type is EML4-ALK including EML4-ALK v1(E13; A20, 37/116, 31.9%) and EML4-ALKv3(E6a/b; A20, 49/116, 42.2%). TP53 (29.1%, 41/141) was the most frequently mutated gene other than ALK. Frequently identified secondary mutations in patients progressing on ALK inhibitors were ALK mutations L1196M and G1202R. ALK G1202R was more common in patient with v3 fusion than in v1 (25.8% vs 0%; P<.001) while ALK L1196M was more common in v1 than in v3 (20.8% vs 3.2%; P=.005). Meanwhile, G1202R was identified at higher ratio in patients progressed on second-generation ALK TKI than first- and third-generation ALK TKI (11.3% vs 0% and 9.1%) whereas L1196M was more found in patients progressed on first-generation ALK TKI (9.1% vs 1.9% and 4.5%). Other identified secondary mutations were ALK F1174C/V/L, E1210K/Q, D1269A, D1203N and L1122M/V. Compound ALK mutations (≥2 concurrent ALK mutations) were more common in patients relapsed on third-generation ALK TKI lorlatinib (36.4%) compared to first- (12.1%) and second-generation (20.8%) ALK TKIs. Using serial plasma specimens, clone evolution analysis showed that five patients developed compound ALK mutations after sequential ALK TKI treatments and two novel ALK compound lorlatinib-resistant mutations D1203N+I1171N and F1174C+G1202R were identified. Conclusions: Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance.
A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.
Authors: Tolcher Anthony W. , Carneiro Benedito A. , Dowlati Afshin , Abdul Razak Albiruni Ryan , Chae Young Kwang , Villella Jeannine A. , Coppola Sheryl , Englert Stefan , Phillips Andrew C. , Souers Andrew J. , Salman Zeena , Penugonda Sudhir , Powderly John D. , LoRusso Patricia 
Published: June 2021

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had > 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in > 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]
Multiomic, plasma-only ctDNA NGS assay for minimal residual disease (MRD) detection in solid tumors.
Authors: Kurata Jessica , Price Kristin Sedgwick , Banks Kimberly , Zotenko Elena , Hite Dustin , Cheng Donavan , Parsana Princy , Ju Jin Hyun , Dinman Tara , Miao Zong , Talasaz AmirAli 
Published: June 2021

3045 Background: Detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) post-curative intent treatment is predictive of recurrence in many solid tumors. Due to biological challenges with low ctDNA shed in early-stage disease and potential to detect non-tumor derived alterations in plasma (e.g. CHIP), most ctDNA MRD assays are dependent on a priori knowledge of genomic alterations from tumor tissue to achieve high sensitivity and specificity. Tissue-dependent methods limit the clinical application of a MRD assay, especially in cancer types where tissue biopsy is challenging, neoadjuvant therapy (NAT) is standard of care, and/or rapid turnaround times are needed for clinical decision making. We previously validated an assay (Guardant Reveal) that combines somatic and epigenomic analysis to detect ctDNA from early-stage colorectal tumors without tumor tissue or peripheral blood cells. Here we describe the expansion of this assay to detect MRD across multiple tumor types. Methods: Cell-free DNA (cfDNA) fragments are extracted from patient plasma, partitioned based on methylation fraction, enriched using a panel to target informative genomic and epigenomic regions, barcoded, and pooled for sequencing. Methylation status is determined non-destructively and with minimal loss of molecules, allowing sensitive genomic and epigenomic analysis of the same cfDNA fragments. A single assay with a total panel size of 5.3 Mb was developed for MRD analysis in multiple cancer types, including CRC, Lung and Bladder. A “ctDNA detected” result is defined by the de novo identification of tumor-derived somatic variants and/or the observation of a tumor-specific methylation profile exceeding predefined thresholds. Results: The assay performance was tested using 163 pre-treatment clinical samples from patients with early-stage non small cell lung cancer (NSCLC) and bladder cancer and 133 self-declared healthy donors. Sensitivity for pre-treatment detection in NSCLC was 68.9% at 95% specificity (20/42 Stage I: 47.6%, 25/30 Stage II: 83.3%, 19/21 Stage III: 90.5%). Sensitivity for bladder cancer was 44.2% at 95% specificity (13/43 NMIBC: 30.2%, 18/27 MIBC: 66.7%). Additional development from larger cohorts and other tumor types is ongoing and data will be presented as available. Conclusions: Using cancer-specific genomic and epigenomic signals combined with learning-based classifiers, we developed a highly specific method for detecting the presence of ctDNA in early-stage NSCLC and bladder cancer patients from plasma without the need for tumor tissue but with comparable sensitivities to tissue-dependent approaches. A plasma-only MRD assay will allow for greater clinical impact by overcoming the challenges of tissue procurement, particularly following NAT, and enabling faster time to results.
Feasibility and clinical utility of cancer whole genome and transcriptome sequencing for pediatric and young adult solid tumors.
Authors: Shukla Neerav , Levine Max , Gundem Gunes , Spitzer Barbara , Gutierrez-Abril Jesus , Bouvier Nancy , Arango Ossa Juan E. , Medina-Martinez Juan , Stockfisch Emily , O'Donohue Tara , Zehir Ahmet , Viale Agnes , Modak Shakeel , Dela Cruz Filemon S. , Slotkin Emily K , Karajannis Matthias A. , Glade Bender Julia Lynne , Walsh Michael Francis , Kung Andrew , Papaemmanuil Elli 
Published: June 2021

3063 Background: Next generation sequencing (NGS) assays have accelerated the identification of mutations and potential matched targeted therapies for patients with cancer. However, a significant proportion of patients do not derive clinical benefit from targeted panel sequencing approaches. Cancer whole genome and transcriptome sequencing (cWGTS) offers the opportunity to fully characterize tumors, but are challenged by significant cost and computational resource requirements, concerns of assay sensitivity, and the need to deliver curated results within clinically relevant time frames. We performed a prospective study to evaluate the feasibility and utility of cWGTS in pediatric and young adults with solid tumors. Methods: We developed an automated analytical workflow (Isabl) for the QC and processing of cWGTS data to include ensembl variant calling for germline and somatic substitutions, indels, and structural variants; fusion genes; gene expression; and mutation signatures. Treatment biomarkers were annotated using OncoKB with generation of a clinical prototype report. We tested the feasibility of cWGTS implementation, evaluated its analytical validity compared to standard diagnostic assays, and characterized the clinical utility of incremental findings in a prospective study of children and young adults treated at Memorial Sloan Kettering Cancer Center. Results: A total of 114 patients were enrolled. Standard NGS assays (MSK-IMPACT, MSK-Fusion) identified clinically relevant biomarkers in 22% of cases. The cWGTS process was completed, from sample acquisition to summary report, in less than 12 days. Comparison against clinically reported NGS results demonstrated high precision and recall for reported mutations (98.8%) with high concordance across variant allele representations (r2> 0.73). cWGTS identified additional oncogenic mutations not captured by targeted sequencing in 49% of patients. Furthermore, incremental findings, beyond those identified by NGS assays, of direct clinical relevance (diagnostic, prognostic, therapy guiding) were identified in 26% of patients. Importantly, < 5% of the incremental findings would have been captured by whole exome or transcriptome sequencing alone. Of possible therapeutic relevance, cWGTS analyses revealed a significantly higher tumor mutation burden than previously reported (range: 0 - 11.23). Conclusions: We demonstrate feasibility, analytical validity and clinical utility of cWGTS approaches in pediatric and young adult cancer patients, with nearly half of all patients having incremental findings that were not captured by standard targeted NGS approaches.
Validation of FAPi PET biodistribution by immunohistochemistry in patients with solid cancers: A prospective exploratory study.
Authors: Mona Christine , Benz Matthias R. , Hikmat Firas , Grogan Tristan , Lueckerath Katharina , Razmaria Ali A , Riahi Rana , Slavik Roger , Grigis Mark D , Carlucci Giuseppe , Kelly Kimberly A , Czernin Johannes , Dawson David D , Calais Jeremie 
Published: June 2021

3066 Background: Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts (CAF), a major component of tumor stroma, confer treatment resistance, promote local progression, metastasis and immunosuppression. Because FAP is selectively expressed in the tumor stroma of many cancers, radiolabeled small molecule ligands targeting FAP are being explored for their use as pan-cancer theranostic agents. The objective was to establish the spectrum of FAP expression across various cancers by immunohistochemistry (IHC) and to explore whether 68Ga-FAPi-46 PET image biodistribution faithfully reflects tumor FAP expression from resected tumor and non-tumor specimens. Methods: This study was a prospective, exploratory, imaging trial in cancer patients. Referred volunteer patients scheduled to undergo surgical resection of the primary tumor and/or metastases were eligible. Patients underwent one whole body 68Ga-FAPi-46 PET/CT scan. Subsequently, patients underwent surgical resection of the primary tumor and/or metastasis. The outcome measure was the correlation of 68Ga-FAPi-46 PET maximum standardized uptake value (SUVmax) with FAP IHC score in patient-matched cancer and non-cancer tissue. Results: The frequency of FAP expression across 14 cancers on tissue microarrays ranged from 25 to 100% (mean 76.6±25.3%). For imaging and IHC correlation, fifteen patients with the following cancer types were prospectively included: colorectal (n = 4), head and neck (n = 3), pancreas (n = 2), breast (n = 2),stomach (n = 1), esophagus (n = 2) and uterus (n = 1). All 15 patients underwent surgery following their 68Ga-FAPi-46 PET scan within a mean time interval of 16.1±14.4 days (range 1 – 50 days). For two patients the tumor was deemed unresectable. 68Ga-FAPi-46 SUVmax and IHC scores were higher in cancer tissue than in normal tissue: mean 68Ga-FAPi-46 SUVmax 7.4±4.6 (range 1.5-15.9) vs 1.6±1.2 (range 0.4-5.1), (p < 0.001) and mean FAP IHC score 2.38±0.65 vs 0.54±0.66 (p < 0.001), respectively. The FAP IHC scores strongly correlated with 68Ga-FAPi-46 SUVmax (p = 0.001, repeated measures correlation r = 0.85 (95% CI 0.53-0.95), p < 0.001). Conclusions: 68Ga-FAPi-46 PET biodistribution across multiple cancers strongly correlates with FAP tissue expression as measured by IHC. This translational validation paves the way for large scale prospective trials on the use of 68Ga-FAPi-46 PET/CT as a biomarker and stratification tool for FAP-targeted therapies. Clinical trial information: NCT04147494.