bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response.
Authors: Wang Max Mu , Choi Mi Ran , Zhang Bin , Gianneschi Nathan
Published: June 2022

2564

Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.
Assessing PD-L1 without a biopsy and through PD-L1 PET imaging with 18F-BMS-986229.
Authors: Postow Michael A. , Mauguen Audrey , Frosina Denise , Jungbluth Achim A. , Busam Klaus J. , Pandit-Taskar Neeta
Published: June 2022

2578

Background: Programmed death ligand-1 (PD-L1) is usually determined by immunohistochemistry (IHC). Determining PD-L1 status by whole body, non-invasive PD-L1 PET imaging with 18F-BMS-986229 tracer infusion may be a way to circumvent limitations to PD-L1 IHC such as poor tissue availability; discrepant PD-L1 IHC results among different tumors within the same patient; and inability to measure PD-L1 longitudinally given challenges with repeated biopsies. Methods: Within the prospective ADAPT-IT trial (NCT03122522) testing an abbreviated course of nivolumab (nivo) + ipilimumab (ipi) in patients with unresectable stage III or IV melanoma, we investigated PD-L1 PET imaging in a 10-patient expansion cohort at baseline and after 6 weeks of treatment. Maximum standard uptake value (SUV max) and mean of all SUV max for lesions for PD-L1 PET were calculated on a whole patient level for each target/ non target lesion. Standard treatment response was determined by RECIST v1.1 at weeks 6 and 12. PD-L1 IHC was scored using the E1L3N antibody by tumor proportion score (TPS), Immune Cell Score (ICS), and a Combined Positive Score (CPS). Comparisons between PD-L1 PET parameters and response were determined by complete or partial response (CR/PR); stable disease (SD), and progressive disease (PD) at respective imaging timepoints. Absolute changes in PD-L1 SUV mean and max were calculated between scans. The correlation between PD-L1 PET and IHC was estimated using Spearman’s coefficient correlation. Results: Five patients (50%) had a PR to treatment at week 6; one of these PR became a CR at week 12 and one PR was not assessable at week 12. All RECIST responders at week 6 (n = 5) had baseline PD-L1 SUV mean ≥3.00, and all progressors at week 6 (n = 3) had baseline PD-L1 SUV mean ≤2.60 (Table). A similar trend was observed when assessing response at week 12 and when considering baseline PD-L1 SUV max. Patients had changes in their PD-L1 SUV levels between baseline and week 6. Baseline PD-L1 SUV mean (inclusive of all lesions within a patient) correlated with PD-L1 IHC by TPS, ICS, and CPS (r = 0.64, 0.5, 0.47, respectively). No patients had side effects from 18F-BMS-986229 tracer infusion. Conclusions: The signal of PD-L1 positivity by PET imaging with 18F-BMS-986229 at baseline appears associated with early efficacy from nivo + ipi in this small cohort and may offer additional information than PD-L1 IHC. The ability to assess PD-L1 on a whole patient level at multiple timepoints on treatment may have future implications in how best to sequence and combine immunotherapies but further study in larger patient cohorts is needed. Clinical trial information: NCT03122522. [Table: see text]
A phase 1 first-in-human dose finding/randomized phase 2 study of IMM60 and pembrolizumab (PEM) in advanced melanoma and non–small cell lung cancer (NSCLC; IMP-MEL).
Authors: Coupe Nicholas , Walters Ian B. , Kramer Robert A. , Gileadi Uzi , Middleton Mark R.
Published: June 2022

2582

Background: Invariant natural killer T-cells (iNKTs) share features of innate cells (NK-like) and T-cells (can prime and boost an adaptive immune response). The importance of this relatively rare lymphocyte subset has generated increased interest due to its dual ability to have a direct cytotoxic effect on CD1d expressing tumors and also its ability to induce long-lasting antitumor CD8 T cell responses mediated by cross priming and licensing of dendritic cells. Various clinical approaches involving the use of allogenic iNKT cells (both untransduced and CARs) are in development and here we describe initial clinical studies with IMM60, a synthetically derived agonist of iNKT cells which is formulated in a liposome( PORT-2). In preclinical studies, IMM-60 treatment results in maturation of DCs and B cells and a potent stimulation of iNKT cell-derived IFN-g. In efficacy studies, IMM60 demonstrated monotherapy activity in PD-1 resistant models, (eg., B16-F10), up-regulation of PD-L1 expression on cancer cells as a consequence of its priming effect, and was able to overcome resistance to PD-1 antibody therapy. Methods: IMP-MEL is an open-label first-in-man phase 1/2 study, currently enrolling adult subjects with advanced NSCLC and melanoma. IMM60 containing liposomes were administered IV Q3W at 3 escalating dose levels for 6 doses alone or with PEM 200mg Q3W. The study seeks to assess the safety and efficacy of IMM-60 alone and in combination with PEM. Results: 5 subjects have been enrolled in the monotherapy cohort having a median of 3 prior therapies (min 2, max 5). Median age was 64.5 years. No treatment related adverse events have been reported nor any objective disease responses in the evaluable monotherapy subjects (n=3) to date. Conclusions: IMM-60 is well tolerated when administered IV as monotherapy at the doses tested. The liposomal formulation leads to a favorable preliminary safety profile. Full results of the phase 1 will be reported at the meeting with analysis of circulating cytokines and flow cytometric analysis. The trial plans to transition to phase 2 testing IMM60-alone vs PEM monotherapy vs the combination of IMM60 with PEM. Clinical trial information: 80472712.
Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.
Authors: Sharma Harsh , Moturi Krishna Rekha , Yilmaz Emrullah , Gbolahan Olumide B. , Kumar Atul , Hashemi-Sadraei Neda
Published: June 2022

2586

Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). Methods: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD,PR,CR)] were selected and outcomes reviewed from their electronic health records. Results: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n=14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n=20, non-cancer related surgery, n=1) (non-irAE group, n=21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 10 of 14 (71%) patients continued to show SDC. Only 4 of 14 (28.6%) patients in this group experienced progression of disease (PD), one of whom was re-challenged with nivolumab and achieved DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. Conclusions: We demonstrate that 23 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 26 (74%) remain in DC. Future prospective malignancy-specific trials such as NCT04637594 are warranted to evaluate optimal treatment duration. [Table: see text]
Actual immune checkpoint inhibitor drug use in U.S. patients with cancer.
Authors: Rawji Alia , Henk Henry J. , DaCosta Byfield Stacey , Malin Jennifer
Published: June 2022

2608

Background: By 2018, seven Immune Checkpoint Inhibitor (ICI) drugs had gained FDA approval in nine cancers and the number of indications has continued to increase. Haslam et al. estimated that between 36.1 and 38.5% of US patients with cancer were eligible for ICI therapy in 2019. We report the use of ICI dugs in the first-line of therapy (LOT1) and second-line (LOT2) among enrollees treated for 9 cancers with an FDA indication approval in or before 2017. Methods: A cohort of patients treated for one of the nine most common cancers with an FDA indication for ICI drugs in 2017 was identified using de-identified data from the OptumLabs Data Warehouse, and clinical information from the Optum Cancer Guidance Program’s electronic prior authorization (ePA) platform. De-identified administrative claims data were then linked to ePA information (cancer type & diagnosis date) at the patient level to identify details of treatment received. Eligible patients were enrolled in a commercial or Medicare Advantage (MA) plan and initiated treatment within six months of diagnosis, enrolled at least six months prior to diagnosis date (ensuring this was the LOT1) and at least thirty days after start of first identified treatment regimen (to identify the full treatment regimen). LOT1 treatment initiation ranged from 1/1/2017 to 12/31/2020 for those who were diagnosed before 6/30/2020. ICI regimens are defined as those with an ICI drug received within first thirty days of the LOT start date. Results: In this population, we identified 17,283 eligible patients treated for non-small cell lung cancer (4654), melanoma (705), renal cell carcinoma (554), bladder cancer (1974), colorectal (4502), hepatocellular carcinoma (673), gastric cancer (1786), head and neck cancer (1923), or Hodgkin lymphoma (512) in 2018, 2019, and 2020. Overall, 3,291 (19%) of these patients received an ICI in LOT1 with rates increasing over time. The highest rates of ICI use in LOT1 are for the treatment of melanoma, remaining consistent over time, while ICI use in LOT2 is highest for the treatment of non-small cell lung cancer although evidence from 2020 suggests this may be waning. Among patients being treated for renal cell carcinoma, ICI use in LOT2 decreased from 43% (2018) to 15% (2020) while LOT1 ICI use increased to 81% in 2020. Conclusions: Overall, ICI use has changed over time in both the first- and second-line setting. In particular, we observe a shift in ICI use from LOT2 to LOT1, consistent with the more recent FDA approvals in earlier lines of therapy.[Table: see text]
Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057.
Authors: Corredor Germán , Ding Ruiwen , Prasanna Prateek , Barrera Cristian , Toro Paula , Viswanathan Vidya Sankar , Zens Philipp , Berezowska Sabina , Baxi Vipul , Balli David , Belete Merzu , Velcheti Vamsidhar , Schalper Kurt A. , Madabhushi Anant
Published: June 2022

2662

Background: Immune checkpoint inhibitors (ICIs) are currently approved for use as therapy in advanced stage lung adenocarcinoma (LUAD). ICIs can decrease risk of progression by up to 60% when compared to chemotherapy, but only about 20% of patients (pts) show response. Given that high levels of tumor-infiltrating lymphocytes (TILs) have been shown to be associated with better prognosis, here, we assess whether computationally derived TIL density measures on digitized H&E images can predict RECIST derived response to nivolumab in LUAD in Checkmate 057 (CM057). CM057 is a clinical trial designed to compare the overall survival of metastatic non-squamous non-small cell lung cancer subjects treated with either nivolumab or docetaxel after failing platinum-based chemotherapy. Methods: H&E-stained samples of 683 LUAD pts were collected from TCGA (n = 421), University of Bern (UBern) (n = 100), and CM057 (n = 162). Tumor response was assessed using RECIST v1.1. Samples were digitized as whole slide images. 294 pts randomly selected from TCGA formed the training set. The remaining 389 pts were used for validation in response to nivolumab in CM057 and prognosticating overall survival (OS) in UBern and TCGA. Computerized algorithms automatically identified TILs and extracted features related to quantity and compactness of TILs with respect to other surrounding nuclei. The top 6 features, determined by least absolute shrinkage and selection operator, were used to train Cox regression models that assign a death risk score to each patient. Pts with risk scores higher than the training median score were considered “high risk” or “non-responders” while pts with lower scores were considered “low risk” or “responders”. Results: The classifier predicted objective response in CM057 with an AUC = 0.61. Additionally, survival analysis showed that the model was prognostic for OS with hazard ratios of 2.38 (confidence interval (CI): 1.32-4.29, p = 0.01, n = 127) in TCGA and 2.37 (CI: 1.32-4.25, p < 0.01, n = 100) in UBern. Conclusions: A computerized image analysis model based on measurements of TIL density showed association with response to treatment in LUAD pts who received nivolumab and was prognostic of OS. Although the AUC was not high, the results suggest analysis of TILs has potential to identify pts who will respond to treatment. Future work will include training a classifier using response to treatment as endpoint and combining the TIL measures with other biomarkers like TMB or PD-L1.
Tumor-infiltrating lymphocyte enrichment predicted by CT radiomic analysis is associated with clinical outcomes of immune checkpoint inhibitor in non–small cell lung cancer.
Authors: Park Changhee , Jeong Dong Young , Choi Yeonu , Oh You Jin , Kim Jonghoon , Pereira Sergio , Paeng Kyunghyun , Ock Chan-Young , Lee Se-Hoon , Lee Ho Yun
Published: June 2022

2663

Background: Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through CT radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we objectively assess TIL enrichment using an artificial intelligence-powered H&E analyzer, Lunit SCOPE IO, and analyze its association with advanced quantitative imaging features extracted via radiomic analysis. Clinical significance of the selected radiomic features (RFs) is then validated in independent NSCLC patients who received ICI. Methods: In the training cohort, which included 235 NSCLC patients with both tumor tissue and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. From tissue, a patient’s TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density, divided by the whole TME area, as measured on an H&E slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was then applied to CT images from the validation cohort, which included 242 NSCLC patients who received ICI as ≥ second line. Results: Among the extracted RFs, 22 features were significantly associated with TILes (p < 0.005). After excluding features of multicollinearity and/or zero-coefficient, two features, gray level variance (coefficient 1.71 x 10-3) and low gray level emphasis (coefficient -2.48 x 10-5), were finally included in the model. The two features were both computed from the size-zone matrix (SZM), the idea of which is to break down a given tumor volume into smaller spatially contiguous compartments of different sizes. In the validation cohort, the patients with high predicted TILes (≥ median) had significantly prolonged progression-free survival compared with those with low predicted TILes (median 3.81 months [95% CI 2.14 – 5.69] versus 1.94 months [95% CI 1.58 – 2.93], hazard ratio 0.69 [95% CI 0.53 – 0.90], p = 0.007). Conclusions: This CT radiomics model is able to assess TIL enrichment in TME, which is significantly associated with favorable ICI outcomes in NSCLC. Analyzing the TME through radiomics may overcome limitations of tissue-based analysis and inform clinical decisions, particularly related to use of ICI.
Differential diagnosis of hematologic and solid tumors using targeted transcriptome and artificial intelligence.
Authors: Zhang Hong , Albitar Maher , Qureshi Muhammad Asif , Wahid Mohsin , Charifa Ahmad , Ehsan Aamir , Ip Andrew , De Dios Ivan , Ma Wanlong , McCloskey James , Donato Michele , Siegel David Samuel DiCapua , Gutierrez Martin , Pecora Andrew L , Goy Andre
Published: June 2022

3018

Background: Diagnosis and classification of tumors is becoming increasingly dependent on biological and molecular biomarkers. RNA expression profiling using next generation sequencing (NGS) provides information on various biological and molecular changes in the cancer and in the microenvironment. We explored the potential of using targeted transcriptome and artificial intelligence (AI) in the differential diagnosis and classification of various hematologic and solid tumors. Methods: RNA from hematologic neoplasms (N = 2606) and solid tumors (N = 2038) as well as normal bone marrow and lymph node control (N = 806) were sequenced by NGS using a targeted 1408-gene panel. The hematologic neoplasms included 20 different subtypes. Solid tumors included 24 different subtypes. Machine learning is used for comparing two classes at a time. Geometric Mean Naïve Bayesian (GMNB) classifier is used to provide differential diagnosis across 45 diagnostic entities with assigned ranking. Results: Machine learning showed high accuracy in distinguishing between two diagnoses with AUC varied between 1 (Sarcoma vs GIST) and 0.841 (MDS vs normal control) (examples in Table). For differential diagnosis between all 45 different diagnoses, we used 3045 samples for training the GMNB algorithm and 1415 samples for testing. Correct first choice diagnosis was obtained in 100% of ALL, 88% of AML, 85% of DLBCL, 82% of colorectal cancer, 88% of lung cancer, 72% of CLL, and 72% of follicular lymphoma. The algorithm had difficulty in typically overlapping diagnoses and diagnosed as first choice 19% of MDS, 46% of normal, and 12% of MPN. Diagnosis improved significantly when second choice was considered. Conclusions: Targeted RNA profiling with proper AI can provide highly useful tools for the pathologic diagnosis and classification of various cancers. Additional information such as mutation profile and clinical information can improve these algorithms, reduce subjectivity, and minimize errors in pathologic diagnoses. [Table: see text]
Monitoring engorgement of phagocytic circulating stromal cells during chemo-radiotherapy induction predicts survival in unresectable stage 2/3 NSCLC.
Authors: Gardner Kirby P , Adams Daniel L , Lopez Bravo Pablo , He Jianzhong , Qiao Yawei , Xu Ting , Liao Zhongxing X. , Tang Cha-Mei , Lin Steven H.
Published: June 2022

3054

Background: Circulating stromal cells, ie Cancer Associated Macrophage-Like cells (CAMLs), are prevalent in the circulation of non-small cell lung carcinoma (NSCLC) patients (pts), appearing as giant phagocytic macrophages that represent an inflammatory pro-tumorigenic microenvironment. Previously it was shown that pts with engorged CAMLs of ≥50µm after treatment are prognostic for poor clinical outcomes. However, analyzing the dynamic changes in CAMLs over time or in response to treatment, ie chemoradiation (CRT) and immunotherapy (IMT) has not been evaluated. We monitored n = 182 unresectable NSCLC stage II/III pts treated with CRT alone (n = 91) or with concurrent IMT (n = 91) to evaluate changes in CAMLs before and after CRT induction at it relates to progression free survival (PFS) or overall survival (OS). Methods: We prospectively procured pts from 3 different regimes, treated with CRT alone (n = 91), treated concurrently with CRT & Atezolizumab (n = 40, clinical trial NCT02525757), or treated concurrently with Durvalumab (n = 51). We recruited 182 pts with pathologically confirmed stage II/III unresectable NSCLC. A total of 15 mL blood samples were drawn prior to start of therapy at baseline (BL) and ̃5 weeks (T1) after CRT induction. Blood filtration was done using CellSieve filters, then CAMLs were identified and measured to evaluate PFS & OS hazard ratios (HRs) by censored univariate and multivariate analyses at 2 years. Results: CAMLs were found in 89% of all samples tested. Increases in CAML size between BL & T1 were significantly correlated with worse clinical outcomes, with higher CAML increases correlated with increasingly worse outcomes, including CAML increases >10μm resulting in PFS HR=1.7 p = 0.027 & OS HR=1.9 p = 0.045, through increases >40μm resulting in PFS HR=2.1 p = 0.013 & OS HR=2.5 p = 0.020. Increases of CAMLs >35μm was optimal at stratifying pts PFS HR=2.2 p = 0.005 & OS HR=2.8 p = 0.005. Specifically, pts treated with only CRT and increasing CAMLs >35μmhad significantly worse PFS HR=2.7 p = 0.029 & OS HR=4.1 p = 0.013. In parallel, pts treated with CRT+IMT and increasing CAMLs >35μm had near significance for worse PFS (HR=2.1 p = 0.073) & OS (HR=2.3, p = 0.147), though follow up clinical data is ongoing. Conclusions: Our data suggest that in unresectable stage II/III NSCLC, tracking the increase of pro inflammatory immune cells (CAMLs) in circulation during therapy induction can identify pts less responsive to CRT or PD-L1/PD-1 IMTs.
Independent validation of a novel noninvasive 4-microRNA diagnostic model for multicancer early detection.
Authors: Zhang Andrew , Hu Hai
Published: June 2022

3065

Background: Cancer early detection is critical to reduce mortality as treating early stage cancers is more likely to have better outcomes. We previously developed a diagnostic model based on 4 serum cell-free microRNAs (miRNAs) capable of detecting 12 cancer types with high accuracy (AACR 2022, Poster 2890; Manuscript submitted). In the current study, we aimed to validate this diagnostic model using independent serum microRNA microarray datasets. Methods: Four microarray datasets assessing the expression of 2588 serum miRNAs in patients with esophageal squamous cell carcinoma, gastric cancer, prostate cancer and glioma, as well as non-cancer healthy controls with a standardized platform were identified from Gene Expression Omnibus (GEO). The datasets were combined, cases that were redundant among them or with the cases used in our previous study (correlation > 0.99) were excluded. The 4-miRNA model was applied to the final combined dataset to calculate a diagnostic index and make prediction of cancer vs. no-cancer using previously determined algorithm and cut-point. The performance of the diagnostic model was assessed using Receiver Operating Characteristic (ROC) analysis, sensitivity and specificity. Results: After excluding redundant cases, the final combined dataset consisted of 3877 subjects, including 447 esophageal, 1267 gastric, 769 prostate and 196 glioma cancer patients, as well as 1198 healthy controls. The 4-miRNA model demonstrated an area under the curve (AUC) of 0.986, 0.995, 0.992 and 0.990 in the ROC analysis, with a sensitivity of 85.0%, 99.6%, 90.6% and 86.7% for esophageal, gastric, prostate and glioma cancers, respectively, while achieving a 99.1% specificity. These performance metrics were highly consistent to those reported in our previous study (Table). Conclusions: The study provided an independent validation of the previously developed 4-miRNA model, further demonstrating that the diagnostic model we developed has the potential to be developed into a simple, inexpensive and noninvasive blood test for multi-cancer early detection with high accuracy. [Table: see text]
64Cu-SAR-Bombesin PET-CT imaging in the staging of ER+/PR+/HER2- metastatic breast cancer: Safety, dosimetry, and feasibility in a phase I trial.
Authors: Wong Keith , Sheehan-Dare Gemma , Nguyen Andrew , Ho Bao , Liu Victor , Lee Jonathan , Brown Lauren Julia , Dear Rachel Fitz-Gerald , Chan Lyn , Pathmanandavel Sarennya , Sharma Shikha , Malaroda Alessandra , Smith Isabelle , Lim Elgene , Emmett Louise
Published: June 2022

3092

Background: Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and 18F-Fluorodeoxyglucose PET-CT (FDG) used in conventional staging of breast cancer has lower sensitivity for these subtypes. Gastrin releasing peptide receptors (GRPR) are a potential alternative diagnostic and theranostic target for ER+/PR+ breast cancers due to their overexpression of GRPR. This phase 1 study aims to assess the safety and potential of the novel radiotracer 64Cu-Sarcophagine(SAR)-Bombesin (BBN) in the re-staging of recurrent metastatic ER+/PR+/human epidermal growth factor 2 negative (HER2-) breast cancer. Methods: Patients with confirmed recurrent or primary metastatic ER+/PR+/HER2- breast cancer undergoing staging prior to a new treatment underwent 64Cu-SAR-BBN PET-CT with imaging at 1, 3 and 24 hours post-injection. Bloods and vital signs were acquired for patients at baseline, 1, 3 and 24 hours post-injection timepoints, and electrocardiogram (ECG) performed 1 hour pre and 1 hour post injection. Blood tracer-clearance and dosimetry was performed. GRPR receptor status was assessed in 4/7 patients from metastatic-site biopsy samples. Staging of the patients was assessed by conventional imaging (FDG, bone scan and diagnostic CT) within 3 weeks of 64Cu-SAR-BBN imaging. All PET scans were assessed visually, and quantitatively using MIM Software. Results: 9 patients were enrolled. 7/9 patients underwent all imaging modalities, while 2/9 did not undergo BBN imaging. 1/7 patient who underwent all imaging had de- novo metastatic ER+/PR+/Her 2- breast cancer and 6/7 recurrent metastatic disease. 2/7 had lobular subtype. There were no adverse events reported, and ECG, vitals and haematological, biochemical and coagulation markers remained unchanged. All 7 patients were positive on conventional imaging, while 6/7 were positive on FDG. BBN was positive in 5/7 patients. Both BBN negative patients had disease identified on FDG. Conversely, 1 patient was BBN positive but FDG negative. 4/7 patients were BBN positive and FDG positive. In these 4 patients, mean SUVmax was higher for BBN than FDG (15 vs. 12). In classical lobular subtype (2/7), BBN was highly avid compared to FDG (SUV max 20 vs 11, and 20 vs <3) and with a higher tumor volume compared to FDG (2034 vs 504, and 634 mL vs FDG negative). Conclusions: 64Cu-SAR-Bombesin is a novel tracer which appears safe and may have a diagnostic and theranostic role in patients with metastatic ER+/PR+/HER2- breast cancer, particularly lobular subtype. Further evaluation appears warranted.
Primary results from JUPITER, a phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with HER2-amplified solid tumors.
Authors: Ikeda Sadakatsu , Kudo Ryo , Yamashita Yamato , Kubo Toshio , Mori Yukiko , Harada Yohei , Shirota Hidekazu , Hayashi Hideyuki , Kano Masayuki , Shimizu Yasushi , Ishibashi Eri , Tateishi Ukihide , Hirakawa Akihiro , Akita Hirotoshi , Matsubara Hisahiro , Nishihara Hiroshi , Ishioka Chikashi , Sueoka-Aragane Naoko , Muto Manabu , Toyooka Shinichi
Published: June 2022

3131

Background: Human epidermal growth factor receptor 2 (HER2) gene amplification or mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. Despite its considerable therapeutic potential, the evidence has not been established. To address this unmet need, we conducted an organ-agnostic basket trial targeting HER2-amplified solid tumors. Methods: JUPITER is a multicenter, single-arm, phase 2 basket trial for solid tumor patients (pts) with HER2 amplification determined by next-generation sequencing (NGS). Both tissue and liquid NGS results were allowed. HER2 amplification by ISH or HER2 overexpression by IHC were not used for inclusion. Pts had treatment-refractory metastatic tumors, or rare cancers without established standard of care. Breast, gastric, and colorectal cancers were excluded. Pts were treated with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks until disease progression or any other reason for discontinuation. Tumor response was assessed using RECIST v1.1. Primary endpoint was ORR by blinded independent central review (BICR), and secondary endpoints were ORR assessed by the investigators, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. We set the ORR threshold 5% and expected ORR was 20%. Estimated sample size was 38 patients with one-sided alpha 2.5% and power 80%. Results: Between April 2019 and June 2020, 42 pts were consented, and 40 pts were treated. Median age was 62 (range, 21-86) and 60% were females. The most common diagnosis was biliary tract cancer (20%), followed by salivary ductal carcinoma (12.5%) and endometrial cancer (12.5%). At data cutoff (1 Sep 2021), ORR by BICR was 22.5% (95%CI: 10.8%-38.5%). ORR assessed by the investigator was 25% (95%CI: 12.7%-41.2%). PFS, OS and DOR were not reached at data cutoff; 3 responders remained on treatment. Of 40 pts, 32.5% had grade ≥ 3 adverse events; 10% were treatment-related, including neutropenia, hypertension, peripheral sensory neuropathy and lymphoedema (all grade 3). No treatment-related death was observed. Exploratory biomarker analysis of response and resistance is in progress. Conclusions: Combination therapy with trastuzumab and pertuzumab was well tolerated and showed promising efficacy for the patients with HER2-amplified solid tumors determined by NGS. Clinical trial information: jRCT2031180150.
STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.
Authors: Chibaudel Benoist , Dourthe Louis-Marie , Andre Thierry , Henriques Julie , Bourgeois Vincent , Etienne Pierre-Luc , Desrame Jérôme , Carola Elisabeth , Dupuis Olivier , Baba-Hamed Nabil , Auby Dominique , Louvet Christophe , Maillard Emmanuel , Romano Olivier , Tournigand Christophe , Garcia-Larnicol Marie-Line , Shmueli Einat Shacham , Healey Bird Brian , Ghiringhelli François , De Gramont Aimery
Published: June 2022

3504

Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B > arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]
Dietary quality in early-onset gastrointestinal malignancies: NHANES 2005-2018.
Authors: Lim Mir , Goksu Suleyman Yasin , Khatib Jude , Reddy Sarah , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali
Published: June 2022

3549

Background: The incidence of early-onset colorectal, stomach, esophageal, and pancreatic cancer, which occur in individuals <50 years of age, is rising worldwide. However, little is known about why rates have been up trending. Previous studies have linked poor diet and nutrition to an increased risk of typical-onset gastrointestinal (GI) malignancies. In this study, we aimed to describe dietary quality in individuals with early-onset GI malignancies and compare it to typical-onset GI malignancies. Methods: We queried the 2005-2018 National Health and Nutrition Examination Survey (NHANES) database for all survey participants diagnosed with GI malignancies, including colorectal, esophageal, gallbladder, liver, pancreas, rectal, and stomach cancer. We classified early and typical-onset GI cancer based on age of diagnosis of <50 and ≥50 years, respectively. Participants <50 without a history of cancer were classified as controls. We assessed the dietary quality by calculating the healthy eating index score (HEI-2015) from NHANES database for all participants. The primary outcome was mean HEI-2015 score for early onset GI malignancies. We performed propensity score weighted analysis to balance gender, race, income, education level, and BMI between the groups. We used logistic regression analysis to assess the relationship between early-onset GI malignancies and HEI-2015 quintiles. Results: Out of 32,235 participants in NHANES database, 330 individuals (1%) reported a diagnosis of GI malignancy. Sixty-eight (20.5%) individuals had early-onset GI malignancies. We identified 17,420 controls who were <50 years old with no reported history of malignancy. Fifty-three percent of early-onset GI cancers were female vs 47% of typical-onset GI cancers; 59% vs 59% were non-Hispanic White; 66% vs 40% had a college degree; 13% vs 7% had high income and 40% vs 36% were obese. The mean HEI-2015 score in early-onset GI cancer was 52.9 (SD 14.7) compared to 53.6 (SD 13.0) in typical-onset GI cancers, which was not significantly different (p=0.72). There was no significant association between poor HEI-2015 scores in individuals with early-onset vs typical-onset GI malignancies on logistic regression analysis (OR 0.84 [0.35-2.03]). In addition, HEI-2015 quintiles were not significantly associated with those with early-onset GI malignancies compared to controls <50 years old (OR 2.06 [0.72-5.9]). Conclusions: The diet quality of early-onset GI malignancies does not align with the national Dietary Guidelines. However, in this analysis of the NHANES database, we did not find a significant difference in HEI-2015 scores between early-onset versus typical-onset GI malignancies.
Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.
Authors: Khawaja Hajrah , Briggs Rebecca , Latimer Cheryl , Rassel Md A.M.B , Griffin Daryl , Hanson Lyndsey , Bardelli Alberto , Di Nicolantonio Federica , McDade Simon , Scott Christopher , Lambe Shauna , Maurya Manisha , Lindner Andreas Ulrich , Prehn Jochen HM , Sousa Jose , Winnington Chris , J LaBonte Melissa , Ross Sarah , Van Schaeybroeck Sandra
Published: June 2022

3557

Background: Novel covalent inhibitors of KRASG12C have shown modest response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRASG12C MT CRC cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option.
A phase 2 trial of sintilimab (IBI 308) in combination with CAPEOX and bevacizumab (BBCAPX) as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
Authors: Fang Xuefeng , Zhong Chenhan , Zhu Ning , Weng Shanshan , Hu Hanguang , Wang Jian , Xiao Qian , Wang Jianwei , Song Yongmao , Sun Lifeng , Xu Dong , Liao Xiujun , Dong Caixia , Zhang Suzhan , Li Jun , Ding Ke-Feng , Yuan Ying
Published: June 2022

3563

Background: The prognosis of metastatic colorectal cancer (mCRC) patients with RAS gene mutation and microsatellite stable (MSS) is poor. MSS patients account for 95% of CRC and have a low response rate to immunotherapy. Previous studies have reported that chemotherapy and anti-angiogenesis therapy can promote immunotherapy response. This study aims to assess the safety and antitumor activity of sintilimab (IBI308) combined with CapeOx and bevacizumab in the first-line treatment of patients with RAS-mutant and MSS mCRC. Methods: This is an open-label, single-arm, phase II trial. Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) evaluated via RECIST 1.1 criteria and adverse events according to CTCAE 5.0. Secondary endpoint was progression-free survival (PFS). Results: 25 patients were enrolled and received at least two cycle treatment. At baseline, median age was 60 years (range 45-74), 72% of patients were male, ECOG PS 0/1 was 100%, 60% had liver metastases (mets), and the primary tumor site was right-sided colon in 36.0% and left-side colorectum in 64.0%. 25 patients completed at least one efficacy evaluation. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease (SD). Patients with liver or lung mets had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). Disease control rate (DCR) reached 100%. Median PFS has not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were anemia (19/25, 76.0%), peripheral neurotoxicity (6/25, 24.0%) and neutropenia (17/25, 68.0%). The most frequent grade 3/4 TRAEs were neutropenia (3/25, 12.0%), elevated aspartate transaminase (1/25, 4.0%), elevated alanine transaminase (1/25, 4.0%) and elevated bilirubin (1/25, 4.0%). Conclusions: Combination treatment with sintilimab (IBI308) plus CapeOx and bevacizumab demonstrated a high ORR (84.0%; 93.3% in patients with liver mets, and 100% in patients with lung mets) and a manageable safety profile in RAS-mutant and MSS mCRC. Clinical trial information: NCT05171660. [Table: see text]
Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.
Authors: Liu Tianshu , Yang Mudan , Li Jin , Pan Yueyin , Yuan Ying , Yi Shanyong , Wang Junsheng , Cheng Ying , Feng Jifeng , Gao Shegan , Wang Xicheng , Qu Song , Zhang Xizhi , Lu Jin , Xiu Peng , Wang Shuni , Yang Xinfeng , Fan Jia
Published: June 2022

3577

Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]