bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and a novel clinicopathologic-genomic nomogram of atezolizumab in advanced non-small cell lung cancer (POPLAR and OAK): A combined analysis of two multicenter, randomized, phase II/III trials.
Authors: Yu Yunfang , Chen Yongjian , Li Anlin , Ou Qiyun , Wang Ying , Ren Wei , Zhang Wenda , Tan Yujie , Yao Herui 
Published: May 2019

2573 Background: Atezolizumab, a programmed death ligand 1 (PD-L1) inhibitor, prolonged overall survival (OS) compared with docetaxel among patients with previously treated advanced non–small-cell lung cancer (NSCLC) in two independent multicentre, randomized trials (POPLAR and OAK). We conducted a combined analysis of the two trials to evaluate its efficacy and genomic biomarkers, and to further developed a novel predictive clinicopathologic-genomic nomogram of immunotherapy in NSCLC. Methods: Patients (N = 1,137) with stage IIIB/IV NSCLC and disease progression after previously platinum-based chemotherapy were randomly assigned (1:1) to receive atezolizumab (1200 mg/kg every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks). The primary endpoint was OS. We applied a two-stage meta-analysis of pooled individual patient data in the intention-to-treat population. In OAK trial, patients treated with atezolizumab were randomly assigned (1:1) to the training group or the validation group to develop a predictive clinicopathologic-genomic nomogram of immunotherapy. POPLAR and OAK were registered with ClinicalTrials.gov, numbers NCT02008227 and NCT01903993. Results: In the pooled analysis, the median overall survival was 13.49 months (95% confidence interval [CI], 11.95 to 15.22) with atezolizumab versus 9.66 months (95% CI, 8.73 to 10.70) with docetaxel. The risk of death was 28% lower with atezolizumab than with docetaxel (hazard ratio [HR], 0.72; 95% CI, 0.62 to 0.83; P < 0.001). The race, sex, tumor histology, eastern cooperative oncology group performance status, PD-L1 expression, and especially pretreatment mutation (TP53, DNMT3A and KEAP1) were significantly associated with OS, and were used for the development of the predictive nomogram. The clinical use of the nomogram showed a closer association with 3-year OS than the blood-based tumor mutational burden (bTMB) or PD-L1 expression alone (nomogram, AUC = 0.818; bTMB, AUC = 0.701; PD-L1, AUC = 0.526) among NSCLC patients who had received atezolizumab. The superior predictability of the nomogram was further confirmed in the validation and entire OAK cohorts. Conclusions: Among patients with advanced, previously treated NSCLC, OS was significantly better with atezolizumab than with docetaxel. Furthermore, we constructed a novel and powerful clinicopathologic-genomic nomogram for personalized immunotherapy options.
Effect of exonic microsatellite instability of B2M on the predictability of MSI/dMMR for immunotherapy.
Authors: Wei Jia , Zhong Fangfang , Wang Weifeng , Wu Nandie , Fu Yao , Mu Shuo , Wang Yue , Qian Xiaoping , Fan Xiangshan , Wang Kai , Liu Baorui 
Published: May 2019

2576 Background: Microsatellite instability/mismatch repair deficiency (MSI/dMMR) has been approved as a biomarker for immune checkpoint inhibitor therapy (ICI) . However, the deficiency of mismatch repair system also caused wide-spreading insertion/deletion (indel) mutations in the exonic microsatellite sites of critical immunotherapy related genes such as β-2-macroglobulin (B2M) whose product is critical to antigen presentation. Cases of aquired resistance to ICI treatment caused by the inactivation of B2M have been reported. Therefore, we investigated the mutational profile of B2M across the MSI/dMMR high prevalent cancers such as colorectal cancer (CRC), gastric cancer (GC) and endometrial cancer (EC). Methods: FFPE tumor samples from 37 CRC, 46 GC and 25 EC patients with matched normal tissues were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and tumor mutational burden were assessed. Immunohistochemistry (IHC) with antibody against B2M were performed on available samples to estimate the expression and localization of these proteins. Results: Exonic microsatellite sites of B2M gene have been found instable in 51% (19/37) of CRC, 22% (10/46) of GC and 8% (2/25) of EC. MSI caused small indels at B2M coding region leads to reading frame shift and the production of nonfunctional truncated proteins. Biallelic frameshift mutations, causing non-functional proteins, were found in 47% (9/19) of CRC and 30% (3/10) of GC patients carrying Indels in B2M gene. IHC assays showed the impaired expression of B2M proteins due to frameshift mutations. In addition, NGS test confirmed concurrent mutation in B2M for a MSI-H CRC patient with primary resistance to forth-line anti-PD1 treatment. Conclusions: The extensive mutations in the coding region of genes caused by the dMMR render the cancer cell sensitive to ICI. However, the concomitant variants in exonic microsatellite sites of B2M gene may compromise the predictability of MSI/dMMR as an ICI biomarker. Biallelic mutation of B2M may cause primary resistance to ICI while the mono-allelic mutation of B2M may gain acquired resistance. Therefore, B2M status could be considered when using MSI/dMMR as a biomarker for ICI.
MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).
Authors: Cassier Philippe Alexandre , Garin Gwenaelle , Eberst Lauriane , Delord Jean-Pierre , Chabaud Sylvie , Terret Catherine , Montane Laure , Bidaux Anne-Sophie , Laurent Séverine , Jaubert Lise , Ferlay Celine , Bernardin Mathilde , Tabone-Eglinger Séverine , Gilles-Afchain Laurence , Menetrier-Caux Christine , Caux Christophe , Treilleux Isabelle , Pérol David , Gomez-Roca Carlos Alberto 
Published: May 2019

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.
Measuring the long-term “tail of curve” survival benefits in oncology trials: A comparison of the ASCO Value Framework and the ESMO Magnitude of Clinical Benefit Scale.
Authors: Everest Louis , Shah Monica , Chan Kelvin K. 
Published: May 2019

2585 Background: Recently, anti-cancer agents have generated excitement due to their capacity to preserve long-term survival in some patients, represented by a “tail of the survival curve”. However, as traditional measures of clinical benefit may not accurately capture long-term survival, amendments to various valuation frameworks have been proposed to capture this benefit. The purpose of this study was to determine how frequently immune checkpoint inhibitor vs. non-immune checkpoint inhibitor anti-cancer agents, displayed trends of long-term survival, as defined by the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), as well as to analyze the degree of agreement between ASCO and ESMO frameworks. Methods: Anti-cancer agents from phase II or III randomized controlled trials (RCTs) cited for clinical efficacy evidence in drug approval by the Food and Drug Administration (FDA) between January 2011 and March 2018 were identified. Data required for ASCO-VF and ESMO-MCBS were extracted. Difference in how often long-term survival bonuses were awarded were calculated in all RCTs, as well as immune checkpoint inhibitor and non-immune checkpoint inhibitor RCTs individually. Cohen’s Kappa statistic was calculated to evaluate agreement between ASCO-VF and ESMO-MCBS. Results: 100 RCTs were analyzed. RCTs were awarded ASCO-VF version 2 (v2) “tail of the curve” bonuses more often than ESMO-MCBS version 1.1 (v1.1) “immunotherapy-triggered” long-term plateau adjustments (45% vs. 2.6%). Comparing to non-immune checkpoint inhibitor RCTs, immune checkpoint inhibitor RCTs were not more likely to receive ASCO-VF v2 bonuses/ESMO-MCBS v1.1 adjustments (p = 0.32/ p = 0.40). Long-term survival agreement between the two frameworks was poor (kappa: 0.01; p = 0.50). Conclusions: The ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement in order to accurately capture the benefit of long-term survival or immune checkpoint inhibitor and non-immune checkpoint inhibitor agents may not preserve substantially different long-term survival populations.
Genetic determinants of adverse events in cancer patients receiving immune checkpoint inhibitors.
Authors: Abdel-Wahab Noha , Yu Robert K , Diab Adi , Dadu Ramona , Shannon Vickie , Futreal Andrew , Criswell Lindsey A. , Shete Sanjay , Suarez-Almazor Maria E. 
Published: May 2019

2586 Background: Immune checkpoint inhibitors (ICI) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAEs susceptibility as the phenotype of toxicity varies among patients (pts) and many pts do not develop toxicity despite continued inhibition. Methods: Genotyping was performed for 89 melanoma pts who received ICI using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data was extracted using PLINK (v1.90b3.34) and processed for quality control including on call rate (>99%), genotyping rate (>95%), minor allele frequency (no less than 5%), and Hardy-Weinberg Equilibrium (p<1x10-6). The pairwise genetic distance was calculated using identity-by-state (IBS matrix) implemented in the genome option of PLINK, and the population-structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p<1x10-3) and phenotype distribution for all pts, resulting in 7 structure groups. In the analytical stage, 602,463 variants in autosomal chromosomes were included for the association test. The test was performed using additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. Results: 44 pts had arthritis, colitis, hypohysitis, thyroiditis, or multiple irAEs (cases), and 45 did not have irAEs after a minimum of one year of treatment (controls); median age was 64 (23-92) years; 71% were male. A total of 30 variants/single nucleotide polymorphisms (SNPs) had p-value smaller than 10^-5 level were identified. The top variants/SNPs are listed in table. Conclusions: Genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings, and to establish their potential functional relevance.[Table: see text]
Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.
Authors: Jiao Xiaodong , Zhang Xiaochun , Qin Baodong , Liu Dong , Liu Liang , Ni Jianjiao , Zhou Ningyu , Chen Lingxiang , Zhu Liangjun , Qin Songbing , Zhou Jianya , Ying Shenpeng , Chen Xueqin , Li Aijun , Hou Ting , Zhang Tengfei , Chuai Shannon , Zang Yuan-Sheng 
Published: May 2019

2589 Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.
CD8+ T cells in tumor parenchyma and stroma by image analysis (IA) and gene expression profiling (GEP): Potential biomarkers for immuno-oncology (I-O) therapy.
Authors: Szabo Peter M , Lee George , Ely Scott , Baxi Vipul , Pokkalla Harsha , Elliott Hunter , Wang Dayong , Glass Benjamin , Kerner Jennifer K , Wapinski Ilan , Hedvat Cyrus , Locke Darren , Pandya Dimple , Adya Neeraj , Qi Zhenhao , Greenfield Alex , Edwards Robin , Montalto Michael 
Published: May 2019

2594 Background: Distribution patterns of CD8+ T cells within the tumor microenvironment (TME) can be assessed by IA, which may reflect underlying tumor biology and serve as a potential biomarker to assess the utility of I-O therapy. These patterns are variable and may be classified as immune desert (minimal infiltrate), excluded (T cells confined to tumor stroma or to the invasive margin), or inflamed (T cells diffusely infiltrating tumor parenchyma and stroma). We hypothesized that association of a GEP signature with abundance of parenchymal and stromal T-cell infiltrates may identify biomarkers of response or resistance to I-O therapy. To test this, we applied an AI-powered IA platform to quantify CD8+ T cells by geographical location and used GEP to define both CD8 abundance and associated geographic localization to tumor parenchyma and stroma. Methods: We performed an analysis using a tumor inflammatory GEP assay and CD8 immunohistochemistry on procured specimens (335 melanoma, 391 SCCHN). Digitized slides were used to train a convolutional neural network to quantify the number of CD8+ T cells in stroma, tumor parenchyma, parenchyma-stromal interface, and invasive margin. Generalized constrained regression models were used to predict GEP signatures specifically for stromal and parenchymal CD8+ T cells. Results: Parenchymal and stromal GEP scores were highly concordant with CD8+ infiltrate geography (adj- r2: 0.67, 0.65, respectively; P ≤ 0.01). Little overlap existed between gene sets associated with parenchymal and stromal CD8 T-cell geographies. CSF1R and NECTIN2 gene expression was observed to correlate inversely with parenchymal localization and directly with stromal CD8+ T-cell abundance. Conclusions: GEP signatures can be identified that are concordant with various CD8+ T-cell localization patterns in melanoma and SCCHN, demonstrating that GEP-IA can be developed to identify the immune status of interest in the TME. The specific genes identified have potential to elucidate mechanisms of resistance and/or inform I-O targets that can be further evaluated in relation to clinical significance in future studies.
Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.
Authors: Shafique Michael Rahman , Fisher Terrence Lee , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae Electa , Mallow Crystal L. , Smith Ernest , Zauderer Maurice , Schröder Andreas , Chin Kevin M. , Beck J. Thaddeus , Baumgart Megan Ann , Govindan Ramaswamy , Sanborn Rachel E. , Goldman Jonathan Wade 
Published: May 2019

2601 Background: Rational combination therapies are needed to overcome resistance mechanisms in NSCLC. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) NSCLC (NCT03268057). The trial is split into dose escalation (n = 12) and dose expansion (n = 50) phases and includes 2 cohorts; 1) pts who are immunotherapy naïve, and 2) pts whose tumors progressed during or following immunotherapy (IO failure). Pts in the dose escalation cohorts received ascending doses of pepinemab i.v. (5, 10, 20 mg/kg, Q2W) in combination with avelumab i.v. (10mg/kg, Q2W). Results: Dose escalation is complete and the RP2D was selected as 10mg/kg pepinemab, Q2W. No pts experienced a TRAE leading to study discontinuation or death. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AEs occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, and resolved without reoccurrence. The disease control rate for pts treated > 2 months is 90% (19/21), and, at this early stage, a PR with a 49% reduction in target lesion was observed in at least 1 of 8 pts in the IO failure cohort. Updated data from the dose expansion phase will be presented. Conclusions: Preliminary data suggest the combination is well tolerated and shows initial signals of antitumor activity. Dose escalation is complete and the expansion phase is ongoing. Clinical trial information: NCT03268057.
Phase I safety and pharmacokinetic study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in Japanese patients with advanced solid tumors.
Authors: Shimizu Toshio , Nakajima Takako Eguchi , Lu Ni , Xue Shilin , Xu Wenlian , Fu Meng , Cao Walt , Lu Haolan , Liu David , Dong RuiPing , Wang Xiaoxiao , Wang Pilin , Zhu Danming , Xu Ting , Gong John 
Published: May 2019

2609 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.