bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, tolerability, pharmacokinetics and preliminary efficacy of MIL93, an anti-Claudin18.2 monoclonal antibody, in patients with advanced solid tumors: A phase 1 clinical study.
Authors: Huang Jing , Zhang Bo , Wang Ying , Wang Feng , Wu Shikai , Zheng Yi , Xu Jianping , Lan Dongmei , Wei Min , Liu Sijun 
Published: June 2022

3086 Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized IgG1 monoclonal antibody targeting CLDN18.2. From January 2021, we started a multicenter, dose escalation and expansion phase 1 study of MIL93, for the treatment of patients with advanced solid tumors (Protocol number MIL93-CT101, Beijing Mabworks Biotech Co. Ltd.) at 6 clinical study sites in China. Currently the study is still ongoing. Methods: We already enrolled 13 pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were planned for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (February 14, 2022), 13 pts were enrolled between April 23, 2021 and February 9, 2022. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 20mg/kg Q3W) as no DLTs were observed, and dose escalation was ongoing at 30mg/kg. In particular, Grade 3 nausea and vomiting occurred in 2 cases in the third dose group, so preventive antiemetic treatment was given from the fourth dose group. 9 pts (69.2%) experienced at least one treatment-emergent adverse event (TEAE) with no Grade 4 or Grade 5 AEs. The most common treatment-related adverse events (TRAEs) occurring in ≥10% of pts were nausea (46.2%), vomiting (46.2%), fatigue (15.4%), anemia (15.4%). Serious adverse events (SAEs) were observed in 3 (23.1%) pts, and MIL93-related SAEs occurred in 1 pt (7.7%, Grade 3 nausea). Among the 10 pts who had at least one post-treatment radiological evaluation, 1 pt with CLDN18.2-positive gastric cancer achieved PR and 3 pts had SD, including 1 case of gastric cancer, 1 case of gastroesophageal junction cancer and 1 case of gallbladder cancer. Conclusions: MIL93 had a favorable safety profile with no DLTs observed through 20mg/kg Q3W. Pts with CLDN18.2-positive gastric cancer responded to the treatment. Dose escalation and expansion in selected tumor types is currently underway. Clinical trial information: NCT04671875.
A phase 1 dose-escalation study of the ABN401 (c-MET inhibitor) in patients with solid tumors.
Authors: Lee Dae Ho , Roohullah Aflah , Cho Byoung Chul , Lemech Charlotte Rose , de Souza Paul L. , Millward Michael , Choi Jun Young , Park Kyung Eui , Kim Na Young , Kim EuiYoung , Lee Saehyung , Kim YeongMun , Shin YOUNGKEE , Han Ji-Youn 
Published: June 2022

3105 Background: MET is a proto-oncogene encoding a receptor tyrosine kinase c-MET for hepatocyte growth factor (HGF). Dysregulated MET signaling by MET exon14 skipping, MET gene amplification and c-MET overexpression in cancer plays a critical role in the development of primary oncogenesis, acquired drug resistance and metastasis. This is a first-in-human trial, phase 1 dose-escalation study of the highly selective MET kinase inhibitor, ABN401. ABN401was evaluated in subjects with advanced solid tumors in South Korea and Australia. Methods: Patients with advanced solid tumors were enrolled in escalating dose cohorts using an accelerated titration design. ABN401 was orally administered daily with 21-day cycle. The primary objective was to evaluate safety and tolerability to define dose-limiting toxicity (DLT), maximum tolerated dose (MTD) according to CTCAE v5. Secondary objectives included pharmacokinetic, recommended phase II dose (RP2D), and preliminary efficacy assessments. Tumor assessment was determined using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: Out of 28 screened patients, 16 patients with 6 different tumor types were treated with ABN401 at daily dose levels of 50, 100, 200, 400, 800 and 1200 mg, 15 patients were evaluated for DLT and one unevaluable. No DLT was observed in all 6 dose levels and the MTD has not been reached. No drug related grade ≥ 3 AEs were observed: only one drug-related SAE (transient peripheral edema) was reported. For treatment response, 5 patients with stable disease, and 2 with partial response were observed. These two patients with partial response had non-small cell lung cancer (NSCLC) with c-MET overexpression and had been treated with ABN401 for 10 and 18 months, respectively. Conclusions: ABN401 dosed up to 1200 mg QD was well tolerated with an acceptable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors. The extension (pilot expansion) for additional efficacy assessment is under way at 800 mg daily dose with c-MET altered NSCLC patients in South Korea and Australia. In addition, a phase 2 expansion study is to start in the United States and South Korea. Clinical trial information: NCT04052971.
Central nervous system (CNS) outcomes and progression patterns in patients with RET fusion-positive lung cancers treated with selpercatinib.
Authors: Murciano-Goroff Yonina R. , Falcon Christina J. , Lin Sabrina T. , Dhawan Aradhika , Grimaldi Grace , Liu Dazhi , Wilhelm Clare , Thomas Reeja , Iasonos Alexia , Drilon Alexander E. 
Published: June 2022

3109 Background: Selpercatinib, a potent/selective RET inhibitor, is approved for the treatment of RET fusion-positive non-small cell lung cancers. While the drug is known to have substantial intracranial activity (intracranial ORR 82%) in patients with existing brain metastases, (1) central nervous system (CNS) outcomes in patients without brain metastases and (2) CNS progression patterns in patients with brain metastases have not been explored. Methods: Patients with advanced RET fusion-positive lung cancers were prospectively treated with selpercatinib on the registrational LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 multi-center expanded access program (EAP, NCT03906331). Key overall and CNS eligibility criteria were previously presented. Patients with and without pre-selpercatinib brain metastases who underwent serial CNS and extracranial imaging were eligible for analysis. The data cutoff was November 24, 2020. Cumulative incidence rates (CIRs) were calculated using a competing risk model with systemic progression of disease (PD) or death as competing risks; patients with simultaneous CNS and systemic PD were treated as having had CNS PD. Results: Sixty-two patients (48 LIBRETTO-001, 14 EAP) were identified. Median age was 64. Thirty-two (52%) were female and 47 (76%) were never smokers. The most common 5’ fusion partner was KIF5B (68%). The median number of prior therapies was 2 (range 1-11); 34% received prior multikinase inhibitor therapy. The median time on treatment was 21.8 months. Thirty-one (50%) patients had no baseline brain metastases. In these patients, the CIR of CNS metastasis was 0% at 6 months and 12 months; none of these patients developed CNS metastasis during selpercatinib treatment. The 9 patients that progressed did so extracranially. Of the 31 patients with baseline brain metastases, 12 (39%) had prior CNS radiation and 3 (10%) had prior CNS surgery. At the time of data cut-off, 23 patients had some evidence of progression, including 8 in both the CNS and systemically, 6 only in the CNS, and 9 only systemically. Overall, 17 of the 31 patients with baseline brain metastasis did not develop evidence of CNS progression as of the data cut. Among patients with baseline brain metastasis, the CIR for evidence of CNS PD was 6.7% at 6 months and 27.4% at 12 months. Conclusions: In patients with RET fusion-positive lung cancers without baseline brain metastases, new CNS metastases were not observed during selpercatinib therapy. Among patients with baseline brain metastasis, a substantial number did not experience progression in the CNS on treatment.
Pan-cancer analysis of exogenous (microbial) sequences in tumor transcriptome data from the ORIEN consortium and their association with cancer and tumor microenvironment.
Authors: Spakowicz Daniel , Hoyd Rebecca , Wheeler Caroline E. , Zakharia Yousef , Dodd Rebecca D. , Ose Jennifer , Hardikar Sheetal , Tarhini Ahmad A. , Robinson Lary A. , Singer Eric A. , Carpten John D. , Chan Carlos Hou Fai , Ikeguchi Alexandra , Ulrich Cornelia M , McCarter Martin ,   The exORIEN Consortium
Published: June 2022

3113 Background: The tumor microbiome holds great potential for its ability to characterize various aspects of cancer biology and as a target for rational manipulation. For many cancer types, little is known about the role of microbes and in what contexts they affect clinical outcomes. Non-human (i.e. exogenous) sequences can be observed in low abundance within high throughput sequencing data of tumors. Here, we describe a collaboration among members of The Oncology Research Information Exchange Network (ORIEN) to leverage tumor biopsy RNAseq data collected under a shared protocol and generated at a single site to better understand the tumor microbiome, its association with prognostic features of the tumor microenvironment (TME) such as hypoxia, and how it may be used to improve clinical outcomes. Methods: Tumor RNAseq samples from 10 primary source locations including the tissues colon, lung, pancreas, and skin from ORIEN and similar cancers from The Cancer Genome Atlas (TCGA) were processed through the exoTIC (exogenous sequencing in tumors and immune cells) pipeline to identify and count exogenous sequences, filter contaminants, and normalize across datasets. Gene expression signatures of the TME, such as hypoxia, were calculated using ‘tmesig’. Microbe relative abundances were modeled with primary tumor location and hypoxia score using a gamma-distributed generalized linear regression via the stats package in R. Results: We analyzed RNAseq data of 2892 and 2720 tumors from ORIEN and TCGA, respectively. Patients’ ages were significantly greater in the ORIEN than the TCGA dataset (62 vs 58 yo, t-test p<0.001). The ORIEN data contained more sarcoma samples than TCGA (n = 691 vs 259) with roughly equivalent numbers in other cancer types. Fewer microbes were significantly associated with the hypoxia score than with cancer type (n = 32 vs 210). This trend was observed in both the ORIEN and TCGA datasets. The largest effect sizes were observed between microbes and small cell lung cancer. Conclusions: We found microbial sequences in all ORIEN and TCGA tumor RNAseq samples tested. Cancer type showed more significant associations with microbes than a hypoxia signature. These observations merit further investigation into the interaction between microbes and the TME. [Table: see text]
Variable detection of actionable alterations across racial groups and association with testing patterns.
Authors: Sturgill Emma , Correia Jessica , Schumacher Cooper , Luckett Daniel , Jones Suzanne Fields , Burris III Howard A. , Spigel David R. , McKenzie Andrew Jacob 
Published: June 2022

3116 Background: Molecular landscape studies are critical to biomarker discovery and precision oncology research. However, non-White patients (pts) have historically been under-represented. In this study, we examine clinico-genomic data from a network of community oncology clinics to evaluate real-world mutational frequencies in Black, White, and Asian pts with cancer. Methods: We utilize Genospace, a precision medicine software, to harmonize clinical data from the Sarah Cannon research network of U.S. community oncology practices with genomic data from commercial NGS vendors. Pts with known race and NGS test results from September 2015 to November 2021 are assessed. Variants of uncertain significance (called by NGS vendor) are excluded. Asian pts are not evaluable in all instances because of low pt number. Statistical analyses include Chi squared and two sample test of proportions with Benjamini-Hochberg false discovery rate correction. Results: A total of 18,399 pts are assessed, with 7% Black (n = 1,319), 92% White (n = 16,903), and 1% Asian (n = 177) pt representation. The most common tumor types include non-small-cell lung (NSCLC; 27% of Black pts, 30% of White pts, 33% of Asian pts), colorectal (15% of Black pts, 12% of White pts, 14% of Asian pts), breast (14% of Black pts, 11% of White pts, 9% of Asian pts), and prostate (6% of Black pts, 5% of White pts, 3% of Asian pts) at roughly equal proportions across racial groups. In NSCLC, EGFR mutations and ALK fusions significantly enrich in Asian pts while KRAS G12C is detected more frequently in Black patients (see table for details; Black: n = 353, White: n = 5,127, Asian: n = 58). In both prostate and breast cancers, plasma-based NGS is less common in Black pts than White pts (plasma-to-tissue ratio = 1.1 (Black prostate: n = 82); 1.5 (White prostate: n = 863); 0.6 (Black breast: n = 178); 0.9 (White breast: n = 1,918)). In prostate, AR mutations are detected less frequently in Black pts. However, when considering plasma-NGS results alone the detection frequency is roughly equal. Similarly, the gap in ESR1 detection frequencies in breast decreases when considering plasma-NGS results alone. Conclusions: Actionable alterations are detected across racial groups at variable frequencies with potential biological and technical underpinnings. In scenarios where plasma-NGS is commonly used to monitor for resistance mutations, discrepancies in NGS ordering patterns likely affect detection frequencies. [Table: see text]
Stress keratin 17 as a novel biomarker of response in immune checkpoint blockade–treated head and neck squamous cell carcinoma.
Authors: Lozar Taja , Fitzpatrick Megan , Wang Wei , Bailey Howard Harry , Yang Bruce Justine Yang , Harari Paul M. , Lambert Paul 
Published: June 2022

3117 Background: Low response rates in immune checkpoint blockade (ICB) treated head and neck squamous cell carcinoma (HNSCC)drive a critical need for robust clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in various types of cancer, including HNSCC; however, its predictive value for ICB response has not been investigated. Preclinical studies suggest K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors. Furthermore, knocking out K17 results in restored response to ICB in a HNSCC mouse model. Here, we evaluated if K17 protein expression predicts response to ICB in human HNSCC patients. Methods: We conducted a retrospective analysis of 26 HNSCC patients that received at least one cycle of pembrolizumab at the University of Wisconsin-Madison Carbone Cancer Center. Pretreatment, archival, formalin-fixed, paraffin-embeded samples were stained by immunohistochemistry using a K17 monoclonal antibody. Clinical outcomes were investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathology review, cases were categorized into K17 high vs K17 low based on a cut-off of > 5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component. Correlation between K17 expression and clinical outcomes was assesed using Fischer's exact test and log rank test. Results: The 26 patients included in this study were 85% male, median age 60.5 years, 74% ECOG performance status < 2, with 80% having received prior chemotherapy. Primary site included oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) showed high K17 expression, and 9 tumors (35%) showed low K17 expression. Eleven patients (42%) had programmed death ligand 1 (PD-L1)+ tumors as determined by combined positive score. Six patients (23%, all K17 low) achieved clinical benefit, while 20 patients (77%, 17 K17 high and 2 K17 low) had progressive disease. High K17 expression was associated with lack of clinical benefit (p < 0.001), shorter time to treatment failure (p < 0.001), progression-free (p = 0.004) and overall survival (p = 0.02). PD-L1 expression by immunohistochemistry (clone 22C3) did not correlate with K17 expression or clinical outcome. Conclusions: Our findings suggest that K17 expression may predict clinical benefit from ICB in HNSCC patients, thus supporting further validation studies. [Table: see text]
Clinical utility of tumor next-generational sequencing (NGS) panel testing to inform treatment decisions for patients with advanced solid tumors.
Authors: Bogdan Lucia , Saleh Ramy R. , Avery Lisa , Del Rossi Samanta , Yu Celeste , Bedard Philippe L. 
Published: June 2022

3119 Background: There is limited information about the clinical utility of targeted NGS panel testing to inform decision-making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is an ongoing prospective study that enrolled over 4,500 solid tumor patients for NGS panel testing. We performed a retrospective survey of 21 medical oncologists enrolling OCTANE patients at a single academic institution to evaluate the impact of NGS testing on treatment decisions. Methods: Patients and treating oncologists were identified at the Princess Margaret Cancer Centre between 2016-2021. Tumor-only sequencing was performed using a custom hybridization capture panel of 555 cancer genes (Hi5) or a commercial 161-gene amplicon DNA/RNA panel (Oncomine Comprehensive v3). Oncologists were asked to review testing results for individual patients and complete a survey indicating whether NGS testing impacted treatment decisions. Mutations were defined as actionable based on clinical judgment and compared to classifications provided by OncoKB, an FDA-recognized precision medicine knowledgebase. The primary outcome of this study was rate of treatment change based on mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed effects model. Results: Two cohorts were surveyed, the first between 2017-2019 and the second in 2021. Of the 582 surveys sent, 394 (67.7%) were completed. Each physician completed a median of 19 surveys (range, 9-48). We found that 188 (47.7%) patients had a mutation classified as actionable by the oncologist, of whom 134 (71.3%) had ≥1 OncoKB-defined actionable mutation(s). 62/394 (15.7%) patients were matched to a treatment, of whom 37 were enrolled in a clinical trial, 13 received an approved drug, 4 were prescribed off-label therapy and 8 avoided ineffective treatment. 127/188 (67.5%) patients with actionable mutations did not receive treatment due to lack of available therapy, stability on current regimen, clinical deterioration or patient decision. Rate of treatment change was highest for bowel (15/37, 40.5%), breast (14/52, 27.5%), biliary tract (6/22, 27.3%) and lung (4/17, 23.5%) cancers. Treatment decisions were not associated with patient age, gender, physician clinical experience, physician gender, testing experience, OncoKB mutation level or time from biopsy to sequencing. There was no difference in overall survival between patients with matched vs. no matched treatment ( p = 0.55, median survival not reached). Conclusions: OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors. Patient, test, and physician characteristics were not significantly associated with treatment change.
De novo EGFR T790M mutations in a community-based oncology practice.
Authors: Holt Marilyn Elaine , Misch Amanda , Rao Smita K. , Sturgill Emma , Jones Carissa , Schlauch Daniel , Luckett Daniel , Spigel David R. , Jones Suzanne Fields , McKenzie Andrew Jacob 
Published: June 2022

3146 Background: With the 2018 FDA approval of osimertinib for first-line treatment in EGFR-mutated lung cancers, the prevalence of acquired EGFR T790M mutations is expected to decrease, heightening the significance of de novo T790M mutations. Previous studies have reported a wide range of de novo T790M prevalence, and smaller retrospective studies have indicated that germline T790M may comprise the majority of de novo T790M mutations. Here, we assess the frequency of de novo T790M mutations in a community-based setting and report on germline T790M mutations occurring within this population. Methods: Patients with T790M-positive lung cancer were identified using Sarah Cannon’s clinicogenomics database containing information for patients treated within the Sarah Cannon research network. All T790M mutations were detected on tissue- and plasma-based NGS tests delivered as part of routine care. De novo and germline EGFR T790M status was determined via manual electronic health record chart review. When available, allele fraction and %cfDNA values were extracted from the structured NGS report and analyzed separately. Results: Of T790M-positive lung cancers with available pretreatment testing results, 36% (16/44) were confirmed to be T790M+ prior to EGFR TKI exposure; five of these patients received germline testing, and all five were confirmed to have originated in the germline. Two patients with germline T790M mutations detected on testing ordered by external providers were added to our de novo T790M+ patient analysis after chart review. Co-occurring EGFR mutations, including L858R, were detected in pre-TKI samples for 78% (14/18) of de novo T790M+ patients (Table). Co-occurring mutations in TP53, KRAS, PTEN, or RB1 were detected in pre-TKI samples of all patients without co-occurring EGFR mutations. EGFR C797S was observed after osimertinib treatment in one of four patients with post-TKI testing results. Of confirmed germline T790M+ cases with available allele frequencies, 100% (4/4) had allele fractions >0.5 (tissue) and/or %cfDNA values >50% (plasma). Average allele fraction and %cfDNA values were higher for de novo T790M mutations (allele fraction: 0.5 ± 0.2; %cfDNA: 40% ± 20%) than for acquired T790M mutations (allele fraction: 0.3 ± 0.2; %cfDNA: 2% ± 2%). Conclusions: Roughly one-third of T790M mutations detected in real-world settings occur before EGFR TKI exposure and may be associated with germline inheritance. Allele frequency may be a potential indicator of de novo T790M mutations in scenarios where pre-treatment data is not available. Future studies will investigate the impact of de novo T790M mutations on treatment response and evolution of resistance mechanisms in osimertinib-treated patients. [Table: see text]