bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.
Authors: Jang Sekwon , Powderly John D. , Spira Alexander I. , Bakkacha Ouiam , Loo Deryk , Bohac Gerry C. , Sharma Manish 
Published: June 2021

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.
Maintenance immunosuppressive therapy with resumption of immune checkpoint inhibitor treatment to reduce recurrence of immune-mediated colitis.
Authors: Abu-Sbeih Hamzah , Zou Fangwen , Dutra Barbara , Altan Mehmet , McQuade Jennifer Leigh , Thompson John A. , Thomas Anusha , Wang Yinghong 
Published: June 2021

2642 Background: Immune-mediated colitis (IMC) may limit immune checkpoint inhibitors (ICI) treatment. Current guidelines recommend consideration of resuming ICI when IMC symptoms subside to ≤ grade 1. We aimed to investigate the effect of maintenance immunosuppressive therapy (IST) on the outcome of IMC in patients who resume ICI therapy. Methods: We retrospectively studied patients who resumed ICI therapy after adequate treatment of IMC from March 2015 to June 2020 at MD Anderson Cancer Center. Relevant demographic, oncologic, and ICI data were collected and analyzed. Univariate logistic regression analysis was conducted to assess risk factors of IMC recurrence. Results: We included 102 patients with a median age of 61 years. 66% were males and 97% were Caucasians. 48 patients (47%) received IST maintenance in conjunction with ICI resumption and 54 patients did not. Symptoms of IMC recurred in 28 patients, 8 (17%) in the concurrent IST group and 20 (37%) in the other group. Compared to no concurrent IST group, patients on concurrent IST were more likely to have received combined ICI regimen (60% vs 41%, p = 0.003) and more initial ICI doses (9 vs 5 doses, p = 0.030). Concurrent IST group had significantly longer ICI treatment duration on resumption (72 vs 62 days, p = 0.023), more ICI resumed doses (5 vs 4 doses, p = 0.038), and lower IMC recurrence (17% vs 37%, p = 0.027). Patient who received more IST doses, both therapeutic and prophylactic, had lower rate of IMC recurrence (OR 0.72, p = 0.012; table). IST maintenance treatment (OR 0.34, p = 0.024) was associated with lower IMC recurrence rate after ICI resumption. Vedolizumab was the predominant IST used. Overall survival was comparable among the two groups (p = 0.934). Conclusions: Concurrent IST treatment with ICI resumption after IMC was associated with significantly lower IMC recurrence and more extended ICI treatment while reserving similar overall survival to patients without IST maintenance therapy. Future prospective randomized trial of concurrent IST is still merited for further clarification.[Table: see text]
A first-in-human, multicenter, open-label, phase 1 study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.
Authors: Ullenhag Gustav J. , Yachnin Jeffrey , Carneiro Ana , Elison Emma , Carlsson Malin , Russell Charlotte Astrid , Enell Smith Karin 
Published: June 2021

2646 Background: ATOR-1017 is a human agonistic IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). It is developed to activate T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. This is a first-in-human, multicenter, phase 1 study (NCT04144842). Methods: In this study, ATOR-1017 is administered intravenously every 21 days as a single agent to patients with solid malignancies. ATOR-1017 is administered until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to determine the maximum tolerated dose, assessed by adverse events (AEs) and dose limiting toxicities (DLTs), and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, immunogenicity and clinical efficacy, assessed with CT scans using response criteria for use in studies testing immunotherapeutics (iRECIST). The study uses a single cohort design for doses up to 40 mg, and thereafter a modified 3+3 design. Results: The first patient was dosed in December 2019; by 22 Jan 2021, twelve patients have been exposed to ATOR-1017. The following dose levels have been evaluated; 0.38 mg; 1.5 mg; 5 mg; 15 mg; 40 mg and 100 mg. Dose escalation is ongoing, and the 200 mg dose level is under evaluation. The maximum tolerated dose has not been reached. The following cancer types are included; ovarian cancer (n = 1), choroidal melanoma (n = 3), anal cancer (n = 1), cholangiocarcinoma (n = 1), gastrointestinal stromal tumor (n = 1), breast cancer (n = 1), pancreatic cancer (n = 1), adenoid cystic cancer (n = 1), malignant melanoma (n = 1), colorectal cancer (n = 1). Drug-related AEs were reported in 5 out of 12 patients; one patient experienced a grade 3, all others were grade 1 or 2. There have been two episodes each of chest pain (grades 2 and 3) and headache (grades 1 and 2). Single cases of pyrexia, upper abdominal pain, mouth ulceration, nausea, leukopenia, neutropenia, cytokine release syndrome (CRS), arthralgia, neck pain, and rash were also reported. No DLTs have been observed in the study to date. The median age of the patients were 48.5 years (range 34-76). Patients received a median of 2 prior lines of therapy (range 1-4). The median time on study were 15 weeks (range 0.14-51). Six patients are on study, and six patients have discontinued treatment. Reasons for discontinuation include; investigator decision (n = 1), confirmed disease progression (n = 1), withdrawal of consent (n = 1), death due to disease progression (n = 1) and other reason (n = 2). Preliminary PK data show dose-proportional kinetics up to 100 mg. Best response has been stable disease. Conclusions: ATOR-1017 is safe and well-tolerated up to 100 mg. Dose escalation continues and the current dose level is 200 mg. Clinical trial information: NCT04144842.
Consensus disease definitions for the spectrum of neurologic immune related adverse events.
Authors: Guidon Amanda C , Burton Leeann B , Chwalisz Bart K , Hillis James M , Schaller Teilo , Reynolds Kerry Lynn ,   Neuro irAE Disease Definition Panel
Published: June 2021

2647 Background: Expanding FDA-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in both therapeutic success and immune related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes evidence-based treatments and research progress. The objectives of this study were to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. Methods: A working group of 4 neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the Neuro irAE Disease Definition Panel, consisting of neurologists, oncologists, neuro-oncologists and irAE subspecialists. A modified Delphi consensus process was used, with 2 rounds of anonymous ratings by panelists and 2 virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. The working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions. Results: Twenty-seven panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for 7 core disorders: irMeningitis, irEncephalitis/Encephalomyelitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, 6 sub-classifications are described: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation and present or absent concurrent irAE. Conclusions: These disease definitions standardize irAE-N classification. They are being incorporated into a multi-institutional registry that our group has initiated to study irAEs. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.
Prevalence of hyperprogressive disease (HPD) mutations and correlations to immune-related biomarkers in a large pan-cancer Chinese cohort.
Authors: Yang Shengli , Liu Xinyi , Bei Ting , Huang Mengli 
Published: June 2021

2649 Background: Immune checkpoint blockade (ICI) therapies have demonstrated inspiring clinical efficacy in multiple types of cancer. However, a subset of patients suffered rapid tumor growth after ICI treatment, which is known as hyperprogressive disease (HPD). Although the mechanism of HPD has not been fully elucidated, some genomic alterations, such as CDKN2A/CDKN2B loss and MDM2/MDM4 amplification were reported to occur in tumors with ICI-related HPD. We analyzed the prevalence of these four “HPD mutations” and their association with PD-L1 expression, TMB, and occurrence of driver gene mutations in a large pan-cancer Chinese cohort. Methods: Patients whose tumor tissues were subjected to molecular profiling using targeted next-generation sequencing from January 2017 – November 2020 were included. Single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels) and fusions were called. PD-L1 expression was stratified by CPS 5. Fisher’s exact test were conducted to compare the frequencies of biomarkers and Mann-Whitney U test was used to compare the TMB level between the “HPD mutations” group and their wild-type counterpart. Results: 45,785 patients of 22 types of cancer were queried. Across all 22 cancers, CDKN2A loss and CDKN2B loss were most commonly seen in ESCA (23.3%, 19.8%), while with the lowest frequency in PRAD (0.18%, 0.18%). MDM2 gain and MDM4 gain occurred most frequently in SARC (14.6%) and BRCA (3.3%), respectively, with the lowest frequency in COAD (0.05%, 0.07%). PD-L1 positive (CPS≥5) rates were similar in CDKN2A/B loss, MDM2/4 amp and wild-type groups in the whole cohort (26.1%, 25%, 27.7%). Enrichment of PD-L1 positivity was not observed in HPD-mutant groups in a specific cancer type. Compared with wild-type group, CDKN2A/B loss significantly correlated with higher TMB levels in NSCLC and SARC (p < 0.05) while MDM2/4 amp correlated with lower TMB levels in NSCLC, BTC, and STAD (p < 0.05). In NSCLC, SNV in EGFR, TP53, KEAP1, NFE2L2, STK11, PIK3CA, and SMARCA4 genes were significantly enriched in the CDKN2A/B loss group, while SNV in EGFR, RBM10, AR, KDR genes, and fusion in RET were significantly enriched in MDM2/4 amp group. Conclusions: HPD mutations were significantly associated with TMB level and occurrence of some driver genes, but were not correlated with PD-L1 expression. Our results revealed the immune-related molecular characteristics in tumors with HPD mutations, providing more insights into the exploration for mechanism of HPD.
Proton pump inhibitors and antibiotics impact on toxicities and clinical outcomes in cancer patients treated with immunotherapy.
Authors: Araujo Haniel alves , Moniz Camila Motta Venchiarutti , Braghiroli Oddone Freitas Melro , Mak Milena Perez , Uratani Lucas Fernando , Dahmer Tiecher Ricardo , Moraes Priscila Muniz , Barbosa Ingrid , Camargo Veridiana Pires De , Braghiroli Maria Ignez Freitas Melro , Castro Gilberto , Hoff Paulo Marcelo , Diz Maria Del Pilar 
Published: June 2021

2652 Background: Gut microbiome dysbiosis impairs systemic immune responses and recent evidence suggests its critical role in patients (pts) treated with immune checkpoint inhibitors (ICI). Proton pump inhibitors (PPI) and antibiotics (ATB) may alter the microbiome and their impact on clinical outcomes and toxicities requires further investigation. Methods: This retrospective cohort included consecutive metastatic cancer pts treated with ICI with palliative intent. We reviewed pts' records, concomitant medication and toxicities graded by CTCAE 4.0. Pts with PPI or ATB exposure were analyzed according to previous use (pPPI and pATB, ≤60 days to ICI) and concomitant use (cPPI and cATB). We estimated median overall survival (mOS) and progression free survival (PFS) by Kaplan–Meier and used a Cox proportional-hazards model to adjust for differences in baseline characteristics. Toxicities and ATB/PPI interaction was calculated using Pearson Chi-square method. Results: We enrolled 216 pts with a median age of 59 years, mostly ECOG-PS 0 (34%) or 1 (58%). ICI employed were mostly anti-PD-1 (60.2%), anti-CTLA-4 (16.2%) and anti-PD-L1 (12.5%). Most frequent primary tumor sites were lung n = 39 (18.1%), gastrointestinal n = 34 (15.7%) and melanoma n = 33 (15.2%). Half of the pts (108) received ATB and 114 (52.8%) PPI. Compared to control, pPPI group n = 57 (26.4%) had shorter mOS (11.6m vs 19.7m, p < 0.001) and PFS (2.8m vs 8.5m, p < 0.001), but no statistically significant difference in toxicities grade ≥3 and/or leading to ICI discontinuation (36% vs 29.1%; p = 0.29). cPPI n = 100 (46.3%) depicted a negative impact on mOS (12.1m vs 17.0m; p = 0.01), PFS (4.3m vs 7.1m; p = 0.04) and augmented toxicities (42% vs 19%; p < 0.001). pATB n = 34 (15.7%) had shorter OS (6.9m vs 19.3m, p < 0.001) and PFS (3.2 vs 7.2m, p = 0.005) and higher incidence of toxicities (45.9% vs 28.1%; p = 0.04 ). cATB use n = 92 (42.6%) did not impact OS (12.1m vs 15.6m; p = 0.32) or PFS (5.5m vs 5.9m; p = 0.82), but had a higher incidence of toxicities: 37% vs. 24.2% (p = 0.05). Multivariate analyses confirmed that pATB therapy and pPPI respectively remained as independent prognostic variables associated with OS (HR 2.39; 95% CI, 1.60-3.59; P <.001 and HR 1.73; 95% CI 1.23-2.44; P = 0.002) and PFS (HR 1.72; 95% CI, 1.14-2.61; P = 0.01 and HR 2.36; 95% CI 1.67 - 3.34; P < 0.001) adjusted by performance status, age and line of treatment. Conclusions: These data suggest that concomitant use of PPI and ATB is associated with increased toxicities in ICI treated pts. pPPI and pATB can negatively impact OS and PFS and merit clinician’s attention.
MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.
Authors: Meric-Bernstam Funda , Hainsworth John , Bose Ron , Burris III Howard A. , Friedman Claire Frances , Kurzrock Razelle , Swanton Charles , Wang Yong , Levy Jonathan , Schulze Katja , Price Richard , Patel Arisha , Sweeney Christopher 
Published: June 2021

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease >4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]
Prevalence of inferred clonal hematopoiesis (CH) detected on comprehensive genomic profiling (CGP) of solid tumor tissue or circulating tumor DNA (ctDNA).
Authors: Antonarakis Emmanuel S. , Kuang Zheng , Tukachinsky Hanna , Parachoniak Christine , Kelly Andrew David , Gjoerup Ole , Aiyer Aparna , Severson Eric Allan , Pavlick Dean C. , Frampton Garrett M. , Venstrom Jeffrey Michael , Oxnard Geoffrey R. 
Published: June 2021

3009 Background: The increased use of ctDNA CGP has paralleled increased detection and interest in CH, which can confound CGP results from ctDNA or tissue, and can be associated with hematologic and cardiovascular morbidity. However, paired-depth sequencing of white blood cells (WBC) for confirmation of CH is not widely available. We here study the prevalence of inferred CH (iCH), which refers to incidental detection on routine clinical CGP of variants attributable to CH due to their known CH association and their negligible prevalence in solid tumors. Methods: A database of clinical CGP results was reviewed, including two 324-gene NGS panels for tumor tissue (FoundationOne CDx) and plasma ctDNA (FoundationOne Liquid CDx). Analysis was limited to NSCLC, breast, prostate, colorectal, and pancreatic cancers. iCH was defined as any pathogenic mutation in ASXL1, DNMT3A, and TET2, and prespecified mutations in JAK2, SF3B1, U2AF1, MYD88, IDH2, MPL, CBL. Variant allelic frequency (VAF) > 2% was considered clinically significant and VAF > 10% was considered high risk. Results: 100,905 total cases were studied; median age was 65 for tissue CGP and 68 for ctDNA. iCH was more commonly detected in ctDNA (1468/2891, 51%) than in tissue (9416/97993, 10%). Among cases with any iCH detected, multiple iCH mutations were seen more commonly in ctDNA (640/2891, 22%) than in tissue (987/98014, 1%). Focusing on clinically significant iCH ( > 2% VAF), prevalence remained higher in ctDNA (22%, 637) than in tissue (8%, 7878), while the higher sensitivity of ctDNA testing identified more low level iCH (< 2% VAF, 40% in ctDNA, 2% in tissue). Across cancer types, iCH > 2% was consistently more common in ctDNA (Table). As expected, prevalence of iCH > 2% increased with age (continuous variable, p < 0.001). High risk iCH ( > 10% VAF) was seen in 4% of total cases (most commonly ASXL1, TET2, DNMT3A); 1% of all cases had multiple clinically significant iCH variants ( > 2% VAF). Focusing on a subset of 439 cases with both tissue and ctDNA results (median 1.5 months between samples), 290 iCH mutations were detected in ctDNA (median VAF 1%) but only 38 in tissue (median VAF 9%). Conclusions: Inferred CH is common on somatic CGP of cancer patients, with a high prevalence in ctDNA likely due to the deeper sequencing depth and WBC contamination. For the minority of patients with high VAF iCH, further research is needed to understand whether this might be representative of an occult hematologic condition deserving of further evaluation.[Table: see text]