tbuckley/cabot-search huggingface dataset:
AdvanTIG-203: A randomized phase 2 study comparing anti-TIGIT ociperlimab plus tislelizumab versus tislelizumab plus placebo as second-line treatment in patients with advanced or recurrent esophageal squamous cell carcinoma (ESCC) expressing programmed death-ligand 1 (PD-L1).
Authors: Rui-hua Xu, Sung-Bae Kim, David Tougeron, Yunxia Zuo, Haiyuan Yang, Juan Zhang, Jingwen Shi, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2021)

TPS4150 Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually estimated combined positive score ≥10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤1 or ≥2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.
Anakinra (AKR) prophylaxis (ppx) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving orvacabtagene autoleucel (orva-cel).
Authors: Luciano J. Costa, Sham Mailankody, Paul Shaughnessy, Parameswaran Hari, Jonathan L. Kaufman, Sarah Marie Larson, David Dingli, Kelvin Lee, Kristin Conte, Todd DeVries, Julia Piasecki, Meng Li, Ronald L. Dubowy, Myo Htut
Journal: Journal of Clinical Oncology (2021)

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 10 6 CAR + T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]
Proteomics meets transcriptomics: Identification of tumor tissue signatures specific to anti-PD1 treatment in late-stage melanoma patients.
Authors: Kamil Sklodowski, Domenico Mallardo, Jakob Vowinckel, Mariaelena Capone, Martin Soste, Gabriele Madonna, Vito Vanella, Sarah Warren, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2021)

e21543 Background: Despite advances of anti-PD1 treatment in melanoma, still large subset of patients does not respond or relapses due to primary or acquired resistance. One potential way to overcome the mechanisms of resistance is to identify molecular signatures associated with response to treatment. Here, we are presenting the results of an integrated deep transcriptomic and proteomic analysis of melanoma tissue samples coming from patients prior the treatment with anti-PD1. The combination of targeted transcriptomic approach with unbiased proteomic approach allowed for identification of a molecular response signature specific to anti-PD1 therapy. Methods: Unbiased quantification of proteins in tumor tissues was done using data-independent acquisition (DIA) LC-MS technology. Proteins from tissue samples were denatured, digested, and analyzed on a mass spectrometer. A deep spectral library was generated, and proteins were quantified using Spectronaut software (Biognosys). From the same tumor tissue RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Integration analysis using latent components, a generalized PLS and sparse sGCCA method implemented in R mixOmics package was used for signature discovery. Results: Studied cohort was balanced for gender, BRAF mutations and stage. Treatment included Nivolumab or Pembrolizumab. Only among responding subjects, low grade (≤ 2) skin toxicity was identified at a significant level (p-value &lt; 0.05). In total, 22 samples were measured (nine non-responders and 13 responders). Overall, the analysis of proteome across all samples resulted in 8548 proteins being identified and quantified. The IO 360 panel contained 770 targets. In combined analysis, 10 mRNA targets together with 64 protein targets were highly associated with response to treatment. Two top candidates identified for mRNA and proteins were SIGLEC5 and ACP6 respectively. The panel of 74 features was sufficient to separate all subjects using unsupervised hierarchical clustering into to two main clusters enriched for responders and non-responders (p-value &lt; 0.05). String-DB analysis revealed numerous interactions and associations within identified panel. Functional analysis using GO enrichment showed major involvement of the selected mRNA and proteins in T-cell regulation as well as in neutrophil degranulation and antigen receptor mediated signaling. Conclusions: Combination of both omics assays provides a very comprehensive image of tumor tissue responses to anti-PD1 treatment in late-stage melanoma patients. Identified candidates show striking changes in responder and non-responder groups and should undergo further validation for use in precision medicine.
Differences between children with severe acute lower respiratory infection with or without SARS-Cov-2 infection
Authors: Vivian Botelho Lorenzo, Cristiana M Nascimento-Carvalho
Journal: Journal of Infection (2021)

Aimto compare clinical features and outcome of children with severe acute lower respiratory infection (ALRI) with or without SARS-CoV-2 infection admitted to Paediatric Intensive Care Unit (PICU).Methodsfor this retrospective cohort study, all children aged<17 years admitted with severe ALRI at a PICU, in Salvador, Brazil were evaluated. Investigation of SARS-CoV-2 infection was performed by real-time reverse-transcription PCR. Clinical data, physical findings upon admission and outcome were registered. Patients were categorized by with or without SARS-Cov-2 infection. Outcomes were death and invasive mechanical ventilation (IMV).Resultswe enrolled 210 patients, whose median age was 2.8 years (IQR: 7.1 months–6.2 years). IMV was used in 33 (15.7%; 95%CI 11.3%-21.1%) patients. Eight (3.8%; 95%CI 1.8%-7.1%) cases died. 62 patients (29.5%) tested positive for SARS-CoV-2. Male gender (67.7% vs. 52.7%, P = 0.045) and sickle cell disease (6.5% vs. 0%, P = 0.007) were associated with SARS-CoV-2 infection. Wheezing upon admission was more common in patients without SARS-CoV-2 infection (38.5% vs. 21.0%, P = 0.01). IMV was more frequent among patients with SARS-CoV-2 infection (25.8% vs. 11.5%, P = 0.009) as well as death (8.1% vs. 2.0%, P = 0.05).Conclusionchildren with severe ALRI infection with SARS-CoV-2 need IMV more frequently than those without it.
In-hospital outcomes of transcatheter aortic valve replacement (TAVR) in patients with localized and metastatic malignancy.
Authors: Hugo Macchi, Miguel Salazar, Juan Del Cid Fratti, Estefania Gauto, Binav Baral, Trilok Shrivastava, Shristi Upadhyay Upadhyay Banskota, Maryam Zia, Nabin Khanal
Journal: Journal of Clinical Oncology (2021)

e18602 Background: There is limited use of transcatheter aortic valve replacement (TAVR) in patients with malignancy, given that current guidelines do not recommend TAVR in patients with a life expectancy of less than 1 year. Data that compare short-term outcomes after TAVR in cancer and metastasis is scarce. Methods: Using the national inpatient sample (NIS) database, we identified patients who underwent TAVR from 2016-2017 using ICD10-PCS codes. Patients were subsequently divided based on local malignancy and metastatic malignancy. In-hospital mortality, total hospital cost, length of hospital stays, and post-procedural complications were evaluated. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: A total of 91, 624 TAVR hospitalizations were identified, 4, 995 (4.7%) with malignancy. Patients with malignancy were most likely to be women, have a higher Charlson comorbidity index, to use private insurance, and being admitted to a teaching hospital. The most common malignancy was hematological, head and neck, prostate, digestive, and breast cancer of these patients 15.6% had metastatic disease at the time of TAVR. After adjusting for confounders there was no difference in mortality, LOS, healthcare utilization, and post-procedural complications. Conclusions: TAVR seems to have a safe short-term outcome in patients with active malignancy and metastatic disease. In this population, we recommend having an oncological evaluation to perform a risk assessment to aid in the decision when to not proceed with TAVR.[Table: see text]
A prospective, phase II, single-arm study of neoadjuvant/conversion therapy with camrelizumab, apatinib, S-1 ± oxaliplatin for locally advanced cT4a/bN+ gastric cancer.
Authors: Song Li, Wenbin Yu, Fei Xie, Zhimin Liu, Weiwei Lv, Duanbo Shi, Dexin Yu, Meng Wei, Jiaqian Wang, Yongtian Zhao, Cheng Chen, Zhikun Zhao, Jing Gao, Lei Sheng, Lian Liu
Journal: Journal of Clinical Oncology (2021)

4061 Background: The prognosis of cT4a/bN+ gastric cancer (GC) is poor due to low R0 resection rate and frequent recurrence. We evaluated the feasibility, safety, and efficacy of a combination of immunotherapy, anti-angiogenesis, and chemotherapy for neoadjuvant/conversion treatment of cT4a/bN+ GC. Methods: Patients with T4a/bN+ GC were enrolled to receive camrelizumab (200mg d1), apatinib (250mg d1-14), S-1 (50mg bid d1-10) ± oxaliplatin (85 mg/m 2 d1) for at least 2 cycles, followed by re-evaluation and operation. Peri-treatment samples were collected for whole-exome, transcriptome, and T cell receptor (TCR) sequencing. Pathological response (PR) and its relationship with genomic biomarkers are primary endpoints. Results: 25 patients were enrolled, with median age 63 (48-70), 19 male, 11 cT4aN2-3 and 14 cT4bN2-3. The radiological response (RR) rate of the treatments was 33.3% (8/24), and tumor down-staging rate 79.2% (19/24). 24 patients completed re-evaluation, with 3 failed conversion, 2 refused surgery, and 1 postponed surgery for immune-related pneumonia. Among the 18 patients with R0 resection, 3 got complete PR (CPR), 2 major PR (MPR, ≤10% residual cancer cells), and 3 partial PR (11̃49% residual cancer cells), with a PR rate of 44.4% and MPR+ (MPR &amp; CPR) rate of 27.8%. 62.5% patients with PR and 83.3% patients with RR overlapped with each other. At a median of 12.5 (3.4-19.5) months of follow-up, 13 of 17 patients (76.5%) with R0 resection were recurrence-free. No ≥3 toxicity was found. Besides high microsatellite instability, tumor mutation/neoantigen burden (TMB/TNB), mutation signatures (“DNA damage repair” and “DNA mismatch repair”) and related gene mutations (BRCA2, PRKDC, ATM, POLD1, POLE), several novel driver mutations (SSPO, TRPS1, and DOCK2) and copy number variants (DUSP15 loss, FDFT1 gain, and RBBP8NL loss) were related to MPR+ GC. The combination therapy decreased TMB/TNB, facilitated infiltration of active immune cells (CD4 + memory T, CD8 + T, activated and plasmacytoid dendritic cells, and M1 macrophage), and specifically boosted TCR clonality in MPR+ patients. Besides, numbers of mesenchymal stem cells decreased in MPR+ but increased in MPR- GC after the treatment. Conclusions: Combination of camrelizumab, apatinib, S-1 ± oxaliplatin is feasible, safe, and efficient in neoadjuvant/conversion therapy for cT4a/bN+ GC. It may remodel immune microenvironments and induce anti-tumor immune responses. Clinical trial information: NCT03878472. [Table: see text]
Responsibility of immune microenvironment for poor response to immune checkpoint inhibitors in CRC patients with KRAS mutation.
Authors: Qiyu Liu, Hushan Zhang, Shenggang Cai, Lin Xu, Rong Zhao, Xiaolong Zhang, Jianhui Yin, Lijun Zhang, Leyang Liu, Xiaolei Gong, Depei Huang, Xudong Shen, Shibi Luo
Journal: Journal of Clinical Oncology (2021)

e15588 Background: The clinical trial Keynote 177 is a breakthrough research in colon rectal cancer (CRC), however, the results of subgroups revealed that immunotherapy did not benefit more than chemotherapy in patients with KRAS mutation. Here we assessed characteristics of tumor immune microenvironment in patients with or without KRAS mutation, to find out the underlying mechanisms that prevent KRAS-mutated CRC patients from benefiting from immunotherapy. Methods: Tumor tissue samples of 77 CRC patients were collected from Janary 2019, several kinds of immune cells including CD8 + T cells, M1/M2 tumor associated macrophages (TAM), CD56bright NK cells and CD56dim NK cells in the tumor tissue were evaluated by multiple fluorescence immunohistochemistry (mIHC), and expression of PD-L1 were detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. In addition, gene mutation was detected by means of next generation squesing (NGS). All these detections were performed in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: According to whether KRAS is mutated, these 77 patients were divided into two groups, KRAS wild type (WT) (n = 49) and KRAS mutation group (n = 28). There was no significant difference in the CD8+T cells infiltrated in tumor tissue of KRAS WT and KRAS mutation samples, however, less CD8+ T cells were found in stroma of tumor tissue of KRAS WT samples than in KRAS mutation. What’s more, both the ratio of M1:M2 and CD56dim NK: CD56bright NK cells in the tumor tissues of KRAS WT were significantly higher than in KRAS mutation samples(p &lt; 0.05). No significant difference was found between two groups, while higher MSI-H proportion was found in KRAS mutation group than in KRAS WT (33.4% and 12.5%, respectively). The proportion of positive PD-L1expression (TPS≥1) in both groups is very low, especially, proportion of strong positive (TPS≥50). Conclusions: The different response to immune checkpoint inhibitors therapy for CRC patient with or without KRAS mutation mainly associated with factors of TIME, not only CD8+T cells, but tumor associated macrophages and different sub-population of NK cells should be put into consideration.
Toripalimab with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a single-arm, open-label, phase Ib/II clinical study.
Authors: Ke Cheng, Wan-Rui Lv, Xiaofen Li, Bole Tian, Dan Cao
Journal: Journal of Clinical Oncology (2021)

e16213 Background: Currently nab-paclitaxel/gemcitabine (AG) is the standard first-line treatment for advanced pancreatic ductal adenocarcinoma (aPDAC), which is still needed to improve. The phase Ib/II study aiming to evaluate safety and efficacy of AG plus toripalimab, an anti-PD-1 monoclonal antibody, showed well tolerability and encouraging efficacy in aPDAC patients (preliminary data presented at 2020 ASCO). Here, we updated new results of this study. Methods: This was a single-arm, open-label, phase Ib/II clinical trial of AG with toripalimab as first-line treatment for aPDAC. Patients received toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m2, d1, d8 plus gemcitabine 1000 mg/m2, d1, d8) until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary objectives were safety and OS; the secondary objectives were ORR, DCR and PFS. Predictive biomarkers including MMR protein and PD-L1 expression, the tumor mutation burden (TMB) based on next-generation sequencing, genomic alteration signatures and the number of TILs were evaluated. Results: At data cutoff (Feb 3, 2021), 20 chemotherapy naïve aPDAC patients (female: 65.0%, median age: 55.5 years) with ECOG PS ≤ 2 were enrolled. Of the 17 evaluable patients, the ORR was 35.3%, the DCR was 82.4%, including 5 patients with PR and 1 patient with CR, respectively. 12 patients were alive and the study treatments for 9 patients were still ongoing. Median PFS was 5.0 months (95% CI：4.216-5.784), the 6-month PFS rate was 60%; median OS was 14.0 months (95% CI：9.445-18.555), the 1-year OS rate was 80%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events were ALT elevation (35.0%), leukocytopenia (30.0%) metabolic disorder (25.0%) and hypothyroidism (25.0%). 4 patients (20.0%) experienced grade 3/4 TRAE (including myocardial enzyme elevation, neutropenia, vomiting and nausea). In the biomarker analysis, all patients were MMR-proficient status; 14 patients were evaluated for PD-L1 expression compared with PD-L1 negative cases (n = 5), PD-L1 positive cases (n = 9) did not show higher RR or longer PFS, responses were observed in both groups. 10 patients were investigated for NGS, 2 patients with TMB &gt; 10 Muts/Mb, the most frequently mutated genes were KRAS (90%), TP53 (90%) and ARID1A (20%). Conclusions: The updated results of this phase Ib/II study provided preliminary evidence that toripalimab in combination with AG has a manageable safety profile consistent with known safety profile for each agent alone and demonstrates signals of clinical activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.
Association of state Medicaid income eligibility limits and long-term survival after cancer diagnosis in the United States.
Authors: Jingxuan Zhao, Xuesong Han, Leticia Nogueira, Ahmedin Jemal, Robin Robin Yabroff
Journal: Journal of Clinical Oncology (2021)

6512 Background: Income eligibility limits for Medicaid, the health insurance programs for low-income populations in the United States, vary substantially by state for the non-elderly population. This study examined associations between state Medicaid income eligibility limits and long-term survival among newly diagnosed cancer patients. Methods: 1,426,657 adults aged 18-64 years newly diagnosed with 17 common cancers between 2010 to 2013 were identified from the National Cancer Database. States’ Medicaid income eligibility limits were categorized as &lt; = 50%, 51%-137%, and &gt; = 138% of Federal Poverty Level (FPL). Survival time was measured from diagnosis date through December 31, 2017, for up to 8 years of follow-up. Multivariable Cox proportional hazard models with age as time scale were used to assess associations of eligibility limits and stage-specific survival, controlling for age group, sex, race/ethnicity, metropolitan statistical area, number of health conditions other than cancer, year of diagnosis, facility type, and the random effect of state of residence. Results: Among newly diagnosed cancer patients aged 18-64 years, 22.0%, 43.5%, and 34.5% resided in states with Medicaid income eligibility limits ≤50%, 51%-137%, and ≥138% FPL, respectively. Compared to patients living in states with Medicaid income eligibility limits ≥138% FPL, patients living in states with Medicaid income eligibility limits ≤50% and 51-137% FPL were more likely to have worse survival for most cancers in both early and late stage. The highest hazard ratios (HRs) were observed among patients living in states eligibility limits ≤50% FPL (p trend &lt; 0.05). For example, for early stage female breast cancer patients, the HRs were 1.31 (95% confidence interval [95% CI]: 1.18 – 1.46) and 1.17 (95% CI: 1.06 – 1.30) for patients living in states with Medicaid income eligibility limits ≤50% and 51%-137% compared to those living in states with Medicaid income eligibility limits ≥138% FPL. Conclusions: Lower Medicaid income eligibility limits were associated with worse long-term survival within stage, with variation below the Medicaid eligibility threshold as part of the Affordable Care Act. States that have not expanded Medicaid income eligibility limits should expand them to help improve survival among cancer patients.