tbuckley/cabot-search huggingface dataset:
Imfirst: A phase IIIb, safety, single arm study of carboplatin (CB) or cisplatin (CP) plus etoposide (ET) with atezolizumab (ATZ) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) in Spain—Primary safety results of the induction phase.
Authors: Maria Rosario García Campelo, Manuel Domine, Javier De Castro, Alberto Moreno, Santiago Ponce Aix, Edurne Arriola, Enric Carcereny, Margarita Majem, Gerardo Huidobro Vence, Emilio Esteban, Jose Fuentes Pradera, Bartomeu Massuti, Ana Laura Ortega, Guillot Mónica, Juan Felipe Cordoba, Natalia Fernandez, Ruben Alonso, Leonardo Crama, Natalia Lerones, Manuel Cobo
Journal: Journal of Clinical Oncology (2021)

8567 Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]
Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
Authors: Concetta Quintarelli, Marika Guercio, Simona Manni, Iolanda Boffa, Matilde Sinibaldi, Stefano Di Cecca, Simona Caruso, Zeinab Abbaszadeh, Antonio Camera, Biancamaria Cembrola, Roselia Ciccone, Alberto Orfao, Lourdes Martin-Martin, Sara Gutierrez-Herrero, Maria Herrero-Garcia, Gianni Cazzaniga, Vittorio Nunes, Simona Songia, Paolo Marcatili, Frederikke I Marin, Marco Ruella, Valentina Bertaina, Luciana Vinti, Francesca Del Bufalo, Mattia Algeri, Pietro Merli, Biagio De Angelis, Franco Locatelli
Journal: Journal for ImmunoTherapy of Cancer (2021)

Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells. Background Methods We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing. Results The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells. Conclusions Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.
Association of TP53 mutation with decreased prevalence of MSI-high, RAS and PI3KCA mutations in metastatic colorectal cancer.
Authors: Minggui Pan, Chen Jiang, Pamela Tse, Aleyda V Solorzano-Pinto, Elaine Chung, Thach-Giao Truong, Amit Arora, Tilak Kumar Sundaresan, Jennifer Marie Marie Suga, Laurel A. Habel, Sachdev P. Thomas
Journal: Journal of Clinical Oncology (2021)

e15578 Background: TP53 tumor suppressor gene is mutated in approximately 50% of colorectal cancer (CRC). How TP53 mutations are associated with the prevalence of the other common genomic alterations such as RAS (KRAS/NRAS), BRAF, PI3KCA, as well as microsatellite stability (MSI) is not clear. Methods: We investigated the impact of TP53 mutations on other common genomic alterations and survival in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC). Results: From November 2017 to January 2021, genomic profiling was performed on 1056 patients with metastatic CRC, of whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). We found that median overall survival (OS) was similar between the TP53wt and TP53mut patients (50.1 vs 47.5 months, p = 0.9), however, the percent with a Ras mutation was significantly higher in patients with TP53wt compared to TP53mut (63.2 vs 45.2%, p = 0.0001). Interestingly, the percent with MSI-high was also significantly higher in TP53wt than TP53mut patients (11.1 vs 1.4%, p = 0.0001), however, the response rate of the MSI-high patients to immune checkpoint inhibitor (ICI) was similar (40 vs 37.5%). In addition, a significantly higher percent of patients with TP53wt had PI3KCA mutations and a significantly lower percent had c-Myc amplifications compared to patients with TP53mut (PI3KCA, 32 vs 10.7%, p = 0.0001; c-Myc, 1.26 vs 4.6%, p = 0.008). There was no significant difference in the percent of BRAF mutations between the two patient populations (6.2 vs 9.8%). A significantly higher percent of patients with TP53wt and a PI3KCA mutation had a Ras mutation compared to patients with TP53mut and a PI3KCA mutation (81.2 vs 57%, p = 0.0004). However, TP53 mutation status was not significantly associated with the OS of patients with either a Ras, or BRAF, or PI3KCA mutation, or combination of Ras and PI3KCA mutations. Conclusions: TP53 mutation is associated with decreased prevalence of Ras, PI3KCA mutation and MSI-high in patients with metastatic CRC, however, without impacting the OS or response rate to ICI.
Artemisinin‐derived dimers from a chemical perspective
Authors: Aysun Çapcı, Lars Herrmann, Halmuthur M. Sampath Kumar, Tony Fröhlich, Svetlana B. Tsogoeva
Journal: Medicinal Research Reviews (2021)

Abstract Considerable progress has been made with the rather recently developed dimer approach, which has already found applications in the development of new effective artemisinin‐derived antimalarial, anticancer, and antiviral agents. One observation common to these potential applications is the significant (i.e., much more than double) improvement in activity of artemisinin based dimers, which are not toxic to normal cells and have fewer or less harmful side effects, with respect to monomers against parasites, cancer cells and viruses. Due to the high potential of the dimerization concept, many new artemisinin‐derived dimer compounds and their biological activities have been recently reported. In this review an overview of the synthesis of dimer drug candidates based on the clinically used drug artemisinin and its semisynthetic derivatives is given. Besides the highlighting of biological activities of the selected dimers, the main focus is set on different synthetic approaches toward the dimers containing a broad variety of symmetric and nonsymmetric linking moieties.
Network meta-analysis (NMA) of immuno-oncology (IO) monotherapy as first-line (1L) treatments (txs) for advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50%.
Authors: Nicholas Freemantle, Yingxin Xu, Florence Wilson, Patricia Guyot, Chieh-I Chen, Sam Keeping, Gerasimos Konidaris, Keith Chan, Andreas Kuznik, Kokuvi Atsou, Emily Glowienka, Lisa Stow, Jean-Francois Pouliot, Giuseppe Gullo, Petra Rietschel, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2021)

e21091 Background: For advanced NSCLC patients (pts) with high (≥50%) PD-L1 expression, effective IO mono options with survival benefits are approved (pembrolizumab mono, current standard of care) and emerging (cemiplimab). In a recent Phase 3 trial, cemiplimab, a high-affinity, highly potent human PD-1 inhibitor approved for tx of advanced cutaneous squamous cell carcinoma, demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) vs chemotherapy (CT) in advanced NSCLC pts with PD-L1 ≥50%. A systematic literature review and NMA were conducted to identify/compare the efficacy/safety from randomized controlled trials (RCTs) for cemiplimab vs pembrolizumab or other IO mono published 2010–19. Methods: Relevant RCTs were identified by searching Embase, MEDLINE, Cochrane, and conference proceedings with predefined search strategies according to ISPOR, NICE, and PRISMA guidelines. An NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR), Grade (G) 3–5 all-cause adverse events (AE), G3–5 immune-mediated AE (IMAE) and discontinuation due to AEs (DAE). Fixed-effect models were used due to limited evidence. Results with standard constant HRs and various sensitivity analyses were conducted to account for differences in RCT designs and other txs. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded since an incompatible PD-L1 assay (SP142) was used for pt selection. For 1L advanced NSCLC with PD-L1 ≥50%, cemiplimab was associated with significantly greater PFS and ORR, and comparable OS, G3–5 AEs, IMAEs, and all-cause DAEs vs pembrolizumab (Table). At 2 yrs, numerically more pts receiving cemiplimab vs pembrolizumab were alive (59% vs 49%) and significantly more were alive w/o progression (37% vs 18%). Conclusions: In advanced NSCLC pts with PD-L1 ≥50%, cemiplimab mono demonstrated significant improvements in PFS and ORR, and comparable OS, safety/tolerability vs pembrolizumab.[Table: see text]
Triple combination therapy comprising angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma.
Authors: Ti Zhang, Jinliang Zhang, Xihao Zhang, Han Mu, Ge Yu, Wenge Xing
Journal: Journal of Clinical Oncology (2021)

e16124 Background: The effects of single-drug therapy for the systemic treatment of advanced unresectable hepatocellular carcinoma (HCC) remain unsatisfactory, promoting the emergence of multi-drug and combination therapies. Here we assess the safety and efficacy of a triple combination therapy for treating advanced HCC. Methods: This single-center retrospective study included patients with unresectable HCC treated with triple combination therapy comprising angiogenesis inhibitors (oral apatinib 250 mg/day, lenvatinib 8 mg/day, or sorafenib 400 mg BID), anti-programmed cell death 1 antibodies (iv camrelizumab or sintilimab, 200 mg every 3 weeks), and hepatic arterial infusion chemotherapy (FOLFOX every 4–8 weeks). Eligible patients had completed at least one cycle of therapy and had an imaging assessment. Treatment-related adverse events (TRAEs) were assessed according to the Common Terminology Criteria for Adverse Events. Efficacy data were summarized according to modified RECIST (mRECIST) and RECIST v1.1. Results: Of 34 patients who received triple combination therapy, 25 (19 men and 6 women; median age: 59 years [range: 49–78]) had an imaging assessment. TRAEs were manageable; 28.0% of patients experienced grade 3–4 TRAEs. Efficacy outcomes are summarized in the Table. The objective response rate was 96.0% (mRECIST), the median time to response was 50.5 days (95% CI: 31.02–64.00) and the surgical conversion rate was 56%, indicating a robust therapeutic effect. Overall, 12 patients (48.0%) achieved a complete response (CR), 12 (48.0%) achieved a partial response, and one (4.0%) had stable disease (mRECIST). Fourteen patients (56.0%) underwent surgical resection, after which seven (28.0%) achieved a pathologic CR. After a median follow-up of 9.67 months, no cases of post-operative recurrence or metastasis emerged. Conclusions: Triple combination therapy had a robust therapeutic effect with a high surgical conversion rate in patients with advanced HCC. TRAEs were acceptable, and long-term efficacy is reasonably expected. Summary of efficacy outcomes (n = 25).[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: Gustav J. Ullenhag, Jeffrey Yachnin, Ana Carneiro, Emma Elison, Malin Carlsson, Charlotte Astrid Russell, Karin Enell Smith
Journal: Journal of Clinical Oncology (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.
Elevated Gas6 Plasma Level As a Predictor of Venous Thromboembolism Recurrence and Mortality in a Prospective Multicenter Cohort of Elderly Patients with Venous Thromboembolism
Authors: Annatina Schnegg-Kaufmann, Sara Calzavarini, Andreas LImacher, Marie Mean, Marc Righini, Daniel Staub, Jürg Hans Beer, Beat Frauchiger, Joseph Osterwalder, Nils Kucher, Jacques Cornuz, Christian M. Matter, Marc Husmann, Martin Banyai, Markus Aschwanden, Lucia Mazzolai, Olivier Hugli, Michael Nagler, Nicolas Rodondi, Drahomir Aujesky, Anne Angelillo-Scherrer
Journal: Blood (2017)
Sensitive and dynamic CTCs measurement for prediction and monitoring of PD-1 therapy in GC/EGJC patients: Results from a pilot phase 2 study.
Authors: Qing Wei, Xu Qi, Lei Chen, Yanlian Yang, Yankun Li, Zhiyuan Hu, Jieer Ying, Cong Luo, Li Jingjing
Journal: Journal of Clinical Oncology (2021)

e16094 Background: Programmed death-ligand 1 (PD-L1) expression is currently being explored as a predictive biomarker for anti-PD-1antibody treatment in patients with advanced gastric or esophagogastric junction cancer (GC/EGJC) patients. Circulating tumor cells (CTCs) can be collected non-invasively and sequentially, and may allow real-time monitoring of immune activation in tumor. The aim of this study was to investigate whether PD-L1 expression on CTCs can accurately represent tumor PD-L1 expression and the potential of CTCs as a companion diagnosis (CDx) biomarker. Methods: We evaluated the CTCs counts and PD-L1 status on CTCs during treatment in a phase 2 clinical trial, where patients with previously treated gastric cancer received JS001 in combination with Apatinib. The multi-center trial was registered with ClinicalTrials.gov, number NCT04190745. Blood samples were collected from patients. Sixteen patients with GC were analyzed to investigate the association between clinical outcome and changes of CTC counts pre and post JS001 plus Apatinib. The correlation between the binary clinical outcome (SD/PR/CR vs. PD) and the change in CTCs counts pre and post treatment was analyzed using a logistic regression adjusting for baseline CTCs counts. PD-L1 expression on CTCs were analyzed to determine whether they were in accordance with tissue biopsy. Results: CTCs were detected in all the patients (16/16，100%) ranging from 1 to 33 CTCs/ml. PD-L1+ CTCs were detected in 12 of 16 patients (75%) ranging from 1 to 5 PD-L1 + CTCs/ml. PD-L1 expression in tumor tissue was positive in 11 of 13 patients (84.6%, positive means CPS &gt; = 1), the sensitivity of PD-L1+ CTCs is 90.9% (10/11) if using biopsy as gold standard. The only false negative patient though with CPS 40%, got no benefit from immunotherapy. The specificity of PD-L1+ CTCs detection is 100%, and the accuracy is 90.9%. Overall response rate of this regimen is 26.6% (4/15). Disease control rate is 53.3% (8/15). Progression free survival (PFS) was 2.43 months in all the evaluable patients. However, patients with PD-L1+ CTCs had a longer PFS compared to patients without PD-L1+ CTC (3.30months vs 1.37months, p = 0.001). Overall Survival is not reached. Change of CTCs counts after treatment was significantly correlated with clinical response (p = 0.024). The logistic model McFadden goodness of fit score was 0.435, which is a strong correlation value. Notably, one of the patients who had pseudo-progression shows remarked decreased CTCs count. Conclusions: Our results reveal the potential of CTCs as a noninvasive CDx biomarker in patients with advanced GC/EGJC.
The risk and tropism of central nervous system metastases (CNS) in patients with stage II cutaneous melanoma.
Authors: Paul Johannet, Min Jae Kim, Melissa Call, Nicholas Gulati, Judy Zhong, Janice M. Mehnert, Iman Osman
Journal: Journal of Clinical Oncology (2021)

9551 Background: Recent data suggest that patients with stage III melanoma are at high enough risk for developing CNS metastases to consider routine surveillance neuroimaging (Journal of Clinical Oncology; PMID: 31990608). Given that a subset of stage II patients have a worse prognosis than stage III patients, we investigated the risk of developing brain metastases in stage II disease and compared it to the risk in stage III disease. Methods: We studied a cohort of prospectively enrolled melanoma patients who had protocol driven follow-up at New York University (NYU) Langone Health. We investigated both the incidence and time to development of CNS metastases, and explored whether the frequency of CNS metastases as a first isolated site of distant disease varies among the different stages. Results: The study cohort included a total of 1,102 patients (stage II: n = 619 with median follow-up 56.5 months; stage III: n = 483 with median follow-up 40.9 months). 85/619 (14%) stage II and 91/483 (19%) stage III patients developed CNS metastases (p = 0.03). The estimated 5-year cumulative incidence was 9% in stage IIA, 14% in stage IIB, and 29% in stage IIC patients (p = 0.0001). It was 10% in stage IIIA, 32% in stage IIIB, 23% in stage IIIC, and 49% in stage IIID (p = 0.0001). The CNS was the site of first metastasis for 32/154 (21%) stage II patients who developed distant disease compared to 28/214 (13%) stage III patients (p = 0.06). Conclusions: A subset of stage II patients are at an elevated risk for developing CNS metastases within 5 years of their initial diagnosis, which is comparable to that seen in stage III patients. The frequency of the CNS as a first site of metastasis in stage II melanoma suggests a propensity for brain tropism that cannot only be explained by a generalized pro-metastatic phenotype. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals.
Covid-19: G7 vaccine promises fail to meet scale of challenge, say critics
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: G7 vaccine promises fail to meet scale of challenge, say critics Jacqui Wise G7 leaders have committed themselves to provide one billion covid-19 vaccine doses for low and low-middle income countries over the next year, but the World Health Organization and campaigners said this falls far short of the 11 billion vaccine doses needed.2 Cabinet Office.100 days mission to respond to future pandemic threats.12 Jun 2021.