tbuckley/cabot-search huggingface dataset:
Economic evaluation of six and 12 month (m) treatment with isatuximab and carfilzomib and dexamethasone (IKd) versus daratumumab and carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma (RRMM).
Authors: Neda AlRawashdh, Briana Choi, Mavis Obeng-Kusi, Matthias Calamia, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

e20010 Background: Isatuximab and daratumumab target the CD38 transmembrane glycoprotein on MM cells. IKd and DKd regimens have shown reductions of HR=0.53 (95%CI 0.32-0.89) and HR=0.63 (95%CI 0.46-0.85) resp. in progression or death risk compared to Kd in RRMM. In the absence of a direct IKd vs DKd trial, we performed an indirect treatment comparison on progression free survival (PFS) to enable cost-effectiveness analyses. Methods: A 3-state (pre-progression, progression, death) partitioned survival model was specified. NMA-adjusted transition probabilities were estimated from fitted exponential functions (time horizon of 6 and 12 m; cycle length 28 days). Inputs included the Wholesale Acquisition Cost of IKd, DKd, and premedications; cost of medication administration; and cost of adverse event management. Utility inputs for pre-progression (0.65) and progression (0.61) were per literature. Costs and utilities were discounted at 3.5%/y. A payer perspective was adopted. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Cost-effectiveness acceptability curves (CEAC) were generated. Results: As detailed in the Table, 6m of IKd treatment was associated with incremental gains of 0.01 (PSA 0.01) LYs but no gains in QALYs at cost savings of $24,188 ($23,762), yielding a dominant ICER of $ -2,418,800 ($-2,376,200) per LYg (ICUR not estimable). Further, 12m of IKd treatment was associated with incremental gains of 0.04 (PSA 0.04) LYs (or 0.48m) and 0.02 (0.03) QALYs at incremental cost of $1,585 ($2,239), yielding ICER of $39,625 ($55,975) per LYg and ICUR of $79,250 ($74,633) per QALYg. Per CEAC, IKd is the dominated strategy in the 6m model and had probability of 50% of being cost-effective at WTP of $100,000 in the 12m model. Conclusions: Clinically, compared to DKd, IKd is associated with slight incremental gains in LYs of 0.12m over 6m and 0.48m over 1y. The 6m clinical gain comes with cost savings of approximately $24,000 or about 15% of IKd therapy, while the 12m gain requires a minimal cost commitment of around $2,000 or 0.6% of DKd treatment. These findings imply a clinico-economic benefit of isatuximab compared to daratumumab containing regimens in RRMM. [Table: see text]
Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).
Authors: Priyanka Sharma, Vandana G Abramson, Anne O'Dea, Lauren Elizabeth Nye, Ingrid A. Mayer, Gregory James Crane, Manana Elia, Rachel Yoder, Joshua M Staley, Kelsey Schwensen, Karissa Finke, Jaimie Heldstab, Stephanie LaFaver, Micki Prager, Stephen K. Williamson, Milind Phadnis, Gregory A Reed, Bruce F. Kimler, Qamar J. Khan, Andrew K. Godwin
Journal: Journal of Clinical Oncology (2021)

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m 2 , D2, 9) plus cisplatin 75mg/m 2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m 2 D2,9 + cisplatin 75mg/m 2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]
The need for compassionate self-harm services
Authors: Faraz Mughal, Leah Quinlivan
Journal: BMJ (2021)

The anonymous author of a recent What Your Patient is Thinking article shares a powerful story of feeling that their self-harm was dismissed and how this affected future help seeking.1 Self-harm is a serious public health issue and is the strongest risk factor for suicide: it must be taken seriously by healthcare professionals and services so that patients do not avoid seeking support and continue to struggle with self-harm and psychological distress.

The author described being free of …
Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals
Authors: Jun Jin, Chulwoo Kim, Qiong Xia, Timothy M. Gould, Wenqiang Cao, Huimin Zhang, Xuanying Li, Daniela Weiskopf, Alba Grifoni, Alessandro Sette, Cornelia M. Weyand, Jorg J. Goronzy
Journal: Science Immunology (2021)

Sustained activation of mTORC1 at late endosomes in primary CD4 + T cell responses of older individuals impairs T helper cell function.
Efficacy of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.
Authors: Prachi Bhave, Angela M. Hong, Rebecca Johnson, Alexander M. Menzies, Georgina V. Long, Joanna Mangana, Douglas Buckner Johnson, Zeynep Eroglu, Ozgecan Dulgar, Hui-Ling Yeoh, Andrew Mark Haydon, Georg Lodde, Elisabeth Livingstone, Muhammad Adnan Khattak, Katharina C. Kähler, Axel Hauschild, Wei Wang, Matteo S. Carlino
Journal: Journal of Clinical Oncology (2021)

9578 Background: Adjuvant (adj) radiotherapy (RT) halves the risk of locoregional (LR) recurrence in patients (pts) with high risk stage III melanoma after lymphadenectomy (CLND), however its role in the adj immunotherapy (IO) era without CLND is unknown. Methods: Pts with resected stage III melanoma who received adj IO and recurred with resectable LR only disease were studied. After resection of this 1st recurrence, adj RT may or may not have been administered. Disease characteristics, treatment at relapse and outcomes were examined. Results: 71 pts from 9 centres were included. Prior to adj IO, median age was 60y, 59% male, 56% BRAF mutant, 61% stage IIIC (AJCC V8), 52% underwent CLND and 17% had in-transit (IT) only disease. Adj IO included: 90% single agent anti-PD1, 8% ipilimumab-nivolumab (IN) and 1% nivolumab or IN (blinded on trial). Median duration of adj IO was 5 months. 21(30%) pts had high risk stage III disease at diagnosis, per previously established TROG criteria; 3 (4%) received upfront adj RT prior to recurrence. Median time to 1st recurrence was 7 months. 49 (69%) pts recurred during and 22 (31%) after cessation of adj IO. At 1st recurrence, 9 (13%) pts had stage IIIB disease, 55 (77%) IIIC, 7 (10%) IIID and 8 (11%) continued prior adj IO, 31 (44%) commenced therapy and 32 (45%) had no systemic therapy. 24 (34%) pts received adj RT after resection of 1st recurrence and 47 (66%) did not (Table). Adj RT was associated with a reduced risk of any 2nd recurrence (7/24, 29% vs 26/47, 55%, p=0.03) and LR 2nd recurrence (2/24, 8% vs 17/47, 36%, p=0.012). Whilst pts who received adj RT at 1st recurrence were more likely to have LN only disease, extra nodal extension and involved surgical margins, these factors did not significantly affect overall risk of 2nd recurrence on multivariate analysis. Of note, 70% of pts who did not receive adj RT at 1st recurrence had IT only disease, and though this did not significantly affect rate of 2nd recurrence (p=0.19), this likely reflects an inherent selection bias in this study. RT toxicity occurred in 16 (67%) pts, 10 with dermatitis only, and all grade 1 or 2. Median follow up was 22 months. Median recurrence free survival to 2nd recurrence was 23 months for all pts, not reached for those who had adj RT at 1st recurrence and 19 months for those who did not have adj RT (p=0.047). Median overall survival was not reached. Conclusions: Whilst adj RT appears to reduce 2nd recurrences, this may have been influenced by an unavoidable selection bias in the data, particularly an imbalance in the percentage of pts with IT disease. Prospective data with larger cohorts is needed to validate our results.[Table: see text]
Abstract TMIM-072: COMBINATIONAL TARGETING OF HDAC6 AND PD-1/PD-L1 IMMUNE CHECKPOINT IN ARID1A-MUTATED OVARIAN CANCERS
Authors: Nail Fatkhutdinov, Takeshi Fukumoto, Rugang Zhang
Journal: Clinical Cancer Research (2019)

Abstract Ovarian clear cell carcinoma (OCCC) typically has a low response rate to platinum-based standard of care, and has no effective therapy for advanced stage disease. About 50% OCCCs harbor a mutation in ARID1A, a subunit of a SWI/SNF chromatin remodeling complex. We have previously demonstrated the dependence of ARID1A-mutated OCCCs on HDAC6 activity. In addition, ARID1A inactivation impairs mismatch repair, thus sensitizing ARID1A-mutated tumors to checkpoint blockade. However, anti-PD-L1 treatment only marginally improved the survival of ARID1A-deficient mice. We sought to determine whether combinational approach will improve efficacy of checkpoint blockade therapy in ARID1A-mutated OCCC. We combined HDAC6 inhibitor ACY1215 and PD-1/PD-L1 immune checkpoint blockade utilizing Arid1a-/-/Pik3caH1047R genetic ovarian clear cell model. Combination further prolonged mice survival as compared to single treatments and observed effects correlated with an increase in the activity of anti-tumor cytotoxic T-cells. In addition, we observed increase in dendritic cell infiltration following HDAC6 inhibition, suggesting of an increase in antigen presentation. Our findings indicate that combination of HDAC6 inhibition with PD-L1 checkpoint blockade could be a potential strategy for ARID1A-mutated OCCCs, not only eliminating ARID1A-mutated tumor cells but also restoring anti-tumor immunity. Citation Format: Nail Fatkhutdinov, Takeshi Fukumoto, and Rugang Zhang. COMBINATIONAL TARGETING OF HDAC6 AND PD-1/PD-L1 IMMUNE CHECKPOINT IN ARID1A-MUTATED OVARIAN CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-072.
The preliminary efficacy of KN026 (Anti-HER2 BsAb) in advanced gastric and gastroesophageal junction cancer patients with HER2 expression.
Authors: Jianming Xu, Yun Zhang, Jun Wu, Nong Xu, Jieer Ying, Xiaojun Xiang, Yanqiao Zhang, Jianhong Wang, Rusen Zhao, Feng Ye, Qiong Wu, Baohong Guo, Yuchen Liu, Juan Liu, Shuning Xing, Ting Xu
Journal: Journal of Clinical Oncology (2021)

e16005 Background: HER2 overexpression or amplification has been proven to be a validated therapeutic target for HER2-positive gastric and gastroesophageal junction cancer (GC/GEJ) in ToGA trial. However, there is a huge unmet medical need in the HER2-positive GC/GEJ patients who progressed or were refractory to trastuzumab treatment. In HER2 low expression patients, the benefit of novel HER2-targeted therapeutics, eg. Bispecifics, ADC and CAR-T, remain to be explored. Here we report the preliminary results of KN026, a bispecific antibody binds two distinct epitopes of HER2 receptors, in GC/GEJ patients with prior at least one line treatment. Methods: GC/GEJ patients who failed to ≥first-line treatment were enrolled into two cohorts according to HER2 overexpression (Cohort 1: IHC3+ or IHC 2+ ISH+) and low expression (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+), and treated by KN026 QW10mpkor Q2W(20mpk) or Q3W(30mpk) until progression of disease (PD) or intolerable toxicity or 2 years. Results: As of 2020/12/25, a total of 31 pts received KN026 treatment including 20 pts in Cohort 1 and 11 pts in Cohort 2. The median drug exposure period was around 20 wks and 6 wks in two Cohorts, respectively. Among 18 efficacy-evaluable pts in Cohort 1, 11 pts were stilling receiving treatment with 55.6% (10/18) ORR and 72.2% DCR (13/18). The 9-m PFS rate was 60.4% (95%CI: 24.4 to 83.5) in Cohort 1, while the DOR, mPFS and mOS were not reached. Of 9 pts receiving prior-HER2 treatment, the median time from the first dose of KN026 to last prior HER2 treatment was 55 days. The ORR was 44.4% (4/9) with 4.1m DoR, and DCR was 66.7% (6/9). The mPFS and mOS were 5.6m(95%CI:1.3 to NE) and 11.0m(95%CI: 1.4 to NE), respectively. In Cohort 2, two partial response was observed out of 9 efficacy-evaluable pts. The ORR and DCR were both 22.2% (2/9) with 1.4 m mPFS (95%CI: 1.0 to 5.9) and 9.6m mOS (95%CI: 3.0 to NE). The overall incidence of KN026 related adverse events was 87.1%, with 9.7% Gr 3 TRAE. The most common KN026-related treatment emergent adverse events (≥10% TRAE) were aspartate aminotransferase increased (n=8,25.8%), rash (n=6,19.4%), anaemia (n=5,16.1%),alanine aminotransferase increased (n=4, 12.9%) and weight decreased(n=4, 12.9%). The ≥Gr 3 TEAE that KN026 related were infusion related reaction(n=1, 3.2%), blood pressure increased (n=1, 3.2%), ureteral stricture with hydronephrosis (n=1, 3.2%). Conclusions: KN026 demonstrated promising efficacy in HER2 overexpressing GC/GEJ pts and in anti-HER2 treated GC/GEJ pts with a favorable safety profile. Clinical trial number: NCT03925974. Clinical trial information: NCT03925974.
The gut microbial metabolite, 3,4-dihydroxyphenylpropionic acid, alleviates hepatic ischemia/reperfusion injury via mitigation of macrophage pro-inflammatory activity in mice
Authors: Rui Li, Li Xie, Lei Li, Xiaojiao Chen, Tong Yao, Yuanxin Tian, Qingping Li, Kai Wang, Chenyang Huang, Cui Li, Yifan Li, Hongwei Zhou, Neil Kaplowitz, Yong Jiang, Peng Chen
Journal: Acta Pharmaceutica Sinica B (2021)

Hepatic ischemia/reperfusion injury (HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to HIRI. Ischemia/reperfusion surgery was performed to establish a murine model of HIRI. 16S rRNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening (ZT12, 20:00) when compared with the morning (ZT0, 08:00); however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite 3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase (HDAC) inhibition in macrophages.
First-line therapy in patients with metastatic renal cell carcinoma (mRCC): Results from consecutive patients over 25 years in a single institution.
Authors: Niels Fristrup, Frede Donskov
Journal: Journal of Clinical Oncology (2021)

e16574 Background: Immune checkpoint inhibitors (ICI) have demonstrated improved activity in metastatic renal cell carcinoma (mRCC). Real-world data comparing the effectiveness of ICI with interleukin-2 (IL-2) is limited. Methods: We retrospectively assessed consecutive patients with biopsy-proven mRCC at our institution between 1994 and 2020. Patients were classified into four groups based on first-line therapy: vascular endothelial growth factor (VEGF) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, IL-2, or ICI. The primary endpoint was overall survival (OS). Kaplan-Meier method was used to compare OS between treatment groups. We used Cox proportional hazards models to adjust for prognostic covariates. Results: A total of 1424 patients were treated with first line therapy; 51% received VEGF, 3% received mTOR, 40% received IL-2, and 6% received ICI. Median follow-up was 97.6 months. Except for the mTOR group, baseline characteristics were largely balanced between the treatment groups. Median OS in the ICI group compared with IL-2, mTOR and VEGF was 40.1, 17.6, 6.3 and 14.7 months (p &lt; 0.001), respectively, and the 5-year survival rate was 36%, 20%, 9% and 14%, respectively. After adjusting for IMDC and MSKCC individual risk factors, histology, age, gender, year of treatment initiation, low sodium, and location of metastases (lung, liver, bone, lymph node), the hazard ratio (HR) (95%CI) for OS with VEGF as reference was 0.50 (0.33-0.74, p = 0.001) for ICI, 0.81 (0.70-0.92, p = 0.002) for IL2, and 1.09 (0.79-1.52, p = 0.6) for mTOR. Conclusions: In this largest single institution cohort to date, patients with mRCC who received CPI achieved longer OS.[Table: see text]
Camrelizumab in combination with TACE for the treatment of unresectable hepatocellular carcinoma (HCC): A multicenter, single-arm, prospective real-world study.
Authors: Ran You, Guowen Yin, Hao Xu, Xiaoli Zhu, Qingqiao Zhang, Qi Wang, Chi Cao, You Lu, Hao Jiang, Jun Liu, Hui Yu, Qingyu Xu
Journal: Journal of Clinical Oncology (2021)

e16114 Background: Transcatheter arterial chemoembolization (TACE) is considered to be the first-line topical therapy for unresectable hepatocellular carcinoma (HCC). However, the long-term efficacy of single TACE treatment is poor, with a five-year survival rate of 8%-43%. This study aims to investigate the efficacy and safety of TACE combined with camrelizumab in the treatment of unresectable HCC. Methods: This is a single-arm, prospective real-word study conducted in 14 hospitals in Jiangsu, China. Patients diagnosed with HCC received Camrelizumab (200mg, i.v. Q2W or Q3W) with or without antiangiogenic therapy (apatinib, lenvatinib, sorafenib, or regorafenib) at any stage of the TACE treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier method was used for survival analysis. This study was registered with ChiCTR.org.cn, number ChiCTR1900026163. Results: From September 2019 to January 2021, 151 patients were enrolled, of whom most were males and younger than 65 years, 92 (60.93%) had extrahepatic metastasis and 120 (79.47%) suffered from HBV infection, 59 (39.07%) had an AFP concentration of 400 ng/mL or higher, 150 (99.34) had an ECOG PS of 0 or 1, a Child-Puph score of A or B, and were classified as BCLC Stage B or C. In addition to TACE, 52 patients received camrelizumab alone, while the others also received antiangiogenic therapy. Most (139, 92.06%) of the patients received camrelizumab 200mg every 3 weeks. Of the 112 patients who were available for efficacy evaluation, 4 patients achieved CR, 25 achieved PR, and 53 achieved SD, resulting in an ORR of 25.89% and DCR of 73.21%. The median PFS was 4.27 months (95% CI, 3.45 to 7.36 months) and the median OS was 14.0 months (95% CI, 10.6 to NE months). The safety data were obtained from 140 patients. Treatment-related adverse events (TRAEs) occurred in 130 (92.86%) patients, with the commonest types including increased alanine and aspartate aminotransferases (65%), thrombocytopenia (57.86%), hypoalbuminemia (54.29%), hyperbilirubinemia (48.57%), anemia (42.86%), leukopenia (42.14%), neutropenia (37.14%) and proteinuria (20.71%). Severe AEs occurred in 52 (37.14%) patients, with the commonest types including thrombocytopenia (17.14%), increased alanine and aspartate aminotransferases (13.57%), neutropenia (8.57%) and hyperbilirubinemia (7.14%). Conclusions: The treatment strategy of TACE in combination with camrelizumab with or without antiangiogenic therapy showed encouraging clinical efficacy and manageable toxicity profile in treating unresectable HCC, which provided a new treatment option for HCC. Clinical trial information: ChiCTR1900026163.