bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive molecular pharmacodynamic assessment identifies response markers of intermediary metabolism associated with BPM 31510-IV treatment in advanced glioblastoma multiforme patients.
Authors: Nagpal Seema , Sarangarajan Rangaprasad , Bruce Can , Miller Greg M , Rodrigues Leonardo O , Shah Punit , Searfoss Richard , Ofori-Mensa Kennedy , Tolstikov Vladimir , Greenwood Bennett , Bussberg Valerie , Kiebish Michael A. , Granger Elder , Narain Niven R. , Recht Lawrence David 
Published: June 2021

2059 Background: BPM 31510-IV is a drug-lipid conjugate nanodispersion containing oxidized Coenzyme Q10 (CoQ10) in clinical development for glioblastoma multiforme (GBM). In a recently concluded Phase 1 study of BPM 31510-IV (NCT03020602), in addition to safety and tolerability, longitudinal pharmacodynamic samples (20 samples/cycle of 28 days) were collected at various times in patient’s refractory to radiation, temozolomide, and bevacizumab. Methods: Comprehensive multi-omic (proteomic, lipidomic, metabolomic) profiles were generated from buffy coat (proteomics only), plasma, and urine matrices. These data were further analyzed using bAIcis, a Bayesian statistics based artificial intelligence (AI) software, creating causal networks linking clinical information and endpoints to molecular composition of diverse biomatrices of patients prior to, as well as during, treatment with BPM 31510-IV. Twelve subjects comprised the intent to treat population (ITT) which were stratified across days of treatment (DR1; ≤28 days; DLT period; n=6) and (DR2, OS; >28 days; n=6). Bayesian networks and regression analysis were performed on the outputs of the analysis. Molecular analyte panels (combination of proteins, lipids, and metabolites) descriptive of progression free survival (PFS), adverse events (possibly/probably related to BPM 31510-IV), and of overall survival (OS) were generated. Results: Significant alteration (p<0.05) of metabolically associated protein and critical metabolite drivers of intermediary metabolism were identified as causally related to PFS. Significant quantitative changes in levels of several proteins (buffy coat) and metabolites (urine) were identified with probable or possible associations to adverse events in BPM 31510-IV treated subjects. Conclusions: Overall, alterations in proteins and metabolites influencing mitochondrial function and intermediary metabolism that differentiated responders versus non-responders and identified potential markers of adverse events associated with BPM 31510-IV exposure were identified and will be further explored for complementary diagnostic utility.
Autologous stem cell transplantation (ASCT) versus whole brain radiation (WBRT) as a consolidation therapy in primary CNS lymphoma (PCNSL): A nationwide analysis.
Authors: Samhouri Yazan , Ali Moaath M , Jayakrishnan Thejus Thayyil , Bakalov Veli , Fazal Salman , Khan Cyrus , Wegner Rodney E. , Lee Seung Tae , Lister John 
Published: June 2021

2062 Background: High dose methotrexate-based regimens remain the most effective treatment against PCNSL but optimal consolidative strategy has yet to be determined. There is lack of high scale clinical trials comparing WBRT versus ASCT as consolidation therapy. Only two phase II randomized clinical trials (PRECIS and IELSG 32) have addressed this question. In this comprehensive national cancer database (NCDB) analysis, we examine the effect of WBRT versus ASCT on survival in PCNSL, we also sought to investigate clinical and socioeconomic predictors of treatment selection Methods: We conducted a retrospective cohort analysis using de-identified data accessed from the NCDB. The NCDB provided records of 16579 patients diagnosed with PCNSL between 2004 and 2016. We excluded patients who tested positive for HIV, and those who started chemotherapy > 120 days or started radiation > 365 days since diagnosis, to account for immortal time bias. Patients were divided into two treatment groups based on consolidation therapy: ASCT and WBRT. Multivariable regression models were used to analyze predictors of treatment selection. To account for variable baseline characteristics, we used propensity score weighting methodology. Survival estimates were calculated using the Kaplan-Meier and Cox proportional hazard regression methods Results: We identified 1620 patients with PCNSL who fulfilled the inclusion criteria. ASCT and WBRT were received by 197 patients and 1423 patients, respectively (Table). On multivariable analysis, increased age decreased the odds of receiving ASCT (OR 0.997, CI: 0.996-0.999, P <.001). Patients live in rural areas (OR 1.174, CI: 1.051-1.312, P=.005), those with higher education (OR 1.089, CI: 1.020-1.163, P=.01), and those who live further from the treating facility (OR 1.001, CI: 1.001-1.001, P<.001) received more ASCT. With a median follow up duration of 27.8 months, adjusted-median OS was 91.4 months and not reached for WBRT and ASCT groups, respectively (log-rank P<.001). Adjusted 3-year OS was 82% and 67% in ASCT and WBRT, respectively (HR: 0.43, CI: 0.29-0.64, P<.001) Conclusions: Consolidation with ASCT had improved OS compared with WBRT. There is a trend toward increased ASCT use and decreased WBRT use over the study period. We found clinical and socioeconomic factors that affected treatment selection.[Table: see text]
Concordance of blood and tissue TMB from NGS testing in real-world settings and their ability to predict response to immunotherapy.
Authors: Sturgill Emma , Misch Amanda , Jones Carissa , Luckett Daniel , Fu Xiaotong , Jones Suzanne Fields , Burris III Howard A. , Spigel David R. , McKenzie Andrew Jacob 
Published: June 2021

2540 Background: Tumor mutational burden (TMB) detected by tissue-based Next Generation Sequencing (NGS) is a biomarker for immunotherapy (IO) response. Plasma-based NGS vendors have developed methods for quantifying TMB from circulating tumor DNA; however, the concordance of blood-TMB (bTMB) and tissue-TMB (tTMB) in real-world settings has not been examined. In this study, we analyzed paired bTMB-tTMB values from cancer patients in community oncology clinics who underwent both plasma- and tissue-based NGS testing to determine whether bTMB predicts response to IO equal to tTMB. Methods: We analyzed 112 patient-matched bTMB-tTMB pairs from 102 unique patients in community oncology settings who received both plasma- and tissue-based NGS profiling at any point in care. NGS results were reported by Foundation Medicine (n = 28 plasma, n = 66 tissue), Guardant Health (n = 78 plasma), and Caris Life Sciences (n = 42 tissue). NGS results were linked with electronic medical records in Genospace, Sarah Cannon’s precision medicine platform. Pearson’s correlation (r) and Lin’s concordance (ρ) coefficients were used for statistical analysis. Results: bTMB exceeded the patient-matched tTMB by an average 2.4-fold; therefore, while the two values showed a positive linear correlation (r2= 0.62, p = 0.01e-27) their concordance was only moderate (ρ = 0.58, n = 112). Gastrointestinal cancers exhibited the lowest correlation (r2= 0.01, p = 0.5) and concordance (ρ = 0.03, n = 35). The discordance between bTMB and tTMB was not an outcome of the specimens being collected on different dates, as the bTMB/tTMB ratio did not correlate with the time between plasma and tissue specimen collection (r2= 0.003, p = 0.84, n = 112). While a majority of bTMB-tTMB pairs had agreement in high vs. low status (High ≥ 10 mut/Mb; Low < 10 mut/Mb), a considerable portion were bTMB-High/tTMB-Low (see table). Strikingly, the bTMB-High/tTMB-Low patients who received IO had an average time to treatment failure (TTF) that surpassed that of the bTMB-High/tTMB-High cohort (see table). Considering bTMB alone, patients with a high status outperformed those with a low status on IO (bTMB-High: TTF = 200 days, n = 21; bTMB-Low: TTF = 125 days, n = 12). Conclusions: In real-world settings where tissue- and plasma-based NGS panels are ordered as standard of care, bTMB values are consistently higher than tTMB values. This discrepancy leads to plasma-based tests resulting a TMB-High designation more frequently than tissue-based NGS tests. Patients who are TMB-High by plasma perform relatively well on IO, indicating that bTMB may be a particularly effective biomarker of IO sensitivity.[Table: see text]
Efficacy of HX008 in high microsatellite instability/mismatch repair–defificient (MSI-H/dMMR) solid tumors: Results from a multicenter phase II open-label study.
Authors: Huang Jing , Song Yan , Luo Suxia , Yin Xianli , LI Enxiao , Wang Hui , He Yifu , Liu Zhihui , Fan Qingxia , Liang Xinjun , Shu Yongqian , Liu Yunpeng , Xu Nong , Zhang Shu , Zhuang Zhixiang , Zhang Jingdong , Kou Xiaoge , Wang Fen , Zhu Xiaodong , Li Shengmian 
Published: June 2021

2572 Background: The subsequent treatment choices are limited for the patients with advanced solid tumors who had failed the standard therapies. PD-1 blockade monotherapy demonstrated robust antitumor activity in patients with MSI-H/dMMR. The aim of this study is to identify the efficacy and safety of HX008, an anti-PD-1 monoclonal antibody, in patients with advanced MSI-H/dMMR solid tumors. Methods: Eligible patients were age ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who have failed at least one line of standard systemic therapy. MSI-H/dMMR status was assessed centrally. Patients received HX008 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed 9 weeks after the first treatment, then every 6 weeks for the first year of therapy, and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST1.1. Results: One hundred patients were enrolled from October 2018 to December 2020, with a median age of 53 (range 20-74) years. All of the patients were ≥ second-line patients. The most common cancer types were colorectal cancer (N=74) and gastric cancer (N=10). Median follow-up is 8.97 (range 0.03-25.53) months at the time of data cutoff. Among 86 patients who had reached the initial response evaluation, there were 8 CR, 33 PR, 24 SD, 17 PD and 4 NE. ORR was 47.67% (95%CI 36.79%-58.73%), and DCR was 75.58% (95%CI 65.13%-84.20%). ORR and DCR for the 66 colorectal cancer patients were 50% (95%CI 37.43-62.57%) and 75.76% (95%CI 63.64-85.46%). Median PFS was not reached (95%CI 6.18-NR) for all enrolled patients, while the 6-month and 12-month PFS rates were 62.66% (95%CI 50.98%-72.31%) and 52.70% (95%CI 39.96%-63.94%), respectively. Median OS was not reached. Treatment-related adverse events occurred in 77 patients (77%). Twelve patients (12%) had grade 3 or 4 treatment-related adverse events and there were no grade 5 treatment-related adverse events. The grade 3 or 4 treatment-related adverse events with incidence >1% included anemia (2%) and leukopenia (2%). Immune-related adverse events were observed in 15 patients (15%), including hypothyroidism in 9 patients (all were grade 1-2), and hepatitis, hyperglycemia, myocarditis, creatin kinase/creatin kinase MB increased, hypopigmentation of the vulva, rash, each in 1 patient. Conclusions: HX008 as a ≥second-line therapy showed promising efficacy and a manageable safety profile in patients with MSI-H/dMMR advanced solid tumors. Clinical trial information: NCT03704246.
AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors.
Authors: Frentzas Sophia , Meniawy Tarek , Kao Steven Chuan-Hao , Wang Ruihua , Zuo Yunxia , Zheng Hao , Tan Wei 
Published: June 2021

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.
The predictive values of loss-of-function variants in histone methyltransferases for response to immune checkpoint inhibitors in solid tumors.
Authors: Liang Naixin , Niu Yanling , Zhang Xin , Ma Tonghui 
Published: June 2021

2586 Background: Dysregulation of histone methyltransferases (HMTs) has been reported to play critical roles in cancer development. Previous studies showed that many HMTs were recruited to DNA damage sites where they posttranslationally modified chromatin to regulate chromatin-based DNA damage repair (DDR) activities. We hypothesized that loss-of-function (LOF) variants of HMTs may associate with genome instability and tumor mutational burden (TMB). Thus, we explored the associations of LOF variants in some HMTs with TMB and benefit from immune checkpoint inhibitors (ICIs) in solid tumors. Methods: An ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was analyzed. The following solid tumor types were enrolled: NSCLC (n = 350), colorectal cancer (n = 110), bladder cancer (n = 215), breast cancer (n = 44), esophagogastric cancer (n = 126), head and neck cancer (n = 139), glioma (n = 117), melanoma (n = 320), and renal cell carcinoma (n = 151). We evaluated 15 HMTs (KMT2A, KMT2B, KMT2C, KMT2D, SETD2, SETD8, EZH1, EZH2, PRDM1, PRDM14, SMYD3, NSD1, WHSC1, WHSC1L1, and DOT1L). Results: The data revealed that LOF variants of KMT2D, SETD2, and KMT2C were more frequent in pan-cancer dataset. Furthermore, we found that LOF variants of 7 HMTs, including KMT2A, KMT2B, KMT2C, KMT2D, NSD1, SETD2, and EZH2, were associated with higher TMB (P < 0.0001). Then we analyzed the associations between LOF variants and overall survival (OS) after ICIs therapy. The results indicated that LOF variants of KMT2A (P = 0.0295), KMT2B (P = 0.0329), KMT2C (P = 0.0122), and SETD2 (P = 0.0004) were significantly associated with prolonged median OS for all the enrolled patients. In this cohort, LOF variants of KMT2A, KMT2B, KMT2C, and SETD2 were most common in bladder cancer, colorectal cancer, colorectal cancer, and renal cell carcinoma, respectively. Then we assessed the predictive values of these four genes for each type of cancer. It was noteworthy that KMT2C LOF variants were significantly correlated with longer median OS in colorectal cancer (P = 0.0171), but not in other cancer types. Surprisingly, we did not observe the predictive roles of LOF variants in KMT2A, KMT2B, and SETD2 genes for response to ICIs therapy in any types of cancer. Conclusions: In pan-cancer dataset, we found that LOF variants of 4 HMTs, such as KMT2A, KMT2B, KMT2C, and SETD2, were correlated with better outcomes of ICIs treatment. However, for different types of cancer, only KMT2C LOF variants were associated with longer median OS in colorectal cancer, suggesting that it may be used as a predictive biomarker for ICIs efficacy in colorectal cancer. Because the sample sizes of patients with KMT2A, KMT2B, or SETD2 LOF variants were small, we did not find the predictive values of LOF variants in these three genes for different types of cancer. Next, we will enroll more patients to address this question.
Association of KMT2C mutations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.
Authors: Liu Chunling , Duan Qianqian , Zhang Qin 
Published: June 2021

2600 Background: The KMT2 (lysine methyltransferase) family of histone modifying proteins play important roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many solid tumor cancers. Recently, there is emerging evidence that KMT2 family genes are involved in sensitivity to immune checkpoint inhibitors (ICIs) by modulating the immune environment. Here we explored the relationship between KMT2C mutation and its efficacy of immunotherapy. Methods: 1661 patients with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC clinical cohort were used to explore the association with KMT2C mutation and TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 6624 pan-cancer patients who also detected MSI and PD-L1 expression from the Chinese clinical dataset were also analyzed relevance of mutation and these immune-related indicators. Results: In total, 9.81% (163/1661) patients in MSKCC cohort harbored KMT2C mutation. In the Chinese cohort, the KMT2C mutation ratio (11.19%, 741/6624) was similar to MSKCC. The TMB level of KMT2C mutation group in both MSKCC cohort and Chinese pan-cancer patient cohort was significantly higher than wild-type group (P < 0.001). A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was significantly associated with better OS (hazard ratio, 0.69; 95%CI, 0.52-0.90; P = 0.006), and association remained significant with bladder (P = 0.039), colorectal (P = 0.024), melanoma (P < 0.001) and renal (P < 0.001), adjusting for cancer age, sex, metastases or primary. In addition, in Chinese cohort, KMT2C mutation was associated with higher PD-L1 positive expression (≥1%) (P = 0.01203) and MSI-H (P < 0.001). Conclusions: KMT2C mutation shows impressive association with efficacy of ICIs. Meanwhile, KMT2C-mutant group has a higher TMB, PD-L1 expression and MSI-H. These results indicated that KMT2C mutation may serve as a good potential biomarker of ICI benefit in patients with multiple cancer types.
A phase 1 study of an off-the shelf, multi-neoantigen vector (ADXS-503) in subjects with metastatic non-small cell lung cancer (NSCLC) progressing on pembrolizumab as last therapy.
Authors: Haigentz Missak , Ramalingam Suresh S. , Gerstner Gregory James , Halmos Balazs , Morganstein Neil , Vangala Surya , Parsi Megan , Kabala Victor , Simkhada Dinesh , Metran Cristiane , GUTIERREZ ANDRES A. , Goldman Jonathan Wade 
Published: June 2021

2616 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programmed death receptor-1 (PD-1)- blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: A phase 1 study of A503 ± Pembro has been conducted in patients (pts) with metastatic squamous or non-squamous NSCLC. In dose-escalation part B, A503 was added-on to Pembro within 12 weeks of the first scan showing disease progression per RECIST criteria v1.1. Both, A503 (1 x108 CFU) and Pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. The dose-escalation cohort has established safety, tolerability and immunogenicity of the combination therapy and it has been further expanded to evaluate efficacy (Goldman JW et.al., SITC 2020). Results: Nine pts have been treated and evaluated in Part B. Pembro + A503 combo has been well tolerated and without immune related AEs. Of the nine evaluable pts, one has achieved partial response (PR) and 3 stable disease (SD), yielding an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Two patients have had clinical benefit for over 12 months (i.e., one PR and one SD) and both of them had been on Pembro therapy for 2 years before enrollment. The two other pts with SD have sustained it for almost 6 months thus far. Seven pts have been evaluated for immunogenicity. In all pts there was a transient release of pro-inflammatory cytokines and proliferation of cytotoxic- and memory-CD8+ T cells. Seven evaluable pts had antigen-specific T cells within 1-2 weeks after starting therapy and 4/7 showed antigen spreading. Conclusions: ADXS-503 as an add-on therapy to Pembro at disease progression has been well tolerated and it has induced antigen specific-T cell responses and durable disease control in 44% of pts. Part B cohort is currently enrolling additional pts to further explore the potential reversal of Pembro resistance with ADXS-503. Clinical trial information: NCT03847519.