tbuckley/cabot-search huggingface dataset:
P02.07 Brain-derived circulating DNA as a biomarker for radiotherapy-induced brain damage
Authors: C Makranz, A Zick, H Zemmour, R Shemer, R Lehmann-Werman, B Glaser, M Maoz, E Sapir, J E Cohen, Y Dor
Journal: Neuro-Oncology (2018)

Radiotherapy is a common treatment for brain metastases. However, it is commonly associated with central nervous system (CNS) toxicity, leading to functional disability. There are no biomarkers capable of detecting preclinical neurotoxicity for the purpose of early detection of radiation-induced CNS damage. Here we explore the utility of cell-free circulating DNA (cfDNA), shed from dying cells, for detection of brain cell death in the context of brain metastases. Using comparative methylome analysis we have previously identified 12 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes and astrocytes. These brain-specific methylation markers were identified in the plasma of patients suffering from multiple sclerosis, as well as traumatic and ischemic brain damage. We hypothesize that brain-derived cell-free DNA (bncfDNA) can be identified in patients suffering from brain metastases receiving radiotherapy, and can potentially be used as a biomarker to help guide treatment. We recruit oncological patients treated by brain radiotherapy for brain metastases. We serially assess each patient before, during and after treatment by neurological examination. MRI studies are performed before and after radiotherapy in 2–3 months intervals. In each study visit a blood sample is collected for bncfDNA. We measure bncfDNA from serial blood samples of each patient, and correlate bncfDNA levels with clinical assessment. Preliminary results on samples from 22 patients show elevation of bncfDNA in patients suffering from brain metastases (average 8501 copies/ml; range 0-112336 copies/ml) compared with an extremely low background in healthy individuals (average 6 copies/ml; range 0–33 copies/ml); p<0.0001). We observed cfDNA derived from neurons, oligodendrocytes and astrocytes, suggesting widespread damage induced by brain metastases. In the next step we studied bncDNA levels following brain radiotherapy. Preliminary results from a patient suffering from an acute central facial paralysis during radiotherapy show clinical correlation of bncfDNA levels with neurological impairment related to acute radiotoxicity. Other patients are still followed-up with bncfDNA measurement during and after end of treatment to test for early and late onset radiotoxicity effect on bncfDNA. BncfDNA may serve as a novel circulating biomarker for brain cell death in patients suffering from brain metastases. BncfDNA reflects brain cell death incurred by metastases, as well as damage associated with radiotherapy. Further studies of bncfDNA in the context of brain metastases and radiotherapy are needed to substantiate this idea.
Multigene sequencing, copy number alteration detection, and survival with first-line PD-1 based therapy in patients with mucosal melanoma.
Authors: Lee S. Gottesdiener, Michael Gormally, Joshua Armenia, Mahmoud El-Jalby, Michael A. Postow, Margaret K. Callahan, Parisa Momtaz, Jedd D. Wolchok, Paul B. Chapman, Nikolaus Schultz, Marc Cohen, Mario M. Leitao, Travis Hollman, Alexander Noor Shoushtari
Journal: Journal of Clinical Oncology (2018)

e21579 Background: Mucosal melanomas (McM) have lower tumor mutational burden (TMB) and higher fraction of genome with alterations (FGA) than cutaneous melanomas. Sequencing efforts to date suggest as few as 40% have an identifiable driver alteration. No genetic features have yet been associated with benefit to PD-1 based therapy. Methods: All patients (pts) with McM who underwent sequencing on a 340+ gene panel at Memorial Sloan Kettering Cancer Center from 2014–2017 were included. Driver alterations were defined as canonical (e.g. BRAF V600, NRAS Q61) or expanded drivers (selected based on OncoKB level 1-3 evidence in other neoplasms). Somatic TMB per megabase (Mb) was collected. FGA reflects fraction of sample with log2 < -0.35x or > 0.35x matched normal DNA. Overall survival (OS) was calculated from time of first PD-1 based treatment using Kaplan Meier methods. Results: 113 patients were sequenced; median age (range) was 65 (22-95). 77 (68%) were female. Sites included gastrointestinal (38%), genitourinary (34%), and head/neck (28%). 100 (89%) had detectable driver alterations. In 87 (77%) cases, these alterations were in canonical melanoma drivers NF1, KIT, N/K/HRAS, BRAF, GNAQ/11. 13 (12%) cases contained only expanded drivers (CDK4, MDM2, ERBB2, EGFR, PDGFRB, NTRK1/2, PIK3CA, BRCA2, MET). 25 (22%) of pts had drivers detected solely by copy number alterations, most commonly NF1 deletions. 53 patients received PD-1 therapy (28 PD-1, 25 PD-1+CTLA-4); median follow up was 18 months (mo). Median TMB was 3.3/Mb (0-9.8). Higher TMB was not associated with median OS (18.6 mo vs not reached (NR); p = 0.11). Median FGA was 0.17 (0.0034-0.48). McM with lower FGA had improved OS versus those with higher FGA (NR vs 14.7 mo, p = 0.006). 18-month OS was 80% in FGA low and 49% in FGA high McM. When McM were classified as KIT, NF1, RAS, BRAF, or other driver, OS did not vary significantly (p = 0.16, log-rank). Conclusions: In the largest cohort of McM to date with multigene sequencing and copy number assessment, we identify a driver alteration in 89% of tumors. In pts with McM receiving frontline PD-1 therapy, FGA is associated with survival. The immunologic consequences of FGA in McM are being investigated.
Management of patients with advanced NSCLC without actionable mutations: A simulation-based assessment of medical oncologists.
Authors: Tara Herrmann, Douglas Blevins, Martin Warters, Cayla Cason, Ramaswamy Govindan, Hossein Borghaei
Journal: Journal of Clinical Oncology (2018)

e21041 Background: There have been many changes to the advanced NSCLC (aNSCLC) treatment algorithm, challenging oncologists to assimilate evidence and guidelines into practice. Methods: A CME virtual patient simulation (VPS) was made available via a website dedicated to professional development. The VPS consisted of 2 cases presented in a platform that allowed oncologists to assess the patient and choose from an extensive database of diagnostic and treatment possibilities matching the scope and depth of practice. Clinical decisions were analyzed using a sophisticated decision engine, and instantaneous clinical guidance (CG) employing evidence-base and faculty recommendations was provided after each decision. Oncologists were allowed a second chance at each decision point post-CG. Data were collected between 12/6/2017 and 1/16/2018. Results: At the time of initial assessment, 73 oncologists, 83% of whom practiced in the community, fulfilled the participation criteria for completing the simulation. Assessment of their practice revealed: In a patient with newly diagnosed disease, up to 44% of oncologists did not order biomarkers recommended by guidelines. Individuals were most likely to order PD-L1 expression and least likely to determine ROS1 translocation status. Moreover, 38% ordered the appropriate regimen. CG led to a 5% -19% improvement in testing and 43% increase in evidence-based treatment (P< .001) In a patient whose disease has progressed on a platinum doublet, 52% of oncologists prescribed an appropriate regimen. CG resulted in a 29% improvement in evidence-based treatment (P = 0.005). The primary rationale for selecting treatment differed based on the chosen regimen, from PD-L1 status (38%) with use of pembrolizumab to guideline recommended (36%) for nivolumab.Conclusions: Despite biomarker testing being a critical element in deciding treatment for patients with aNSCLC, testing is not uniformly conducted. In addition, there is a lack of clarity about what is the most appropriate regimen for these patients. Our findings demonstrate a continued need to educate oncologists about how to select and prescribe the most appropriate regimen for a patient with aNSCLC.
Preliminary results from a study of sevacizumab in Chinese patients with metastatic colorectal cancer resistant to oxaliplatin-based first-line chemotherapy.
Authors: Nong Xu, Junning Cao, Yanqiao Zhang, Yanhua Ding, Chenyu Mao
Journal: Journal of Clinical Oncology (2018)

e15530 Background: The purpose of this study was to evaluate the safety, the maximum tolerated dose, the antitumor activity, and pharmacokinetics of sevacizumab in patients with mCRC resistant to oxaliplatin-based first-line chemotherapy. Methods: This is an open-label, multicenter, Phase 1b, dose-finding study. Adult patients aged 18-74 years old with mCRC, who had been previously treated with oxaliplatin-based chemotherapy were enrolled and received intravenous sevacizumab (3-5 mg/kg) and FOLFIRI every 14 days. Standard 3+3 design was used in the dose escalation phase. The DLTs assessments were based on the first 2 cycles. In the expansion phase, the number of patients of every dose group can be expanded to 8-12. The primary endpoint was safety and tolerability. The secondary endpoint included PK and tumor response. The study was originally designed to assess the doses of 3, 4, and 5 mg/kg. Since high frequency and severity of proteinuria in the patients treated with sevacizumab was observed, the protocol was amended in the expansion phase to add 2 additional dose groups (2mg/kg and 1mg/kg) and these two dose groups can be directly expanded to 8-12 patients. Results: Totally forty-nine (49) patients were enrolled (3mg/kg, n = 12, 4mg/kg, n = 12, 5mg/kg, n = 11, and 2mg/kg, n = 14). Median duration of therapy was 7.3 cycles (range, one to 26.5 cycles). Up to January 18, 2018, 3 patients of 2mg/kg dose group are still on treatment. Tumor response was assessed in 35 patients, in which 54% patients (19 patients) achieve PR. And the maximum response rate in one patient treated with 3mg/kg was 80%. There were 3 dose limiting toxicities observed, including neutropenia with fever, grade 3 hypertension and grade 3 proteinuria (the urine protein can’t be back to < 2g/24h). The most common adverse events (grade 3+) were neutropenia (41%), proteinuria (24.4%), leukopenia (22.4%), hypertension (20.4%) and diarrhea (16%). Conclusions: Preliminary results from this study showed good efficacy of sevacizumab in mCRC patients and the study also provide good insights of dose selection in future clinical development of sevacizumab. Clinical trial information: NCT02453464.
Characteristics of breakthrough therapy designation requests (BTDRs) submitted to the Office of Hematology and Oncology Products (OHOP), FDA.
Authors: Daniel L. Suzman, Paul Gustav Kluetz, Amy E. McKee, Ashley Flynn Ward, Leigh Jessica Marcus, Sandra J. Casak, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

e18236 Background: Breakthrough therapy designation is an FDA program intended to expedite the development of drugs and biologics that provide preliminary clinical evidence of a substantial improvement over existing therapies. The factors needed to demonstrate this improvement in oncologic therapies have not been well-described. Methods: We reviewed the characteristics of BTDRs submitted to OHOP from program initiation to the present. Results: From November 2013 through July 2016, there were 134 BTDRs for 96 drugs submitted to OHOP, not including 14 BTDRs intended for benign hematologic or supportive care indications. The most common drug mechanisms of action (MoA) were tyrosine kinase inhibitor (TKI) (37; 28%), immunotherapy (24; 18%), and targeted antibodies (21; 16%). Of the 134 BTDRs, 56 (42%) were granted. BTDRs were granted most frequently for TKIs (22; 59%) and immunotherapy (14; 58%) and were rarely granted for cytotoxic (1; 10%) or endocrine (0) therapies. BTDRs based on randomized trials were more frequently granted than those based on single-arm trials (49% vs 39%), as were BTDRs based on OS versus ORR or PFS (57% vs 41%). In BTDRs based on single-arm trials, the median number of patients was higher in those granted versus denied or withdrawn (41 vs 26 patients). Among BTDRs granted based on ORR in solid tumors, the ORR ranged from 24% to 94%, reflecting variation in available therapies, MoA, toxicity, and durability of response. Conclusions: The likelihood of a successful BTDR increases with randomized trial design and larger sample size. Additional considerations include MoA, duration of ORR, and choice of endpoint. [Table: see text]
TCT-381 The SCAMI-NSTEMI Score: a Simplified risk score based on China Acute Myocardial Infarction registry to predict in-hospital mortality of Non-ST segment Elevation Myocardial Infarction patients
Authors: Rui Fu, Chenxi Song, Jingang Yang, Kefei Dou, Dong Yin, Yuejin Yang
Journal: Journal of the American College of Cardiology (2018)
Phase II trial of pembrolizumab (P) in patients (pts) with previously-treated mesothelioma (MM).
Authors: Arpita Desai, Theodore Karrison, Buerkley Rose, Erika Pemberton, Bianca Hill, Christopher M. Straus, Yi-Hung Carol Tan, Tanguy Y. Seiwert, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2018)

8565 Background: We conducted a phase II trial (NCT02399371) of P in previously treated MM to characterize activity in a non-selected population and determine a PD-L1 expression threshold Methods: Eligible pts had histologically confirmed MM, PS 0-1, disease progression, 1-2 prior regimens. P 200 mg was given Q21 days; CT scans Q9 weeks. 10 endpoints determine 1) objective response rate (RR) in an unselected and a PD-L1 positive population 2) optimal threshold for PD-L1 expression (22C3 IHC tumor cell/tumor proportion score (TPS) assay). Part A required ≥3 responses in 35 PD-L1 unselected pts. Part B PD-L1 preselects if a threshold is found in Part A. We previously reported (WCLC 2016) 7 responses in Part A; as no PD-L1 threshold was found (ROC 0.62), Part B enrolled 30 pts with no biomarker enrichment. Results: 65 pts enrolled 5/15-2/18; 1 withdrew. Median age: 68 (range 26-85); PS 0: 53%; male: 77%; epithelioid/biphasic/sarcomatoid: 76.6%/15.6%/7.8%; pleural/peritoneal: 87.5%/12.5%; 1 prior regimen: 61%. Mean cycles: 9 (range 1-34). Partial response: 12 (19%), stable disease: 29 (47%). Median progression-free survival (PFS): 4.5 months (mo) (95% CI: 2.3, 6.2). Median overall survival: 11.5 mo (95% CI: 7.6, 14). Grade ¾ toxicity: adrenal insufficiency 3%, pneumonitis 3%, rash 3%, colitis 1.6%, confusion 1.6%, hepatitis 1.6%, hyperglycemia 1.6%. Grade 5: hepatitis 1.6%, unknown 1.6%. PD-L1 expression by TPS (N = 62): none ( < 1%) 45%; low (1-49%) 32%; high (≥50%) 23%. RR by TPS: none 7%, low 26%, high 31%. RR by histology: epithelioid 16%, biphasic 10%, sarcomatoid 40%. RR by site: pleural 20%, peritoneal 12.5%. PD-L1 did not correlate with RR as a continuous metric (ROC area 0.65; 95% CI: 0.48, 0.82); there was a trend to higher RR in PD-L1 ≥1% (28%) vs. PD-L1 < 1% (7%). Median/1-year PFS by TPS: none 3.1 mo/7%; low 6.2 mo/7%; high 6.1 mo/31%. Conclusions: P has clinically meaningful single-agent activity in PD-L1 unselected, previously treated MM, yielding a 19% RR, a 66% disease control rate, and manageable toxicity. Though an optimal PD-L1 threshold could not be established, there was a trend to higher RR and more durable PFS with increasing PD-L1 expression. Responses were more frequent in pleural and sarcomatoid MM. Funded by MARF. Clinical trial information: NCT02399371.
Comparative effectiveness of carboplatin-pemetrexed (Carbo-Pem) with vs. without bevacizumab (Bev) in patients with advanced non-squamous (Sq) non-small cell lung cancer (NSCLC).
Authors: Stephen Joseph Bagley, Nandita Mitra, Neal J. Meropol, Benjamin Holzman, Roger B. Cohen, Corey J. Langer, Anil Vachani
Journal: Journal of Clinical Oncology (2018)

9073 Background: The majority of patients with advanced non-sq NSCLC do not have high programmed death ligand 1 (PD-L1) expression or a targetable genetic alteration. Carbo-pem-bev is commonly used as first-line therapy in these patients, but it is unknown whether the addition of bev to carbo-pem improves overall survival (OS). Methods: Using nationally representative electronic health record data from Flatiron Health, we performed a retrospective cohort study of patients diagnosed with advanced non-sq NSCLC from 2011-2017 who received ≥1 cycle of carbo-pem, with/without bev, as initial systemic therapy for metastatic disease. Patients with alterations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) were excluded. The survival impact of adding bev to carbo-pem was assessed using a Cox proportional hazards model. Results: Patient characteristics are listed in Table 1 (n = 5,264). Median follow-up time and OS were 31 (IQR 16-49) and 10.2 (95% CI 9.8-10.8) months (mo), respectively. After adjusting for the covariates in Table 1, the addition of bev was associated with improved OS (median 12.1 vs 8.8 mo; HR 0.80, 95% CI 0.74-0.85, p < 0.001). In a sensitivity analysis of patients with known Eastern Cooperative Oncology Group Performance Status (ECOG PS) (N = 2,708), the effect of bev was similar (HR 0.79, 95% CI 0.72-0.88, p < 0.001). Conclusions: In this large, real-world dataset, the addition of bev to first-line carbo-pem for metastatic non-sq NSCLC was associated with improved OS. To our knowledge, this is the first study to address whether bev improves outcomes when added to carbo-pem. Median Age (IQR) Carbo-pem (n = 3108) Carbo-pem-bev (n = 2156) 69 (61-75) 67 (60-73) Sex - - Male 1611 (52%) 1084 (50%) Race - - Caucasian 2062 (66%) 1429 (66%) Black 227 (8%) 136 (6%) Asian 41 (1%) 32 (2%) Other 254 (8%) 206 (10%) Unknown 524 (17%) 353 (16%) Stage - - IV (de novo metastatic) 2558 (82%) 1839 (85%) Metastatic recurrence of stage I-III 550 (18%) 317 (15%) Median # days from metastatic diagnosis to chemo start (IQR) 34 (22-52) 32 (21-49) ECOG PS - - 0-1 1208 (39%) 931 (43%) 2 319 (10%) 160 (7%) 3-4 58 (2%) 32 (2%) Unknown 1523 (49%) 1033 (48%)
P02.01 Altered FoxM1 expression contributes to the meningioma malignancy and can be a critical target for the tumor progression
Authors: S H Kang, H Kim, K Park, B Ryu, M Yu, Y Choi, S Park
Journal: Neuro-Oncology (2018)

Meningioma, the most common primary brain tumor, is intractable for various treatment modalities in case of malignant progression. The transcription factor Forkhead box M1 (FoxM1) is overexpressed in malignant meningioma. However, the functional importance of this factor in human meningioma is not known. In this study, we examined FoxM1 expression and oncogenic potential in meningioma. To verify the correlation between FoxM1 expression and meningioma grades, human meningioma tissues and cell lines were used. In addition, FoxM1 associated target gene profiles, malignant phenotype, in vivo tumorigenesis and chemotherapeutic drug sensitivity analysis were performed under altered regulation of FoxM1. It revealed that FoxM1 expression is positively correlated with meningioma grade, including recurrent tissues derived from primary tumors by mRNA assay and immunostain. Inhibition of FoxM1 suppresses cell proliferation, anchorage-independent growth in vitro, and tumorigeneicity in vivo by regulation of downstream targets including beta-catenin, cyclin D1, p21, MMP9, EMT profiles in malignant meningioma. In siomycin A treatment, a selective FoxM1 inhibitor, IOMM Lee malignant meningioma cells result in more sensitization for growth inhibition than SF4433 benign meningioma. In case of Siomycin A pretreatment, decreased FoxM1 and Ki67 expression are found at tumor tissue in vivo. These data showed that FoxM1 may have a driving role for meningioma progression and its inhibition is effective strategy in meningioma therapy.
Pharmacodynamics of first-in-class p97 inhibitors that disrupt protein homeostasis in cancer.
Authors: Apurva K. Srivastava, Jeevan P Govindharajulu, Melinda G. Hollingshead, Howard Stotler, Feng Wang, Tsui-Fen Chou, Kelly Banfield, Francesca Tomaino, Gordon Stott, James H. Doroshow, Ralph E. Parchment
Journal: Journal of Clinical Oncology (2018)

e14539 Background: The AAA (ATPases Associated with diverse cellular Activities) enzyme p97 is an emerging target involved in protein homeostasis. A first-in-class ATP-competitive p97 inhibitor CB-5083 has recently entered phase 1 clinical trials, and non-ATP-competitive p97 inhibitors are being explored. We developed and validated quantitative pharmacodynamic (PD) biomarkers to guide preclinical and early clinical development of p97 inhibitors. Methods: To measure pharmacodynamic response to p97 inhibitors, we focused on three major steps in the mechanism of action: 1) blockage of the ubiquitin proteasome system (UPS); 2) induction of unfolded protein response (UPR) due to endoplasmic reticulum (ER)-associated degradation (ERAD); and 3) execution of apoptosis. Polyubiquitinated proteins linked via lysine-K48 of ubiquitin (K48) provide a specific measure of UPS blockage. A transcription factor CHOP (CCAAT-enhancer-binding homologous protein) in the nuclear fraction provided a measure of UPR, and measurement of cleaved caspase-3 (CC3) levels provided a measure of apoptosis. The biomarkers were developed on Luminex multiplex platform. Fitness of biomarkers to monitor PD response was demonstrated in nude mice bearing HCT116 tumors, dosed orally with NSC-788636 (CB-5083) (12.5-100mg/kg), and tumor/blood samples collected at 1, 4, 6, 14 and 24 hour (hr) for PD/PK analysis. Results: In vitro, p97 inhibition by NSC-788636 (1µM) significantly increased: 1) K48 levels by > 2-fold within 1 hr; 2) CHOP levels by 50-80% between 1-6 hr; and 3) CC3 levels by > 20-fold at 24 hr. In vivo, NSC-788636 treatment (50-100 mg/kg/dose) increased K48 levels by > 2-fold within 1 hr (P < 0.01 vs vehicle group), which decreased slowly over a 24 hr period but remained higher than controls (P < 0.05). Changes in biomarkers occurred during a timeframe suitable for clinical assessment of tumor biopsies. Conclusions: We describe PD biomarkers of p97 inhibitors suitable for proof-of-mechanism studies. These biomarkers offer broad applicability for confirming target engagement/MOA of several 3rd generation proteasome inhibitors currently under clinical development. Funded by NCI Contract No HHSN261200800001E as part of NExT CBC project.