tbuckley/cabot-search huggingface dataset:
Tumor gene signature associated with neurotoxicity in R/R B-ALL patients treated with JCAR015, a CD19-directed CAR T cell product.
Authors: N. Eric Olson, Seamus P. Ragan, Stefan Ponko, Nikolaus S. Trede, Howard Marvin Stern, Claire L. Sutherland
Journal: Journal of Clinical Oncology (2018)

7007 Background: CD19-directed chimeric antigen receptor modified T (CAR T) cells produce therapeutic responses in adult R/R B-ALL. However, CAR T therapy is also associated with serious toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). NT mechanisms are emerging and thus far efforts have focused on patient factors and CAR T product attributes and performance post infusion. Methods: RNA-Seq analyses was performed on pre-apheresis bone marrow samples obtained from 31 JCAR015 treated patients (ROCKET trial; NCT02535364). Results: Gene expression analysis identified a gene set that is differentially expressed between severe (grades 4-5, n = 7) NT patients and low (grades 0-1, n = 10) NT patients. The NT associated genes clustered B-ALL samples in public datasets (TARGET and GSE79533) by molecular subtype, with genes highly expressed in low NT ROCKET patients also being highly expressed in Ph+ and Ph-like subtypes. Genes highly expressed in severe NT ROCKET patients were highly expressed in non Ph-like subtypes in the public datasets. Machine learning applied to all ROCKET patients classified 16 patients as having Ph-like gene expression and 15 patients having non Ph-like expression. No grade 4+ NT events occurred in Ph-like patients, and grades 3+ (p = 0.03) and 4+ NT (p = 0.0002) were significantly more frequent in the non Ph-like patients. Looking at 3 other B-ALL CD19 CAR T studies (FHCRC2639, NCT01865617; MSK 09-114, NCT01044069 and PLAT-02, NCT02028455), no grade 4+ NT events were observed in any Ph+ patients, suggesting that this finding may not be limited to the ROCKET trial. Pre CAR T infusion plasma levels of CCL17, a chemokine highly expressed by RNA-Seq in low NT ROCKET patients and in the Ph-like B-ALL datasets, were also significantly higher in the grade 0-1 versus grade 4-5 NT group (p < 0.05). Conclusions: This exploratory analysis suggests that B-ALL subtypes differ in risk for CD19 CAR T associated NT with Ph-like patients being at significantly lower risk than non Ph-like patients. Risk stratification by molecular subtype or gene expression signature could play an important role in identifying patients at elevated risk for severe NT.
Efficacy of combined hypofractionated radiotherapy and anti-PD-1 monotherapy in patients with melanoma.
Authors: Anissa Roger, Adeline Finet, Blandine Boru, Jean-Jacques Mazeron, Yves Otmezguine, Astrid Blom, Christine Longvert, Marie-Florence De Maleissye, Alain Beauchet, Philippe Saiag
Journal: Journal of Clinical Oncology (2017)

e21008 Background: Information on the role and type of radiotherapy in melanoma pts treated with anti-PD1 is limited. We report a cohort of advanced melanoma pts having received simultaneous hypofractionated radiotherapy and anti-PD-1 monotherapy. Methods: Database search in the prospective database of a referral center with standardized radiotherapy procedures for all pts having received both treatments between 1/1/15-30/6/16. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions. Results: 25 pts with inoperable AJCC stage 3-4 melanoma, mean age 60.5 Y. Anti-PD-1 monotherapy was first systemic treatment in only 40% of pts. Median follow-up after onset of anti-PD-1 therapy (83% nivolumab, 17% pembrolizumab) was 13.3 m, with 48% of pts still alive at last follow-up. Radiotherapy was performed either early (within first 3 m of PD-1 blockade) in pts with rapidly progressing symptomatic lesion(s) (60% of pts) or late ( &gt; 3 m) in pts with slow progression or dissociated response (40% of pts). It consisted of 1 weekly radiation during 4-5 w (84% of pts), or 1 gammaknife radiation for cerebral mets (16% of pts). Median delay between onset of PD-1 blockade and radiotherapy was 1.8 m (range 0.5-11 m). For radiated lesions, rates of complete (CR), partial (PR) responses, stabilization (S) or progression (P) were 24%, 8%, 44%, and 28%, respectively. For non-radiated lesions (84% of pts), rates of CR, PR, S, and P were 29%, 19%, 19%, and 33%, respectively. Among pts radiated late for insufficient response to anti-PD-1 monotherapy, CR or PR in non-radiated lesions (i.e. abscopal response) was observed in 56% of pts. Anti-PD-1 therapy could be discontinued in 4 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in difficult-to-treat pts. Controlled studies are needed.
Association between mutation variant allele fractions (mVAFs) and response to immunotherapy (IO) in metastatic renal cell carcinoma (mRCC).
Authors: Nazli Dizman, Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Joann Hsu, Jacob Adashek, Meghan Salgia, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2018)

e16575 Background: Quantitation of mVAFs in ctDNA can provide a reliable surrogate of cancer clone frequency. Using a cutoff of 0.3% may exclude subclonal entities and thus specifically capture driver alterations. We seek to identify if detection of mVAFs in excess of 0.3% is associated with IO response in mRCC Methods: From an institutional database, consecutive patients (pts) with mRCC who had ctDNA assessment performed in routine clinical care were assessed. All patients were assessed using a CLIA-certified 73 gene panel. Data regarding systemic treatment was collected and duration of treatment (DOT) on 1st immunooncology agent (DOT-IO) was calculated for each patient. Best response was assessed using RECIST v1.1 criteria, and patients were characterized as either having clinical benefit (CB; complete/partial response or stable disease) or no clinical benefit (NCB; progressive disease). CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 718X for up to 315 cancer-related genes plus introns from up to 28 genes frequently rearranged in cancer. The mean of VAFs > 0.3% were calculated. The correlation between mean VAFs and DOT-IO as well as CB rate was assessed Results: Of 36 patients (27:9 M:F) who received IO, 31 pts had clear cell and 5 pts had non-clear cell (papillary = 3; sarcomatoid = 1; chromophobe = 1) histology. The most common 1st IO agent rendered was nivolumab (75%), and this was administered most commonly in the post-2nd-line setting (63%). The most frequent genomic alterations encountered were TP53 (20%) and VHL (15%). The mean value for mVAFs in the cohort was 1.1%. Mean mVAFs did not differ between CB and NCB groups. (1.6% vs 0.4%; p = 0.304). When segregated in groups by estimate of mVAF, DOT-IO was similar in high mVAF and low mVAF pts (160 days and 252 days, respectively; P = 0.442). Survival analysis revealed no difference between CB and NCB in terms of DOT-IO (p = 0.253) Conclusions: Our results failed to demonstrate a link between IO response and cancer clone frequency which was assessed by using the mean value of VAFs that are higher than 0.3%. Given our limited sample size, this association warrants exploration in larger series.
A phase I trial of pomalidomide in combination with liposomal doxorubicin in the treatment of advanced or refractory Kaposi sarcoma in individuals with or without HIV.
Authors: Ramya Ramaswami, Kathryn Anne Lurain, Priscila Hermont Goncalves, Anaida Widell, Matthew Lindsley, William Douglas Figg, Cody J. Peer, Seth M. Steinberg, Vikram Khetani, Peter L. Choyke, Joseph R Fontana, Denise Whitby, Thomas S. Uldrick, Robert Yarchoan
Journal: Journal of Clinical Oncology (2018)

TPS11586 Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor caused by the gammaherpesvirus Kaposi-sarcoma herpesvirus (KSHV, or human herpesvirus 8 [HHV-8]) that is commonly seen among people living with HIV. KSHV also contributes to the pathogenesis of multicentric Castleman disease (KSHV-MCD) and KSHV inflammatory cytokine syndrome (KICS). Advanced KS can occur alone or in combination with KSHV-MCD or KICS. KS can be difficult to treat when it occurs with KSHV-MCD or KICS and can result in high mortality rate. Pomalidomide is an orally available third generation thalidomide analog with immunomodulatory and antiangiogenic properties that has been shown to be safe and to have activity in patients with KS with or without HIV. Liposomal doxorubicin (LD) is a preferred treatment for KS. The tolerability and activity of pomalidomide in combination with LD with advanced KS or KS and concurrent KSHV-MCD or KICS are unknown. Methods: The primary objective is to evaluate the safety, tolerability and pharmacokinetics of pomalidomide (in escalating dose levels I - 2mg, II - 3mg, or III- 4mg) in combination with liposomal doxorubicin in two groups of patients: Group I) KS requiring systemic therapy; Group II) KS with concurrent KSHV-associated MCD or KICS. Patients will receive LD intravenously on day 1 of a 28-day cycle combined with pomalidomide once a day, days 1 to 21 at a specific dose level. Dose escalation of pomalidomide for each cohort will stop when 2 or more dose-limiting toxicities (DLTs) occur (in a cohort of 3 or 6 patients). Assessment of the KS antitumor effect, using a modified AIDS Clinical Trials Group KS response criteria; effects on manifestations of KSHV-MCD or KICS in those patients with these diseases; and changes in quality of life in patients receiving pomalidamide and LD will be evaluated. Patients with confirmed cutaneous, pulmonary or visceral KS are eligible. Adherence to combination antiretroviral therapy for 1 month is required for participants in Group I except for those with progressive disease or end-organ disease. The study began enrollment in January 2016. Clinical trial information: NCT02659930.
Performance of preoperative plasma HE4 and CA-125 levels in predicting ovarian cancer mortality in women with epithelial ovarian cancer (EOC).
Authors: Isabelle Bairati, Jean Gregoire, Marie Plante, Pierre Douville
Journal: Journal of Clinical Oncology (2017)

e17076 Background: Additional prognostic biomarkers are needed to better manage women with EOC, especially dichotomized indicators for decision making. The objective of this external validation study was to assess the performance of preoperative plasma HE4 and CA-125 levels in predicting mortality by EOC. Methods: Eligible EOC women were newly diagnosed cases treated by upfront debulking surgery in a gynecology oncology center (CHU de Québec, L’Hôtel-Dieu, Canada) in 1988-2006 (cohort 1, n=136) and in 2007-2013 (cohort 2, n=177). All FIGO stages were included. Preoperative plasma HE4 and CA-125 levels were measured by Elecsys® automated immunoassay (Roche Diagnostics). Dates and causes of death were obtained by record linkage with the Quebec mortality files. In cohort 1, time-dependent receiver operating characteristic (ROC) curves were performed and optimal thresholds for HE4 and CA-125 were generated using the Youden index J. In cohort 2, crude and standardized Cox proportional models were done to validate the usefulness of these biomarkers according to their optimal thresholds. Standardized models included standard prognostic factors. The Likelihood Ratio (LR) tests were done to compare the standardized models with and without each biomarker. Results: In cohorts 1 and 2, medians of follow-up were respectively 5.3 and 3.2 years. Five-year disease free survival rates were 53% in cohort 1 and 54% in cohort 2. In cohort 1, the AUC for HE4 and CA-125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA-125. In cohort 2, higher levels of plasma HE4 (≥277 pmol/L) were significantly associated with death by EOC (adjusted hazard ratio (aHR): 1.80; 95% CI: 1.03-3.15; p-value for LR test: 0.03), while higher levels of CA-125 (≥282 U/ml) were not associated with death by EOC (aHR: 1.50; 95% CI: 0.88-2.55; p-value for LR-test: 0.12). In serous EOC, the associations with mortality were respectively 2.46 (95% CI: 1.26-4.80) for HE4 and 1.56 (0.87-2.80) for CA-125. Conclusions: Preoperative plasma HE4 is a promising prognostic biomarker in women with EOC and performs better than CA-125 to predict mortality.
Correlation of FDG PET/CT heterogeneity with disease recurrence in early-stage, non-small cell lung cancer.
Authors: Justin David Blasberg, Stephanie Harmon, Christopher W. Seder, Anne M. Traynor, Robert Jeraj
Journal: Journal of Clinical Oncology (2016)

e20049 Background: Preoperative identification of Non-Small Cell Lung Cancer (NSCLC) patients at risk for disease recurrence has proven unreliable using standard molecular imaging techniques. PET-derived quantitative heterogeneity metrics have emerged as potential prognostic factors in several malignancies. The purpose of our study was to evaluate the association between FDG PET/CT heterogeneity metrics and disease recurrence following resection of early stage NSCLC patients. Methods: 65 patients with stage I and II NSCLC and preoperative FDG PET/CT scans were identified for analysis. 53 heterogeneity imaging metrics were extracted based on intensity and texture of the primary tumor. Imaging and clinical variables were evaluated as predictors of recurrence by logistic regression. Squamous cell carcinomas (SCC, N = 27) and adenocarcinomas (AC, N = 38) were compared using Wilcoxon Signed-Rank test. Results: Preoperative clinical and pathologic characteristics were similar between recurrence (n = 34) and non-recurrence (n = 31) patients, including tumor size, pulmonary function tests, and smoking history. SUVmax normalized to liver (n SUVmax ) was independently associated with recurrence (p = 0.02). Stratification by histology identified first-order metrics that were different between groups, including SUVhetero (p = 0.003), which was independently associated with recurrence in adenocarcinoma (AC). Modeling first-order SUV metrics (n SUVmax , SUVhetero , volumePET ) with tumor size demonstrated the strongest predictive ability for recurrence in AC patients (R2= 0.47). (Table) Conclusions: Specific FDG PET/CT heterogeneity metrics are correlated with disease recurrence in early stage NSCLC patients. The predictive ability of FDG PET/CT is strongest when patients are stratified by histology. Incorporating FDG PET/CT heterogeneity metrics with clinical and tumor characteristics may improve identification of high-risk patients. Univariate predictors of recurrence. Imaging Metrics AC patients All patients OR p-value OR p-value n SUVmax 1.29 0.03 1.20 0.02 SUVhetero 1.96 0.003 1.37 0.08 SUVmax 1.10 0.09 -- n/s SUVmean 1.23 0.08 -- n/s Kurtosis 0.66 0.07 0.78 0.09 Skewness 0.29 0.05 -- n/s
Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non–small cell lung cancer (NSCLC): Efficacy updates and exploratory analysis of CNS ORR and overall ORR by baseline (BL) brain lesion status.
Authors: Rudolf M. Huber, Dong-Wan Kim, Myung-Ju Ahn, Corey J. Langer, Marcello Tiseo, Howard West, Harry J.M. Groen, Karen L. Reckamp, Maximilian J. Hochmair, Natasha B. Leighl, Karin Holmskov Hansen, Scott N. Gettinger, Luis G. Paz-Ares, Edward S. Kim, Egbert F. Smit, Sang-We Kim, William Reichmann, David Kerstein, D. Ross Camidge
Journal: Journal of Clinical Oncology (2018)

9061 Background: ALTA (NCT02094573) evaluated 2 doses of the ALK inhibitor BRG post-CRZ. Overall ORR contains both CNS and extra-CNS target lesion data. Methods: In ALTA, stratification included BL CNS disease (+/−). Pts were randomized to BRG 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). To differentiate CNS and extra-CNS efficacy we compared CNS ORR with overall ORR by BL CNS status. Results: 222 pts were randomized (n = 112/110, arm A/B); 71%/67% had BL CNS lesions. Of 247/204 total target lesions in A/B, 38 (15%) and 32 (16%), respectively, were in the CNS; 28 (25%) pts in A and 23 (21%) in B had ≥1 target CNS lesion. Median follow-up was 19.6/24.3 mo. Per independent review, CNS ORR in pts with measurable BL CNS lesions (n = 26/18, A/B) was 50%/67%; in pts with any BL CNS lesions (n = 81/74, A/B), median intracranial PFS (iPFS) was 12.8/18.4 mo. Table shows long-term overall efficacy updates by BL CNS status. Dose reductions or discontinuations due to AEs (A/B): 7%/29% and 4%/11%. Conclusions: With > 24 mo follow-up, the recommended BRG 180 mg dose (with lead-in) continues to demonstrate long PFS and iPFS and high CNS ORR. Comparable CNS ORR (67%) and overall ORRs in pts with (61%) or without (55%) BL CNS target lesions support BRG's broad whole-body activity. Clinical trial information: NCT02094573. Investigator Assessed Independent Review Arm A (n = 112) Arm B (n = 110) Arm A (n = 112) Arm B (n = 110) Confirmed ORR, % All pts 46 (35–57a) 56 (45–67a) 51 (41–61b) 56 (47–66b) BL CNS target lesions 43 (25–63b) 61 (39–80b) — — Yes (n = 28/23, A/B) No (n = 84/87, A/B) 47 (36–58b) 55 (44–66b) — — Median DoR, responders,c mo 12.0 (9.2–17.7b) 13.8 (10.2–19.3b) 16.4 (7.4–24.9b) 15.7 (12.8–21.8b) Median PFS,c mo Events, % 9.2 (7.4–11.1b) 69 15.6 (11.1–21.0b) 58 9.2 (7.4–12.8b) 58 16.7 (11.6–21.4b) 49 OSc Median, mo 29.5 (18.2–NRb) 34.1 (27.7–NRb) — — 1-y,c % 70 (61–78b) 80 (71–87b) — — 2-y,c % 55 (44–64b) 66 (56–74b) — — DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. a97.5% CI (primary endpoint); b95% CI; cKaplan-Meier estimate.
TCT-663 Comparison of Conformability and Wall Shear Stress Between Resolute Integrity Zotarolimus-Eluting Stent and the XIENCE Xpedition Everolimus-Eluting Stent in Angulated Vessels: An Interim Analysis of the SHEAR-STENT Randomized Controlled Study
Authors: Arnav Kumar, David Molony, Mohamad Raad, Hossein Hosseini, Won Lee, Elizabeth Thompson, Adrien Lefieux, Olivia Hung, Kalina Machado, Sonali Kumar, Sameer Khawaja, David Sternheim, Mostafa Vasigh, Sonu Gupta, Bill Gogas, Alessandro Veneziani, Joo Myung Lee, Shao-Liang Chen, Hiromasa Otake, Takashi Akasaka, Eun-Seok Shin, Bon-Kwon Koo, Goran Stankovic, Dejan Milasinovic, Andrejs Erglis, Karthic Chandran, Chang-Wook Nam, Javier Escaned, Andrejs Erglis, Don P. Giddens, Habib Samady
Journal: Journal of the American College of Cardiology (2018)
Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study.
Authors: Hyun Cheol Chung, Jan H. M. Schellens, Jean-Pierre Delord, Ruth Perets, Antoine Italiano, Ronnie Shapira-Frommer, Lyudmila Manzuk, Sarina Anne Piha-Paul, Jiangdian Wang, Susan Zeigenfuss, Scott K. Pruitt, Aurelien Marabelle
Journal: Journal of Clinical Oncology (2018)

5522 Background: The KEYNOTE-158 study (NCT02628067) is a phase II basket study investigating the antitumor activity of pembrolizumab, an IgG4 anti-PD-1 monoclonal antibody, in 11 cancer types. An updated analysis of all 98 patients (pts) included in the cervical cancer cohort is presented. Methods: Key eligibility criteria for this cohort included histologically or cytologically confirmed advanced cervical cancer, progression on or intolerance to ≥1 line of standard therapy, ECOG PS 0 or 1, and provision of a tumor sample for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 wks for the first 12 mo, and every 12 wks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥1, was evaluated retrospectively by IHC. Primary endpoint was ORR assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included DOR, PFS, OS, and safety. Results: 98 pts were treated. Median age was 46.0 (range, 24-75) y, 65.3% had ECOG PS 1, and 93.9% had stage M1 disease. 83% of enrolled pts had PD-L1+ tumors. As of the August 23, 2017 data cutoff, the median follow-up duration was 10.3 mo (range, 0.6 to 18.0 mo). ORR was 13.3% (95% CI, 7.3%-21.6%), with 3 CR and 10 PR. 17 pts had SD, and the DCR was 30.6%. All 13 responses were in pts with PD-L1+ tumors, and the ORR was 16.0% (95% CI, 8.8%-25.9%) in the PD-L1-positive cohort (N = 81). 9 of 13 responses were ongoing after ≥9 mo follow-up. Median DOR had not been reached (range, 3.7+ to 12.4+). Median (95% CI) PFS and OS were 2.1 mo (2.0-2.2 mo) and 9.4 mo (7.9-13.4 mo), respectively. Treatment-related AEs occurred in 65.3% of pts, and the most common were hypothyroidism (10.2%), decreased appetite (9.2%), fatigue (9.2%), and diarrhea (8.2%). 11.2% of pts had treatment-related grade 3-4 AEs. Conclusions: Similar to the initial report, durable antitumor activity and manageable safety were demonstrated with pembrolizumab in advanced cervical cancer. Clinical trial information: NCT02628067.
Risk factors for brain metastases after prophylactic cranial irradiation in small cell lung cancer.
Authors: Haiyan Zeng, Peng Xie, Xue Meng, Shuanghu Yuan, Xindong Sun, Wanlong Li, Jinming Yu
Journal: Journal of Clinical Oncology (2016)

e20095 Background: Despite administration of prophylactic cranial irradiation (PCI), some patients with small cell lung cancer (SCLC) still suffer from brain metastases (BM). We conducted this study to identify the risk factors for BM after PCI in SCLC. Methods: The characteristics of all the patients with SCLC underwent PCI in our institute from July, 2003 to June, 2014 were reviewed. The primary endpoint was BM free survival (BMFS), the secondary endpoints were extracranial disease free survival (ECDFS), disease free survival (DFS) and overall survival (OS). All these outcomes were estimated by the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were performed to explore risk factors for BM. Results: A total of 175 eligible patients were analyzed, among whom 36 (20.6%) developed BM with median follow-up time of 42.1 months. Univariate analysis showed that 2-category TNM classification (P= 0.009, HR = 2.525, 95% CI 1.259-5.064), thoracic hyperfractionated accelerated radiation therapy (HART) (P= 0.023, HR = 2.171, 95% CI 1.111-4.243) and the time interval from the end of chemoradiotherapy to the start of PCI (CRT-PCI interval) (P= 0.036, HR = 0.442, 95% CI 0.206-0.950) were significant variables associated with BM. In multivariate analysis, HART (P= 0.016, HR = 2.602, 95% CI 1.197-5.654) and 2-category TNM classification (P= 0.007, HR = 3.080, 95% CI 1.360-6.977) were independent high risks for BM. The two-stage system was not related with BM (P= 0.273), neither ECDFS (P= 0.570), DFS (P= 0.283) nor OS (P= 0.728). Whereas the 2-category TNM classification was significantly associated with BM (P = 0.009, HR = 2.525), ECDFS (P= 0.006, HR = 1.786), DFS (P= 0.005, HR = 1.795) and OS (P = 0.010, HR = 2.002). Conclusions: HART and 2-category TNM classification were independent risk factors for BM after PCI in SCLC. Patients with HART or stage IIIB-IV were more likely to develop BM. The 2-category TNM classification was of greater prognostic value than the two-stage system. We propose a novel hypothesis that the IASLC staging criteria for limited stage and extensive stage could be further modified to TNM stage IA-IIIA and stage IIIB-IV, respectively. Further large-scale studies are needed to confirm our findings.