bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.
Authors: Lum Lawrence G. , Le Tri Minh , Choi Minsig , Thakur Archana , Reilley Matthew , Kunk Paul Raymond , Deol Abhinav , Ballen Karen K. , Kindwall-Keller Tamila L. , Schalk Dana , Kubicka Ewa , Huang Manley , Philip Philip Agop , Aoun Hussein , Dyson Gregory , Liu Qin , Shields Anthony Frank 
Published: May 2019

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 1010 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 1010 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 1010 BATs/infusion over 4 weeks for a total of 8 x 1010 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3rd infusion, and IFN-γ EliSpots increased from < 20 to 1000 IFN-γ EliSpots/106 PBMC (p < 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/106 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p < 0.04). Levels of IP-10 increased significantly (p < 0.04), and levels of IL-8 decreased but not significantly (p < 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.
A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma.
Authors: Sheng Xinan , Zhou Ai-Ping , Yao Xin , Shi Yanxia , Luo Hong , Shi Benkang , Liu Jiyan , Yu Guohua , He Zhisong , Hu Changlu , Han Weiqing , Fang Jianmin , Guo Jun 
Published: May 2019

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.
Active surveillance in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer information system (CKCis).
Authors: Kushnir Igal , Basappa Naveen S. , Ghosh Sunita , Lalani Aly-Khan A. , Soulieres Denis , Bjarnason Georg A. , Wood Lori , Dawe David , Kollmannsberger Christian K. , Heng Daniel Yick Chin , Kapoor Anil , Hansen Aaron Richard , Pouliot Frederic , Reaume M. Neil 
Published: May 2019

4516 Background: Active surveillance (AS) is a commonly used strategy in patients (pts) with low tumor burden or slow growing disease. However, few studies have assessed AS for mRCC compared to immediate treatment. We aimed to assess the outcomes and safety of AS in comparison to immediate systemic treatment for mRCC pts. Methods: Using CKCis, mRCC pts diagnosed between January 1, 2011 and December 31, 2016 were identified. AS strategy was defined as: (1) start of systemic therapy ≥6 months after diagnosis of mRCC; or (2) never receiving systemic therapy for mRCC with an overall survival (OS) ≥1 yr (OS ≥ 1 yr a surrogate to exclude pts not started on treatment due to poor prognosis). Pts starting systemic treatment < 6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until 1st line treatment failure (TTF) between the two cohorts were compared. Results: A total of 863 pts met criteria for AS (cohort A). Of these, 370 started treatment ≥ 6 months after their initial diagnosis (cohort A1) and 493 never received systemic treatment and were alive for ≥1 year (cohort A2). 848 pts received immediate systemic treatment (cohort B). Median age for pts in cohort A and B was 65.1 (19.0-91.5) vs. 62.2 yrs (23.1-87.1) (p < 0.0001). Sex distribution was not statistically different. Pts in cohort A had fewer sites of metastatic disease vs. cohort B ( < 0.0001) and 23% of pts in cohort A had metastasectomy vs. 5% in cohort B (P = < 0.0001). Five-year OS probability was significantly greater for cohort A than for cohort B (70.2% vs. 32.1%; P < 0.0001). After adjusting for IMDC risk criteria and age, both OS (HR 0.46, 0.38-0.56, P < 0.0001) and TTF (HR 0.79, 0.69-0.92, P = 0.0021) were greater in cohort A1 vs. B. For cohort A1 the median time on AS was 14.2 m (range 6 – 71). Conclusions: Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of pts may be safely observed without immediate initiation of systemic therapy. Prospective validation is required in the contemporary immunotherapy era.
Treatment (tx) characteristics of patients (pts) with locally advanced or metastatic urothelial cancer (mUC) receiving checkpoint inhibitor (CPI) monotherapy in a US clinical practice.
Authors: Morgans Alicia K. , Rahma Osama E. , Mhatre Shivani K. , Chuo Ching-Yi , Davies Jessica , Martinalbo Jorge , Davarpanah Nicole N. , Pachynski Russell 
Published: May 2019

4526 Background: Approval of anti–PD-L1/anti–PD-1 CPI agents has changed the mUC tx landscape, but real-world (RW) tx patterns are not well described. Here, we describe pt characteristics, time on tx (TOT), tx-cycle distribution, relative dose intensity (RDI) and subsequent tx for pts receiving atezolizumab (atezo), nivolumab (nivo) or pembrolizumab (pembro) monotherapy. Methods: Pts diagnosed with mUC who completed atezo, nivo or pembro in the first-line (1L) or prior-platinum second-line and beyond (2L+) settings by April 30, 2018, were identified from the US-based Flatiron Health electronic health record–derived database. TOT was defined as time from first to last CPI administration + 1 cycle, tx cycles as number of CPI doses received during TOT and RDI as ratio of actual to planned dose per week to reflect any dose interruption. Results: RW data from pts receiving atezo, nivo and pembro were analyzed (Table). Up to 38% of pts had ECOG PS > 1. Median TOT ranged from 2.1-2.8 mo, with overlapping 95% CIs; mean TOT ranged from 2.7-4.1 mo. Over 50% of pts had ≤ 4 tx cycles. 21%-38% of pts did not have RDI within 95%-105% of the labeled dose. Most common subsequent txs were platinum-based chemotherapy combinations with gemcitabine or taxanes (post–1L CPI) and taxane monotherapy or other CPI monotherapy/combinations (post–2L+ CPI). Conclusions: Here, we present the largest analysis of RW CPI use in mUC to date. Overall, this unadjusted descriptive analysis showed relative comparability of pt and tx characteristics and TOT across CPI-treated groups. Insights into RW tx allow for an understanding of how clinical trial data translate to broader pt populations, including those with ECOG PS > 1, and may be useful for practitioners. [Table: see text]
Prognostic value of sequential 18F-FDG + Na18F PET/CT (NaF+FDG PET) in metastatic genitourinary (GU) cancer patients (pts) treated with cabozantinib/nivolumab +/- ipilimumab (CaboNivoIpi).
Authors: Verdini Nicholas Peter , Lim Ilhan , Mena Esther , Lindenberg Liza , Mortazavi Amir , Pal Sumanta K. , Lara Primo , Graap Katherine , Mallek Marissa , Keen Corrine , Thompson Ryan , Mayfield Christian , Turrell Corinne , Cadena Jacqueline , Saraiya Biren , Lilly Ray L , Knopp Michael V. , Wright Chadwick , Steinberg Seth M. , Apolo Andrea B. 
Published: May 2019

4544 Background: NaF+FDG PET imaging are used to assess soft tissue and bone metastases. The prognostic value of NaF+FDG PET in GU cancer pts was assessed as a secondary endpoint within a phase I trial of combination CaboNivoIpi. Methods: NaF+FDG PET scans were collected at baseline and cycle (C)3 day (D)1 for 50pts. Up to 50 lesions/patient were analyzed at baseline, up to 10 lesions/organ in case of extensive disease. Lesion number and whole-body metabolic tumor volume (wMTV) were recorded at baseline, C3D1 and percent change for FDG and NaF scans. Whole-body total lesion glycolysis (wTLG) and its percent change was obtained for FDG scans. Parameters were evaluated with respect to OS using Kaplan-Meier and log-rank, with quartiles, then refined to show strongest distinction, adjusting p-values to account for this exploration. Parameters with strongest OS association were also analyzed for associations with OS in urothelial carcinoma (UC) pts. Results: 50 pts, (UC (n = 20); others (renal cell, prostate, urachal/adenocarcinoma, germ cell, penile, bladder squamous cell (n = 2-7 each)). Median (m) overall survival (OS) was 23.9 months (mo) (95% CI: 13.7mo – NE) with 29.7mo m potential follow up and mOS of 24.7mo (95% CI: 13.7mo-NE) for UC. For FDG in all pts, wMTV: baseline ≤ vs > 51.6, mOS (NR vs 10mo, p = .0006), C3D1 ≤ vs > 85 mOS (25.9mo vs 5.1mo, p = .0001), percent change (0/increase vs decrease, mOS 14mo vs 25.9mo, p = .015); wTLG: baseline ≤ vs > 178, mOS (NR vs 11.5mo, p = .011), C3D1 ≤ vs > 300, mOS (25.9mo vs 8.3mo, p < .0001), percent change decrease vs increase, mOS (25.9mo vs 14.0mo, p = .016); and lesion number: baseline ≤ vs > 13, mOS (25.9mo vs 9.9mo, p = .0090), C3D1 ≤ vs > 13 mOS (25.9mo vs 9.9mo, p < .0001) significantly predicted OS. In UC pts, wMTV percent change (0/increase vs decrease, mOS 14mo vs. 25.9mo, p = .057), wTLG percent change decrease vs increase, mOS (NR vs 8.4mo, p = .0015), and lesion number C3D1 ≤ vs > 13 mOS (25.9mo vs 2.8mo, p = .022) significantly predicted OS. NaF parameters failed to do so. Conclusions: FDG wMTV and wTLG at baseline, C3D1, and percent change and lesion number at baseline and C3D1, predicted OS in GU cancer pts on CaboNivoIpi. Clinical trial information: NCT02496208.
5-factor prognostic model for survival of patients with metastatic urothelial carcinoma receiving three different post-platinum PD-L1 inhibitors.
Authors: Sonpavde Guru , Manitz Juliane , Gao Chen , Hennessy Daniel , Makari Doris , Niegisch Guenter , Rosenberg Jonathan E. , Bajorin Dean F. , Grivas Petros , Apolo Andrea B. , Dreicer Robert , Hahn Noah M. , Galsky Matt D. , Necchi Andrea , Srinivas Sandy , Powles Thomas , Gupta Ashok Kumar , Abdullah Shaad Essa , Pond Gregory Russell 
Published: May 2019

4552 Background: A prognostic model for overall survival (OS) of metastatic urothelial carcinoma (mUC) was previously reported in the setting of post-platinum atezolizumab (Pond GR, GU ASCO 2018). This model was limited by employing only atezolizumab treated patients (pts), small size of the validation dataset and unclear applicability to other PD-1/L1 inhibitors. Hence, we constructed a robust prognostic model utilizing the combined atezolizumab cohort as the discovery dataset and used 2 separate validation datasets comprised of post-platinum avelumab or durvalumab treated pts. Methods: The discovery dataset consisted of pt level data from 2 phase I/II trials (IMvigor210 and PCD4989g) evaluating atezolizumab (n = 405). Pts enrolled on 2 separate phase I/II trials, EMR 100070-001 that evaluated post-platinum avelumab (n = 242) and CD1108 that evaluated durvalumab (n = 189) comprised the validation datasets. Cox regression analyses evaluated the association of candidate prognostic factors with OS. Factors were dichotomized and laboratory values were normalized by logarithmic transformation. Stepwise selection was employed to propose an optimal model using the discovery dataset. Discrimination and calibration were assessed in the avelumab and durvalumab datasets following the validation procedure by Royston and Altman (2013). Results: The 5 factors included in the optimal prognostic model in the discovery dataset were ECOG-PS (1 vs. 0; HR 1.80; 95% CI [1.36-2.36]), presence/absence of liver metastasis (HR 1.55; 95% CI [1.20-2.00]), number of platelets (HR 2.22; 95% CI [1.54-3.18]), neutrophil-lymphocyte ratio (NLR; HR 1.94; 95% CI [1.57-2.40]) and lactate dehydrogenase (LDH; HR 1.60; 95% CI [1.28-1.99]). There was robust discrimination of survival between low, intermediate and high-risk groups based on 0-1, 2-3 and 4 factors. The concordance of survival was 0.692 in the discovery and 0.671 and 0.775 in the avelumab and durvalumab validation datasets, respectively. Acceptable or good calibration of expected 1-year survival rate was observed. Conclusions: A 5-factor prognostic model is prognostic for survival across 3 different PD-L1 inhibitors (atezolizumab, avelumab, durvalumab) in this large study totaling 836 pts overall in the setting of post-platinum therapy for mUC. This model may assist in prognostic stratification and interpreting nonrandomized trials of post-platinum PD1/L1 inhibitors.
Multi-omics profiling of upper-tract urothelial carcinomas.
Authors: Malouf Gabriel G. , Yao Hui , Mouawad Roger , Roupret Morgan , Kurtz Jean-Emannuel , Spano Jean-Philippe , KHAYAT INSTITUT CANCEROLOGIE Meyer , Comperat Eva , Su Xiaoping 
Published: May 2019

4560 Background: Upper-tract urothelial carcinomas (UTUC) may harbor similar genetic profile as compared to bladder cancer, although frequencies of mutated genes have been shown to differ between them. However, to the best of our knowledge, the epigenetic landscapes of UTUC and their association with genetic alterations and clinico-pathological tumor features remain unknown. Methods: We collected 40 UTUC samples (20 non-muscle invasive (NMI) and 20 muscle-invasive (MI) and carried out whole-exome sequencing (n = 30), DNA methylation using Infinium EPIC arrays (n = 35) and RNA sequencing (n = 20). Validation was performed on TCGA bladder cancer dataset. Results: We identified 3232 putative somatic mutations with an average of 2.1+/-2.6 mutations per megabase. Significantly mutated genes were FGFR3 (50%), KDM6A (27%), MLL2 (27%) and ARID1A/B (23%). No difference in term of genetic alterations were identified between MI- and NMI- UTUC. Unsupervised hierarchical clustering using most variable DNA methylation probes uncovered two robust DNA methylation epi-clusters. Epi-cluster C1 (n = 23; 65.7%) displayed markedly higher DNA methylation relative to Epi-cluster C2 (n = 12; 34.3%). Notably, all muscle-invasive samples were enriched in C1 (16/17, 94.1%); conversely, C2 was enriched with non-muscle-invasive samples (p = 0.0009). Overall, 14.209 probes were significantly hypermethylated in C1 as compared to C2 epi-cluster; Gene Set Enrichment Analysis (GSEA) demonstrated that those were enriched for PRC2 targets (p = 6x10-65). Integrative analysis with tumor genetic landscape showed that C1 epi-cluster was enriched for mutations in SWI/SNF complex as compared to C2 (p = 0.02). We then applied our epi-signature to bladder TCGA cohort and obtained two similar epi-clusters associated with patients overall survival (p = 0.035). Conclusions: Our study demonstrate for the first time that difference between MI- and NM- invasive UTUC might be related to epigenetic rather than genetic alterations. This might pave the way for testing epigenetic therapies in non-muscle invasive tumors with the aim to prevent recurrence and distant metastasis.
Deferred cytoreductive nephrectomy among patients with newly diagnosed metastatic renal cell carcinoma treated initially with sunitinib.
Authors: Bhindi Bimal , Graham Jeffrey , Wells Connor , Donskov Frede , Pasini Felice , Lee Jae-Lyun , Basappa Naveen S. , Hansen Aaron Richard , Wood Lori , Kollmannsberger Christian K. , Kanesvaran Ravindran , Yuasa Takeshi , Ernst D. Scott , Srinivas Sandy , Rini Brian I. , Bowman I. Alex , Pal Sumanta K. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: May 2019

4578 Background: While the CARMENA trial prompts more caution with upfront cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC), 17% of patients in the sunitinib alone arm underwent deferred CN (dCN). Upfront systemic therapy has been proposed as a potential litmus test to identify patients suitable for CN, but data on outcomes are limited. We sought to characterize outcomes of dCN after upfront sunitinib relative to sunitinib alone. Methods: Patients with newly diagnosed mRCC receiving upfront sunitinib were identified from the International mRCC Database Consortium (IMDC) from 2006-2018. All CNs done after initial sunitinib were included, excluding CNs performed after sunitinib failure. The outcomes were overall survival (OS) and time to treatment failure (TTF). Kaplan Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias. Results: The cohort included 708 patients of whom 53 (7.5%) underwent dCN at a median of 6.5 months (IQR 3.5,10.5) from diagnosis. Patients in the dCN group were more likely to have better Karnofsky performance status (KPS), intermediate IMDC risk, fewer metastatic sites, and response to upfront sunitinib (Table). There were 604 deaths during a median follow-up of 63 months. Median OS and TTF with dCN were 43.5 and 19.8 months vs. 9.4 and 4.3 months without, respectively. Upon multivariable analysis, dCN remained significantly associated with OS (HR 0.45, 95%CI 0.31-0.65; p < 0.001) but not TTF (HR 0.73, 95%CI 0.52-1.01; p = 0.056). Conclusions: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted. [Table: see text]
Malignant pheochromocytoma (MP): A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Necchi Andrea , Shapiro Oleg , Jacob Joseph , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Ali Siraj Mahamed , Chung Jon , Reddy Prasanth , Miller Vincent A. , Alexander Brian , Schrock Alexa Betzig , Liu Nick , Ross Jeffrey S. 
Published: May 2019

4584 Background: We CGP to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 201,766 consecutive clinical cases, 44 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. 23 patients were females and 21 patients were males. There were 34 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site where the exact primary site was unknown. The primary tumor was used for sequencing in 14 (32%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (68%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (25%), TP53 (21%), SDHB (13%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 8 (18%) of cases involving SDHB (5 cases) and BRCA1, MEN1, and MSH2 (1 case each). The genomic signatures of primary MP were not significantly different from that obtained from sequencing of metastatic site biopsies. 0 (0%) of 5 MP stained positively for PD-L1 expression. The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. There 2 (5%) of MP with TMB ≥ 10 mutations/MB and 0 (0%) with TMB ≥ 20 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: Although the GA/tumor is relatively low for MP, CGP can reveal important potential therapy targets including RET, NF1 and FGFR1. MP do not reveal strong potential for immunotherapies with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies.