bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.
Authors: Kelly Ronan Joseph , Zaidi Ali Hussainy , Smith Matthew A , Omstead Ashten N , Kosovec Juliann E , Matsui Daisuke , Martin Samantha A , DiCarlo Christina , Werts E. Day , Silverman Jan F , Wang David H. , Jobe Blair Anderson 
Published: September 2018

4060 Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.
Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis.
Authors: Teufel Michael , Köchert Karl , Meinhardt Gerold , Bruix Jordi 
Published: September 2018

4078 Background: REG is a multikinase inhibitor which improved overall survival (OS; HR 0.63, 95% CI 0.50, 0.79; P<0.0001) and time to progression (TTP; HR 0.44, 95% CI 0.36, 0.55; P<0.0001) compared with placebo in patients with HCC who progressed during prior sorafenib treatment in the RESORCE trial. This exploratory analysis evaluated the impact of baseline AFP and c-Met on REG treatment benefit (OS and TTP) in the RESORCE trial. Methods: Circulating AFP and c-Met protein (shed ectodomain) levels were quantified by a Luminex assay (Myriad RBM) in plasma samples collected at baseline from patients enrolled in the RESORCE trial. Valid biomarker data were available from 497 (AFP) and 499 (c-Met) out of 573 patients. Patients were subgrouped according to the median protein concentration (high vs low), and the treatment effect HR and its 95% CI were evaluated using a Cox proportional hazards model. The predictive effect was modeledas a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Results: Baseline characteristics of patients were balanced across protein subgroups. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P<0.001) and c-Met (HR 1.32, CI 95% 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for TTP (HR 1.05, 95% CI 1.03, 1.07; P<0.001). REG treatment benefit for both OS and TTP was independent of AFP and c-Met protein expression (Table). The protein–treatment interaction effect was not statistically significant. Conclusions: The treatment benefit of REG in patients with HCC was independent of AFP and c-MET protein expression at baseline. So far, no single protein has been associated with REG clinical benefit. Clinical trial information: NCT01774344. [Table: see text]
Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.
Authors: Qin Shukui , Kim Tae-You , Lim Ho Yeong , Ryoo Baek-Yeol , Scheele Jürgen , Zhou Dongli , Becker Andreas , Cheng Ann-Lii 
Published: September 2018

4087 Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival > 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.
Biomarker prediction of efficacy to vandetanib plus gemcitabine in a phase II double blind multicenter randomized placebo-controlled trial in locally advanced or metastatic pancreatic carcinoma.
Authors: Neoptolemos John P. , Palmer Daniel , Greenhalf William , Ghaneh Paula , Jackson Richard , Evans Anthony , Shaw Victoria , Wadsley Jonathan , Valle Juan W. , Wasan Harpreet , Falk Stephen , Cunningham David , Coxon Fareeda Y. , Ross Paul J. , Wadd Nick , Hickish Tamas , Costello Eithne , Campbell Fiona , Rawcliffe Charlotte , Middleton Gary William 
Published: September 2018

4104 Background: We investigated the potential of biomarkers to predict efficacy of vandetanib and gemcitabine in patients with locally advanced (N = 41) or metastatic (N = 101) pancreatic cancer in a phase II double-blind multicentre randomised placebo-controlled trial. Methods: All patients were 18y or above, (ECOG = 0-2), with at least 3 mths life expectancy had gemcitabine (1000mg/m2 30min iv wkly for 7 wks, followed by a 1wk break, then cycles of wkly treatment for 3wks with a 1-wk break) and randomly assigned to 300mg/d vandetanib or placebo once daily until disease progression. The primary outcome was overall survival (OS) by intention to treat. A panel of potential biomarkers was tested to predict best survival with vandetanib and gemcitabine. Results: 142 patients were randomised, median FU = 24·9 mths with 131 deaths. The median (95% CI) OS in the 70 gemcitabine-placebo patients was 8·95 (6·55-11·7) mths and 8·83 (7·11-11·6) mths in the 72 gemcitabine-vandetanib patients (HR = 1·21, 95% CI = 0·85, 1·73; log rank X21df = 1·1; P = 0·303). A CTCAE V.4.02 rash grade 2 or above occurred in 4 (6 %) of 70 placebo patients versus 14 (19%) of 72 vandetanib patients. The median OS for the 14 vandetanib patients and with rash was 11·92 (10·89 – NA) mths, 7·76 (4·34 – 11·5) mths for the 58 vandetanib patients and without rash and 8·95 (6·55 – 11·7) mths for the gemcitabine-placebo patients (log rank Χ2 2df = 7·23; P = 0·03). We identified two biomarkers that could select patients for response to vandetanib (JN101, JN102). The biomarker combination was present in 26 patients with median OS of 12.1 (10.9, 16.0) mths versus 8.15 (6.67, 11.7) mths for 23 patients with the same biomarker profile in the placebo group (HR = 0.53 [0.29, 0.97], p = 0.0396). A logistic regression model showed that patients with JN102 were more likely to develop a rash (OR =0.81 [0.713, 0.925] p = 0.002). Conclusions: A two biomarker combination and a rash grade 2 or above may predict response to vandetanib and gemcitabine. This requires prospective evaluation. Clinical trial information: 96397434.
A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts).
Authors: Bekaii-Saab Tanios S. , Starodub Alexander , El-Rayes Bassel F. , O'Neil Bert H. , Shahda Safi , Ciombor Kristen Keon , Noonan Anne M. , Hanna Wahid Tewfik , Sehdev Amikar , Shaib Walid Labib , Mikhail Sameh , Neki Anterpreet S. , Oh Cindy , Li Youzhi , Li Wei , Borodyansky Laura , Li Chiang 
Published: September 2018

4106 Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]
Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT).
Authors: Motzer Robert J. , Haas Naomi B. , Donskov Frede , Gross-Goupil Marine , Varlamov Sergei , Kopyltsov Evgeny , Lee Jae-Lyun , Melichar Bohuslav , Rini Brian I. , Choueiri Toni K. , Zemanova Milada , Wood Lori A , Fahlenkamp Dirk , Reaume Martin Neil , Stenzl Arnulf , Bao Weichao , Aimone Paola , Doehn Christian , Russo Paul , Sternberg Cora N. 
Published: September 2018

4507 Background: PROTECT (NCT01235962) evaluated the efficacy and safety of pazopanib (PAZ) versus placebo in patients (pts) with locally advanced renal cell carcinoma (RCC) post nephrectomy. Methods: 1538 pts with resected pT2 (high grade), pT3 or greater clear cell RCC were randomly assigned to PAZ or placebo for 1 year. The starting dose (800 mg) following treatment of 403 pts was lowered to 600 mg to improve tolerability and primary endpoint was changed to disease-free survival (DFS) with PAZ 600 (N = 1135). Primary analysis was performed after 350 DFS events in intent-to-treat (ITT) PAZ 600, and DFS follow-up analysis was performed after an additional 12 months. Secondary endpoints included DFS with ITT PAZ 800 and ITT ALL, and safety. Results: Disease characteristics were similar between arms. The primary analysis results of DFS ITT 600 were not significant [HR: 0.862; 95% CI, 0.699, 1.063; p = 0.165] (Table). The secondary endpoint of DFS in ITT PAZ 800 and ITT ALL yielded 31% and 20% risk reduction, respectively. Updated DFS analysis in ITT 600 showed a higher HR with longer follow up. Increased ALT and AST were the most common adverse events leading to treatment discontinuation in the PAZ 600 (ALT 16% and AST 5%) and PAZ 800 (ALT 18% and AST 7%) groups. Conclusions: The study did not meet the primary DFS endpoint in ITT 600; however, a 31% decrease in the risk of recurrence was observed in ITT 800. The safety profiles in the 600 mg and 800 mg groups were similar and consistent with PAZ prior experience. Clinical trial information: NCT01235962. [Table: see text]
DNA damage repair and response (DDR) gene alterations (alt) and response to PD1/PDL1 blockade in platinum-treated metastatic urothelial carcinoma (mUC).
Authors: Teo MinYuen , Seier Kenneth , Ostrovnaya Irina , Regazzi Ashley Marie , Kania Brooke Elizabeth , Moran Meredith Maisie , Cipolla Catharine Kline , Bluth Mark J. , Chaim Joshua , Al-Ahmadie Hikmat , Solit David B. , Funt Samuel , Wolchok Jedd D. , Iyer Gopa , Snyder Charen Alexandra , Bajorin Dean F. , Rosenberg Jonathan E. , Callahan Margaret K. 
Published: September 2018

4509 Background: Somatic DDR alts are associated with increased mutation load (ML) and improved clinical outcomes for platinum-treated mUC (Teo et al, CCR 2017). We examined the relationship between DDR alts and response to PD1/PDL1 blockade. Methods: mUC pts enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT) were identified. Pts were dichotomized based on presence of alts in a panel of 34 DDR genes. Analyses were performed based on: (1) any DDR alts and (2) deleterious DDR alts (frameshift, splice site, nonsense or Hotspot point mutations). Study endpoint was overall response (OR) per RECIST. ML was defined as total number of nonsynonymous mutations by MSK-IMPACT. Fisher exact, Wilcoxon rank sum, and stratified logistic regression were used. Results: Fifty two pts were identified (atezo: n=18, nivo: n=34). Median age was 67 years (range: 32 – 84) and majority (44) was male. Median platinum-free interval was 10.2 months (range: 0.3 – 150.4). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) pts (including 2 MSI and 1 POLE). OR rate was 46.2%. Responses were associated with DDR alts but not with age, gender, treatment, platinum-free interval or ML (table). In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with ML as a continuous variable (p=.051). While DDR alts were associated with higher ML (all: p=.001, deleterious: p=.004), the effect of DDR alts on OR remained significant regardless of ML (>median: p=.027; ≤median: p=.023), indicating that the effect of DDR was independent of ML. Conclusions: DDR alts appeared to be associated with OR to PD1/PDL1 blockade and should be integrated into future validation efforts along with other potential predictors of response. [Table: see text]
Association of on-treatment plasma HGF levels with overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (INF) +/- bevacizumab (BEV): Results from CALGB 90206 (Alliance).
Authors: George Daniel J. , Halabi Susan , Starr Mark D. , Hurwitz Herbert , Brady John C. , Barak Ian , Morris Michael J. , Rini Brian I. , Small Eric Jay , Kim Won , Taplin Mary-Ellen , Nixon Andrew B. 
Published: September 2018

4522 Background: Elevated baseline HGF levels were associated with shorter OS in pts treated with BEV+INF. We evaluated on-treatment HGF levels to describe treatment-related changes and associations with outcome. Methods: We analyzed baseline EDTA plasma samples from 310 pts (148 INF; 162 BEV+INF) using an optimized multiplex ELISA platform for HGF at baseline and after 4-weeks (wks) on treatment. Primary endpoint of this analysis was OS. The Kaplan-Meier estimated the OS distribution and the proportional hazards model tested the prognostic importance of change at 4-wks from baseline in HGF levels in predicting OS, adjusting for treatment arm, bone metastases and stratification variables. Results: The median baseline HGF level in 310 pts was 161.4 pg/ml. Elevated HGF at 4-wks (>median) was associated with a worse OS (median OS = 14 vs 27 months; adjusted hazard ratio (HR)= 1.75, p< 0.0001). Only 9/155 pts (5.8%) with baseline HGF levels ≤ median developed elevated HGF (>median) at 4-wks; 66/155 pts (43%) with baseline HGF levels >median lowered HGF (<median) at 4-wks from baseline. Compared to pts with persistently elevated HGF levels, a decline in HGF levels at 4-wks (< median) was associated with improved OS (19 vs 13 months, adjusted HR=1.41, p=0.043). Conclusions: In RCC pts with low baseline HGF levels (< median), levels remain consistently low and are associated with improved OS. Conversely, in pts with high baseline HGF levels results are split; some patients continue to have high levels on treatment and are associated with a worse OS, suggesting that, HGF predicts for therapeutic benefit and represents a potential mechanism of resistance. Support: U10CA180821, U10CA180882. Clinical trial information: NCT00072046 .
Immune response results from vesigenurtacel-l (HS-410) in combination with BCG from a randomized phase 2 trial in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Steinberg Gary D. , Shore Neal D. , Karsh Lawrence Ivan , Bailen James L. , Bivalacqua Trinity , Chamie Karim , Cochran James S. , David Richard , Grubb Robert L. , Harb Wael A. , Holzbeierlein Jeffrey M. , Kamat Ashish M. , Trabulsi Edouard John , Walsh William Vincent , Williams Michael Brandon , Wolk Fredrick , Woods Michael , Price Melissa Leigh , Early Brandon , Schreiber Taylor Houghton 
Published: September 2018

4531 Background: Vesigenurtacel-L (HS-410) is a vaccine comprised of an allogeneic cell line, selected for high expression from a series of bladder tumor antigens, and transfected with gp96-Ig. Cell-secreted gp96-Ig delivers these cell-derived antigens to a recipient's own antigen presenting cells, activating CD8+ cytotoxic T cells. Here we present the secondary immune outcomes from a randomized Phase 2 trial with HS-410 in combination with BCG in NMIBC. Trial ID NCT02010203. Methods: 78 patients with intermediate- (n = 5) or high-risk (n = 73) NMIBC who are either BCG-naïve or recurrent, with or without carcinoma in situ (CIS), were enrolled 1:1:1 to one of two doses of HS-410 (either 106 or 107cells/dose) or placebo in combination with 6 weeks of induction BCG, followed by 6 more weeks of HS-410 in the induction phase. Maintenance treatment consisted of 3-weekly treatments at the following timepoints: 3 mo., 6 mo., 12 mo. Concurrently, 16 patients (1 int. risk, 15 high-risk) were enrolled in an open-label monotherapy HS-410 arm for patients who did not receive BCG. The primary endpoint was 1-year RFS. Secondary immune evaluations include ELISPOT, tumor IHC, tumor antigen profiling, flow cytometry, urine cytokine analysis, and T cell receptor sequencing. Results: HS-410 treatment was well tolerated; AE profiles were similar across the treatment arms. HS-410 antigen expression showed prominent overlap with patient tumors. IFNγ ELISPOT assay demonstrated a high baseline response to HS-410; responses to overlapping peptide pools of HS-410 derived antigens defined immune responders (doubling of IFNγ-secreting cells). IHC demonstrated that ~60% of NMIBC patient tumor biopsies were TIL negative at baseline (n = 84), but that only ~15% of tumor biopsies were TIL negative post treatment (n = 40). Thus, TIL status may be used to define a responder and non-responder population to HS-410. Conclusions: Vesigenurtacel-L is well-tolerated, and immunologic responses consistent with vaccine mechanism of action may correlate with efficacy and suggest future biomarkers. Vesigenurtacel-L warrants further investigation as a potential treatment for NMIBC. Clinical trial information: NCT02010203.