bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of DLL3 expression in gastroenteropancreatic neuroendocrine neoplasms with loss of RB1 and prognostic significance.
Authors: Liverani Chiara , Bongiovanni Alberto , Mercatali Laura , Pieri Federica , Spadazzi Chiara , Miserocchi Giacomo , Di Menna Giandomenico , Foca Flavia , Ravaioli Sara , De Vita Alessandro , Cocchi Claudia , Recine Federica , Ibrahim Toni 
Published: May 2020

4611 Background: Neuroendocrine neoplasms (NENs) are a rare subgroup of tumors with challenging management due to their unpredictable and heterogeneous behaviour. The identification of clinically useful biomarkers is a top priority need in this disease. The negative notch regulator DLL3 has gained increasing attention in small cell lung carcinoma, large cell neuroendocrine carcinoma and neuroendocrine prostate cancer, confirming the tumor suppressor function of Notch-1 signaling in neuroendocrine cells. Methods: A retrospective immunohistochemical analysis of DLL3, PD-L1 and RB1 was performed on FFPE samples from 43 patients with gastroenteropancreatic (GEP)-NENs and correlated with clinical characteristics. Results: DLL3 was expressed in high-grade (G3) GEP-NENs. The presence of DLL3 was significantly associated with poorly differentiated NEC (77.8% positive tumors), while none of the patients with well-differentiated NET expressed this marker. Expression of DLL3 was correlated with loss of RB1 and negative 68Ga-PET/CT scan. The 85.7% of DLL3- positive tumors showed loss of RB1 expression, while only 1 out of 35 DLL3- negative tumors had RB1 loss. DLL3 was expressed in 75% of patients with negative 68Ga-PET/CT, while only in 25% of patients with positive 68Ga-PET/CT scan. The presence of DLL3 was negatively associated with PFS and OS. Median PFS was 41.9 months in DLL3-negative patients versus 7.9 months in DLL3-positive patients; median OS was 72.9 months in DLL3-negative patients versus 11.7 months in DLL3-positive patients. No correlation was found with DLL3 and PD-L1 expression. The presence of PD-L1 was not associated with any clinical characteristics. Conclusions: DLL3 is expressed in high grade GEP-NENs and is associated with loss of RB1, negative 68Ga-PET/CT scan and unfavourable clinical outcome. The presence of DLL3 discriminates poorly differentiated NEC from well-differentiated NET. DLL3 could represent the ideal prognostic factor to stratify patients with GEP-NENs and a candidate therapeutic target in NEC patients.
Inefficacy of chromogranin a assays as neuroendocrine tumor diagnostic tools compared to the NETest.
Authors: Malczewska Anna , Kidd Mark S. , Kitz Alexandra , Kos-Kudla Beata , Modlin Irvin Mark 
Published: May 2020

4612 Background: Chromogranin A (CgA) remains a commonly used diagnostic and monitoring tool for neuroendocrine tumor disease despite NCCN guidelines identifying it as a category 3 (major concerns about utility) biomarker. Several commercial assays have been developed to measure this protein (or its fragments) and are available both at CLIA-certified laboratories (USA) as well as in NET Centres of Excellence (CoEs - Europe). CgA is typically reimbursed by insurance companies and appears in several guidelines (e.g., ENETS). We sought to directly evaluate the accuracy of detecting NET disease using two different CgA assays, one in the USA (NEOLISA, EuroDiagnostica, IBL-America, CLIA-certified laboratory) and one in an ENETS CoE (CgA ELISA, Demeditec Diagnostics, Germany). We compared the results to the NETest, a circulating mRNA assay, recently validated as an IVD for NETs. Methods: Patients: NETs ( n=258) including lung: n=43; duodenum n=9; gastric: n=44; pancreas: n=67; small bowel: n=40; appendix: n=10; rectum: n=45. No image-evidence of disease ( n=122) (IND) and image-positive disease (IPD) ( n=136). CgA assays (plasma): NEOLISA, ULN >108ng/ml, DD: ULN>99ng/ml. Data mean±SEM. NETest (whole blood): qRT-PCR - multianalyte algorithmic analyses, CLIA-laboratory. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation & McNemar-test. Results: In the entire group ( n=258), NEOLISA assay CgA levels were significantly ( p<0.0001) higher (216±91ng/ml) vs. the DD-assay (76±8ng/ml). The assays exhibited a high concordance in output (Pearson r=0.81, p<0.0001), but there were 10.9% ( n=31) discordant results. This reflected the NEOLISA assay detecting more CgA-positive samples. IPD group: CgA-positives were detected in 48/136 (35%, NEOLISA) vs. 28 (21%, DD-assay). McNemar’s Chi2=15.04, p<0.001 OR: 11.0, indicating the NEOLISA was significantly better than the DD-assay. The NETest, in contrast, was positive in 135/136 (99%; OR: 87-106, p<0.0001). IND group: CgA-positives were detected in 12/122 (10%, NEOLISA) vs. 9 (7%, DD-assay; p=NS). The majority (75%) of positives were associated with gastric NETs. The NETest was positive in 7 (6%); 4 were gastric NETs and 3 exhibited elevated CgA. Conclusions: Two standard CgA assays used for NET management (one accepted by Medicare in the USA, the second used at a CoE in Europe) only detect NET disease in 21-35% of cases. In contrast, a circulating mRNA fingerprint, the NETest, is ~99% accurate for detecting NET disease.
POLO: Quality-adjusted (QA) progression-free survival (PFS) and patient (pt)-centered outcomes with maintenance olaparib in pts with metastatic pancreatic cancer (mPaC).
Authors: Yoo Hyun Kyoo , Kindler Hedy L. , McCutcheon Susan , McGuinness David , Patel Nikunj , Hettle Robert , Goodbody Rory , Joo Seongjung , Locker Gershon Y. , Golan Talia 
Published: May 2020

4626 Background: In the Phase III POLO trial (NCT02184195), maintenance olaparib significantly prolonged PFS vs placebo in pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPaC (median 7.4 vs. 3.8 months). The aim of maintenance treatment is to extend PFS and survival without compromising health-related quality of life due to adverse events. The duration of time spent without symptoms or toxicities (TWiST) and the QA-PFS were assessed in a post hoc analysis of the POLO trial. Methods: Patients were randomized 3:2 to receive maintenance olaparib (tablets; 300 mg bid) or placebo. Restricted mean (RM)-PFS was calculated by estimating the area under the Kaplan–Meier PFS curve between randomization and 29.8 months after randomization (maximum follow-up for the placebo arm in POLO). Patient-centered outcomes were assessed by QA-PFS (derived from the product of the EQ-5D-5L single-index utility score from randomization to disease progression and RM-PFS) and TWiST (RM-PFS minus time with toxicity after randomization). Results: RM-PFS was significantly longer with olaparib, with a between-treatment difference of 4.8 months ( P=0.009; Table). Over this period, no significant or meaningful differences in mean EQ-5D-5L index were observed between treatment groups. The corresponding mean QA-PFS was significantly longer with olaparib vs placebo. TWiST analysis demonstrated a benefit with olaparib over placebo (Table): between-arm difference, 3.8 months ( P=0.039) for the primary analysis (criteria 1: grade ≥2 nausea, vomiting or fatigue). Sensitivity analysis (criteria 1 plus abdominal pain, diarrhea, decreased appetite or constipation) also revealed a trend toward benefit with olaparib (difference: 3.4 months, P=0.062). Conclusions: Consistent with the primary PFS analysis of the POLO trial, RM-PFS and QA-PFS were significantly longer with maintenance olaparib than with placebo. As demonstrated by the findings of the TWiST analyses, the PFS benefit observed with olaparib in pts with a gBRCAm and mPaC persists even when symptoms of toxicity are considered. Clinical trial information: NCT02184195 . [Table: see text]
FOLFIRINOX de-escalation in advanced pancreatic cancer (aPC): A multicenter real-life study.
Authors: Chevalier Hortense , Vienot Angélique , Lièvre Astrid , Edeline Julien , El Hajbi Farid , Peugniez Charlotte , Vernerey Dewi , Meurisse Aurelia , Hammel Pascal , Neuzillet Cindy , Borg Christophe , Turpin Anthony 
Published: May 2020

4639 Background: FOLFIRINOX (5FU, irinotecan, and oxaliplatin) is a reference first line (L1) of chemotherapy (CT) in fit patients (Pts) with advanced pancreatic cancer (aPC). Limiting toxicities (in particular, neuropathy) are frequent and maintaining quality of life without a lack of efficacy is a crucial need. Modalities and efficacy of maintenance strategy in aPC remain scarcely studied. Our study describes the French practices of a FOLFIRINOX de-escalation and maintenance in a real-life multicentric cohort. Methods: We performed a retrospective multicentric study in 5 French centers. Pts receiving FOLFIRINOX L1 for aPC were recruited between January 2011 and December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan in patients without tumor progression, after at least 4 cycles of FOLFIRINOX. Maintenance schedules were oral capecitabine or intravenous (IV) 5FU, FOLFOX or FOLFIRI. Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1) and, in case of reintroduction of FOLFIRINOX, second progression free survival (PFS2). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 321 patients included, 147 (46%) received a maintenance therapy. Median age was 60.0 (53-66), 35 (24%) had locally advanced PC and 91 (62%) had metastatic PC. The median number of cycles of FOLFIRINOX was 9.0 (6.0-11.0). Median OS was 16.1 months (95%CI=13.7-20.3). Median PFS1 was 9.4 months (95%CI=8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%), vs fluoropyrimidine (FP) in 52 (35%) and FOLFOX in 25 (17%). Among 118 Pts who received a maintenance CT with FP or FOLFIRI, there was no difference in PFS1 (median: 10.1 vs 9.0, respectively, p=0.33) or OS (median: 16.6 versus 18.7, p=0.86) between the 2 maintenance regimens. After progression under maintenance CT with FOLFIRI or FP, reintroduction of FOLFIRINOX was performed in 20.2% of Pts, with a median PFS2 of 2.8 months (95%CI=2.0-22.3). The rates of G3-4 toxicity were significantly higher during FOLFIRI maintenance CT than with FP (41% vs 22%, p=0.03), especially neuropathy (73% vs 9%). Conclusions: FOLFIRINOX de-escalation in aPC is largely used in France. Fluoropyrimidine maintenance chemotherapy appears to be as effective as FOLFIRI.
Ramucirumab in patients with advanced HCC and elevated alpha-fetoprotein (AFP): Outcomes by treatment-emergent ascites.
Authors: Zhu Andrew X. , Ikeda Masafumi , Galle Peter R. , Yamashita Tatsuya , Llovet Josep , Liang Kun , Wang Chunxiao , Sakaguchi Sachi , Abada Paolo , Widau Ryan C , Kudo Masatoshi 
Published: May 2020

4644 Background: REACH and REACH-2 investigated ramucirumab (RAM) vs placebo (PL) in patients (pts) with advanced HCC following sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. Ascites is common in HCC and associated with poorer outcomes. An exploratory analysis of outcomes by treatment-emergent (TE)-ascites was done. Methods: Pts with HCC, Child-Pugh A, ECOG PS ≤1, prior sorafenib, and no clinically meaningful ascites were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or PL Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was done. OS and PFS were evaluated by Kaplan-Meier estimator and Cox models. Prognosis of TE-ascites in OS was evaluated by multivariate Cox models (adjusted for baseline ECOG PS, AFP, macrovascular invasion (MVI), and treatment [trt]). Results: Baseline characteristics were generally balanced between TE-ascites and non-ascites pts; however, more pts with ascites had MVI at baseline. Any-grade ascites was reported at a higher rate in RAM than PL (66 [21%] vs 33 [15%] pts, respectively), with most being low grade. Rate of Gr ≥3 ascites was similar between arms (15 [5%] vs 9 [4%] pts). Median time to onset (43 vs 47 days) and median duration of ascites (13 vs 18 days) were similar in RAM vs PL, with furosemide (22%) and spironolactone (19%) as most common trt and paracentesis (18%) as most common procedure for ascites in both arms. Ascites trended as a prognostic factor for OS after adjustment (with vs without; HR=1.3, 95% CI: 0.99, 1.62). Ascites was more commonly linked with hypoalbuminemia (odds ratio 4.9, 95% CI: 2.5, 9.3), but was not associated with proteinuria or hypertension. TEAEs occurred more frequently in pts with ascites in both arms. The most frequent Gr ≥3 TEAE in pts with ascites was hypertension. One RAM pt discontinued trt due to ascites. RAM trt was beneficial irrespective of presence of ascites (Table), and pts with ascites received more post-discontinuation therapy on RAM than PL (18% vs 6%). Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit in pts who did or did not experience TE-ascites. RAM was well tolerated and no new safety findings were observed. Clinical trial information: NCT011400347; NCT02435433 . [Table: see text]
SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).
Authors: Choueiri Toni K. , Heng Daniel Yick Chin , Lee Jae-Lyun , Cancel Mathilde , Verheijen Remy B , Mellemgaard Anders , Ottesen Lone , Frigault Melanie M. , L'Hernault Anne , Szijgyarto Zsolt , Signoretti Sabina , Albiges Laurence 
Published: May 2020

5002 Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]
Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer.
Authors: Srinivasan Ramaprasad , Gurram Sandeep , Al Harthy Munjid , Singer Eric A. , Sidana Abhinav , Shuch Brian M. , Ball Mark Wayne , Friend Julia C. , Mac Lisa , Purcell Erin , Vocke Cathy , Kong Heidi H , Cowen Edward W. , Choyke Peter L. , Malayeri Ashkan A. , Long Lori , Shih Joanna H. , Merino Maria J. , Linehan W. Marston 
Published: May 2020

5004 Background: HLRCC is a familial cancer syndrome associated with a type 2 papillary RCC (pRCC) variant. HLRCC is caused by germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH). FH inactivation results in VHL-independent upregulation of hypoxia inducible factor, a reliance on aerobic glycolysis, and activation of the NRF2 pathway, features also shared by some sporadic pRCC tumors. We hypothesized that the metabolic alterations underlying these tumors would be susceptible to targeted therapy with a combination of bevacizumab and erlotinib. Methods: Patients with advanced pRCC were eligible to enroll on this phase II study. To enrich for patients with FH deficiency, those with 1) HLRCC and 2) sporadic pRCC were enrolled into parallel, independent cohorts. All patients received bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily. Patients who had received no more than two agents targeting the VEGFR pathway were included. Patients remained on treatment until unacceptable toxicity or progression. The primary endpoint was overall response rate (ORR); secondary endpoints were progression free survival (PFS) and duration of response. Results: A total of 83 patients with pRCC, including 42 in the HLRCC cohort and 41 in the sporadic cohort were enrolled on study. The majority of patients were IMDC intermediate risk (53/83, 64%) and 27 (33%) had at least one prior treatment. The ORR was 51% (42/83; 95% CI, 40 – 61) in all patients, 64% (27/42; 95% CI, 49 – 77) in the HLRCC cohort, and 37% (15/41; 95% CI, 24 – 52) in the sporadic cohort. The median PFS was 14.2 months (95% CI, 11.4 – 18.6) in all patients, 21.1 months (95% CI, 15.6 – 26.6) in the HLRCC cohort, and 8.7 months (95% CI, 6.4 – 12.6) in the sporadic cohort. The majority of treatment related adverse events (TRAEs) were grade 1 or 2 with the most common being acneiform rash (92%), diarrhea (77%), proteinuria (71%), and dry skin (61%). Grade ≥3 TRAEs occurred in 47% of patients, including hypertension (34%) and proteinuria (13%), with one patient (1.2%) with a grade 5 GI hemorrhage possibly related to bevacizumab. Conclusions: The combination of bevacizumab and erlotinib is well tolerated and is associated with encouraging activity in advanced pRCC, particularly in patients with FH deficient tumors. This is the first and largest prospective study in HLRCC and provides the basis for considering bevacizumab and erlotinib as a preferred option in a patient population that has no widely accepted standard. Clinical trial information: NCT01130519 .
Optimized management of nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma (RCC): A response-based phase II study (OMNIVORE).
Authors: McKay Rana R. , Xie Wanling , McGregor Bradley Alexander , Braun David A. , Wei Xiao X. , Kyriakopoulos Christos , Zakharia Yousef , Maughan Benjamin Louis , Rose Tracy L , Stadler Walter Michael , McDermott David F. , Harshman Lauren C , Choueiri Toni K. 
Published: May 2020

5005 Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]