bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic correlates of response to capecitabine and temozolomide (CAPTEM) in pancreatic neuroendocrine tumors.
Authors: Lee Patrick , Blais Edik Matthew , Gong Jun , Osipov Arsen , Moshayedi Natalie , Thomassian Shant , Ng Camille , Chuy Jennifer W. , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Hendifar Andrew Eugene 
Published: June 2022

4124 Background: Despite the frequent use of capecitabine and temozolomide (CAPTEM) to treat metastatic, well-differentiated pancreatic neuroendocrine tumors (PNETs), no reliable genomic predictors of response currently exist. PNETs commonly harbor mutations in MEN1, ATRX, DAXX, and the PI3K/AKT/mTOR pathway. We sought to determine whether the mutational status of these genes correlates with response to CAPTEM. Methods: A retrospective cohort of PNET cases seen at Cedars-Sinai Medical Center or from Perthera’s Real-World Evidence Database included 23 patients who were treated with CAPTEM in 1st or 2nd line and had targeted next-generation sequencing (NGS) of their tumors available. Genomic alterations were correlated with progression-free survival (PFS) using multivariate Cox regression analysis. Results: We analyzed 23 PNET patients, 4 (17.4%) of whom had documented functional tumors. We identified MEN1 mutations as positively associated with CAPTEM response, but this effect was less pronounced for the subset with co-occurring DAXX mutations, which are commonly found alongside MEN1 alterations. With and without accounting for line of therapy, we found that PFS on CAPTEM was significantly longer in MEN1-mutated, DAXX-wildtype tumors compared to other mutation profiles ( P < 0.01, see Table). ATRX (67%) and PTEN (33%) alterations were also enriched in the MEN1-mutated/ DAXX-wildtype subset; however, other PI3K/AKT/mTOR alterations were common across all MEN1-mutated cases. Conclusions: We describe a novel genomic signature ( MEN1 mut/ DAXX wt) that correlates with PNET response to CAPTEM therapy and is exploratory in nature. Prospective validation of these associations is warranted while taking into account other therapies, histopathologic factors, and other genomic correlates. [Table: see text]
REGOMUNE: Phase II study of regorafenib plus avelumab in solid tumors—Results of the gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Portales Fabienne , Hollebecque Antoine , Metges Jean Philippe , Cassier Philippe Alexandre , Gomez-Roca Carlos A. , Bouteiller Fanny , Kind Michèle , Palussière Jean , Pernot Simon , Soubeyran Isabelle , Bessede Alban , Italiano Antoine 
Published: June 2022

4125 Background: There is no standard treatment for patients (pts) with advanced extra-pulmonary neuroendocrine tumors (NET) and carcinomas (NEC) after failure of chemotherapy in the metastatic setting. PD-1/PD-L1 expression is frequent in these tumors. Combining anti-PD1/PDL1 agents with anti-angiogenics has been shown to be synergistic in several tumor models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in pts with advanced or metastatic grade 2 or 3 (G2/3) gastroenteropancreatic (GEP)-NET or GEP-NEC. The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between May 2019 and Apr. 2021, 46 pts were enrolled in 6 centers. Median age was 63 (range 31 – 80). 10 pts presented with a NEC and 36 pts with a G2/3 NET. Median follow-up was 6.5 months (95% CI: 5.3 - 9.6). Median number of previous treatment lines was: 2 (range 0 – 8). 39 (84.8%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were : Hypertension (13% of pts), fatigue (13%), and diarrhea (11%). One death was related to the treatment. Among the 42 assessable pts, 7 (16.7%) achieved a partial response: 6 pts with a G2/3 NET and 1 patient with a NEC. 22 (52.4%) pts demonstrated stable disease, 22 (52.4%) pts had tumor shrinkage and 10 (23.8%) pts had progressive disease. 3 (7.1%) pts were inevaluable as per RECIST. The median duration of response was 15.5 months (95%CI: 3.7 - not reached (NR)). The median PFS and OS were 5.5 months (95% CI: 3.6 – 9.2) and NR respectively. One year OS rate was 69.4 % (95% CI: 45.1 % – 84.5 %). Conclusions: REGOMUNE is the largest prospective study ever conducted in pts with grade 2/3 GEP-NET or GEP-NEC refractory to cytotoxic chemotherapy. The R+A combination has significant clinical activity in pts with refractory disease. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
Targeted alpha-emitter therapy with 212Pb-DOTAMTATE in neuroendocrine tumor subjects who progressed following prior 177Lu/90Y-PRRT.
Authors: Delpassand Ebrahim , Esfandiari Rouzbeh , Tworowska Izabela , Torgue Julien , Hurt Jason Daniel , Nunez Rodolfo 
Published: June 2022

4128 Background: Targeted Alpha-Emitter Therapy (TAT) with 212Pb-DOTAMTATE has been shown to be safe and effective in subjects with neuroendocrine tumors (NET) who have not received previous PRRT, however, data is lacking for the use of TAT once progression occurs. Herein, we present the safety and efficacy of 212Pb-DOTAMTATE in subjects with recurrent NETs following prior 177Lu/90Y-PRRT. Methods: Subjects with biopsy-proven unresectable or metastatic SSTR expressing NETs from different primary sites with at least one measurable lesion who had received progressed after receiving prior PRRT were enrolled and received up to four 8-week cycles of 212Pb-DOTAMTATE at 67.6 μCi/kg/cycle. Response to treatment was measured per RECIST 1.1 criteria and by 68Ga/64Cu-DOTATATE PET/CT. Safety parameters were also obtained. Results: A total of 11 PRRT subjects were enrolled regardless of primary tumor location (pancreas (4), small bowel (3), midgut (1), ileum (1), thymus (1), and lung (1)). 8/11 subjects (73%) completed all four cycles. The mean cumulative dose was 20.9 mCi. As of January 2022, an objective radiological response (ORR) was demonstrated in 30% of evaluable subjects (1CR, 2PR, and 7 SD). In addition, 70% (7/10) evaluable subjects demonstrated a response per 68Ga/64Cu-DOTATATE PET/CT SSTR imaging. One hundred forty-five AEs were reported, with Grade 1 (79%). There were 23 (16%) Grade 2 AEs and 5 (3%) Grade 3/ 4 AEs. Of the AEs reported, 84 (58%) were considered possibly related, and 61 (42%) were considered not related or unlikely related. The most frequent AEs (reported in ≥ 4 subjects) include: alopecia (100%), fatigue (100%), nausea (91%), anemia (36%), alanine aminotransferase increased (36%), aspartate aminotransferase increased (36%) and lymphopenia (46%). Three SAEs were reported (achalasia, asthma exacerbation, and septic shock) one of which resulted in the death of the subject (septic shock). No SAEs were considered related to study drug. Conclusions: This is the first clinical trial of 212Pb-targeted alpha-emitter therapy in subjects with NETs who progressed following prior PRRT. The use of 212Pb-DOTAMTATE in the recurrent setting is highly effective with manageable toxicity and warrants further investigation. Clinical trial information: NCT03466216.
Do we need postoperative chemotherapy after preoperative FOLFIRINOX in resected borderline or locally advanced pancreatic cancer? A retrospective analysis.
Authors: Mari Roxane , Garnier Jonathan , Lapeyre-Prost Alexandra , Rochigneux Philippe , Dahel Yanis , Caillol Fabrice , Giovannini Marc , Turrini Olivier , Mitry Emmanuel , Chanez Brice 
Published: June 2022

4150 Background: Pancreatic ductal adenocarcinoma (PDAC) has poor outcome and surgical resection remains the only curative treatment. Post-operative (Post-Op) chemotherapy (CT) improves survival and FOLFIRINOX (FFX) regimen is the standard of care. Increasing number of patients with borderline resectable (BL) or locally advanced (LA) disease are treated with pre-operative (Pre-Op) CT with FFX. However, the benefit of Post-Op CT after Pre-Op FFX remains unclear. The aim of this study was to analyze the impact on survival of Post-Op CT in patients with resected BL or LA PDAC after Pre-Op FFX CT. Methods: 116 consecutive patients treated at the Institut Paoli-Calmettes comprehensive cancer center between 2014 and 2020 were retrospectively analyzed. All patients underwent pancreatectomy after Pre-Op FFX for a BL or LA PDAC. Patients who progressed or died within 3 months after surgery were excluded from the analysis. We compared median relapse-free survival (mRFS) and median overall survival (mOS) defined by time from surgery to relapse or death in patients who received or not Post-Op CT. Results: 116 patients (80% BL, 20% LA) were included: 82 received Post-Op CT (CT+) and 34 did not (CT-). The median number of Pre-Op FFX cycles was 4 in the CT+ group vs 6 in the CT- group. 24 (29.3%) patients received Post-Op FFX, 37 (45.1%) received Gemcitabine, 9 (11%) received Gemcitabine + Capecitabine, and 9 (11%) received a 5FU-based CT. Median time between surgery and first Post-Op CT cycle was 63 days. No difference in mRFS nor in mOS were found between CT+ and CT- groups: mRFS 15.0 vs 13.6 months, HR 1.1 [IC95% 0.69–1.77] and mOS 33.8 vs 36.1 months, HR 0.94 [IC95% 0.55–1.60]. Among patients with pathologic node positive disease (N+) (n = 79), mRFS was 13.9 months in the CT+ group vs 6.9 months in the CT- group (HR 0.68 [IC 0.35 – 1.19]), and mOS was 31.8 months in the CT+ group vs 16.5 months in the CT- group (HR 0.96 [IC95% 0.51-1.81]). Patients who received peri-operative (Peri-Op) FFX (n = 24) experienced longer mOS compared to patients who received Gemcitabine Post-Op CT: NR vs 33.8 months, HR 0.45 [IC95% 0.25-1.02]. Patients who received Peri-Op CT for a total of six months or more (n = 31) had increased mOS (55 vs 32 months, HR 0.61 [IC 95% 0.37- 1.11] and mRFS (16 vs 14 months HR 0.80, [IC95% 0.50 -1.31]) than patients receiving less than 6 months Peri-Op CT (n = 85) Conclusions: Post-Op CT does not clearly impact survival in BL or LA pancreatic cancer pretreated with Pre-Op FFX. We observed a trend in the N+ population for a survival benefit. Peri-Op FFX was associated with longer survival than Gemcitabine Post-Op regimen. Further randomized data are needed to assess the impact of Peri-Op FFX for these patients
Cross-trial validation of molecular subtypes in patients with metastatic clear cell renal cell carcinoma (RCC): The JAVELIN Renal 101 experience.
Authors: Saliby Renee Maria , Jammihal Tejas , Labaki Chris , Xie Wanling , Motzer Robert J. , Powles Thomas , Rini Brian I. , Albiges Laurence , Pal Sumanta K. , McKay Rana R. , Signoretti Sabina , Shukla Sachet A. , Van Allen Eliezer Mendel , Braun David A. , Choueiri Toni K. 
Published: June 2022

4531 Background: Vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (IO) combinations are a standard in mRCC. Molecular clusters of patients have been identified and correlated with outcomes in the phase 3 IMmotion151 (IM151) trial of atezolizumab + bevacizumab (IO+VEGF) vs. sunitinib (Sun) (Motzer, Cancer Cell 2020 & JAMA Oncol 2021). Avelumab+axitinib (AA) is an approved IO+VEGF combination in mRCC. This work aims to evaluate these clusters in patients from the phase 3 JAVELIN Renal 101 (JR101; NCT02684006 ) trial of AA vs. Sun. Methods: Bulk RNA-sequencing of primary and metastatic samples and clinical data (data cutoff: 28 January 2019) from JR101 were obtained. A random forest model designed to predict molecular clusters based on transcriptomic data was trained on the IM151 dataset. Using this model, patients from JR101 study were categorized into previously defined molecular subgroups. We then evaluated treatment outcomes including progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) from JR101 in relation to molecular subgroups. Results: The proportion of patients in each molecular subtype and across MSKCC risk groups were largely comparable between the 2 trials (accuracy: 81.6%; p=0.2). AA was generally superior to Sun. for PFS and ORR across all molecular subsets, including angiogenic and immune-based clusters (Table). Combining immune and/or cell cycle-enriched clusters 4+5 resulted in improved PFS (HR: 0.65; 95% CI: 0.44-0.97) for AA vs. Sun. Conclusions: We were able to largely validate the molecular clusters classification and some of the associations with survival outcomes from IM151 in the JR101 clinical trial cohort. Biomarkers of specific VEGF+IO combinations in mRCC should be prospectively validated in randomized trials. [Table: see text]
First-line therapy for elderly patients with advanced renal cell carcinoma (aRCC): A systemic review and network meta-analysis.
Authors: Fujiwara Yu , Miyashita Hirotaka , Liaw Bobby Chi-Hung 
Published: June 2022

4532 Background: Multiple regimens incorporating tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI), either alone or in combination, confer a significant OS benefit in 1L metastatic clear cell RCC. However, guidance for optimal treatment selection in elderly patients remains limited. A network meta-analysis (NMA) was performed to compare the efficacy of 1L treatments for elderly patients with aRCC. Methods: Database search was performed through Pubmed, Embase, Web of Science, and Scopus. Eligible studies were randomized controlled trials (RCTs) evaluating first-line regimens for patients with aRCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Indirect comparisons of available regimens were estimated using a random-effects NMA. Results: 14 RCTs with more than 2,100 patients and 5 RCTs with 1,529 patients were eligible for PFS and OS analyses, respectively. Compared with sunitinib (Sun), the pembrolizumab (Pem) + axitinib (Axi) (HR 0.68, 95% CI 0.48-0.97) and Pem + lenvatinib (Len) (HR 0.61, 95% CI 0.4-0.94) regimens were associated with significantly improved OS. In comparing the TKI-ICI combinations with dual ICI nivolumab (Niv) + ipilimumab (Ipi), no significant OS differences were observed (Pem + Len: HR 0.71, 95% CI 0.40-1.27; Pem + Axi: HR 0.79, 95% CI 0.47-1.34; Avelumab (Ave) + Axi: HR 1.03, 95% CI 0.58-1.85; Niv + cabozantinib [Cab]: HR 1.03, 95% CI 0.57-1.93, using Niv + Ipi as a reference). Pem + Len, Niv + Cab, Pem + Axi, and Cab alone each showed improved PFS over Sun (Table). Among these, Pem + Len showed a PFS advantage compared to Pem + Axi (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared with the other regimens (vs Niv + Cab: HR 0.63, 95% CI 0.39-1.03; vs Cab alone: HR 0.84, 95% CI 0.40-1.77). Conclusions: Pem + Len and Pem + Axi provided the largest OS benefit in elderly patients for 1L aRCC. Pem + Len showed improved PFS compared with Pem + Axi, but no difference compared with Niv + Cab or Cab alone. Further validation using real-world data is needed to confirm the efficacy and safety of first-line regimens for the geriatric population with aRCC.[Table: see text]
Prognostic value of the lung immune prognostic index in patients with untreated advanced renal cell carcinoma (aRCC) receiving nivolumab plus ipilimumab (N+I) or sunitinib (SUN) in the CheckMate 214 trial.
Authors: Carril-Ajuria Lucia , Motzer Robert J. , Tannir Nizar M. , McDermott David F. , Hammers Hans J. , Plimack Elizabeth R. , Donskov Frede , Rini Brian I. , Jiang Ruiyun , Lee Chung-Wei , Desilva Heshani , Albiges Laurence 
Published: June 2022

4538 Background: The Lung Immune Prognostic Index (LIPI), defined by lactate dehydrogenase (LDH) and derived neutrophil to lymphocyte ratio (dNLR), has been shown to correlate with outcomes of immune checkpoint inhibitor therapy in patients (pts) with lung and other cancers, including pts with previously treated aRCC receiving nivolumab in the phase 2 NIVOREN GETUG-AFU 26 trial. We report an analysis of LIPI in pts with previously untreated aRCC receiving N+I or SUN in the randomized phase 3 CheckMate 214 trial with 5 years minimum follow-up. Methods: Data were used from CheckMate 214 comparing N+I (N 3 mg/kg + I 1 mg/kg) vs SUN (50 mg) for untreated aRCC (N = 1096). Pts with available LIPI data were categorized into 3 LIPI groups (good [LG], dNLR ≤ 3 and LDH ≤ upper limit of normal [ULN]); intermediate [LI], dNLR > 3 or LDH > ULN; and poor [LP], dNLR > 3 and LDH > ULN). This analysis focused on the prognostic value of LIPI using overall survival (OS) outcomes. Univariable analyses (UVAs) were conducted to evaluate LIPI groups alongside known risk factors including age, sex, IMDC risk, baseline PD-L1 status, prior nephrectomy, and baseline tumor burden. Variables that were statistically significant in UVAs ( P < 0.1) were included in the full multivariable analyses (MVAs), from which a reduced model was generated. Results: A total of 1085 pts were evaluable for LIPI (N+I, n = 542; SUN, n = 543). Pts were distributed evenly between treatment arms for all 3 LIPI groups, but distribution between LIPI groups was unbalanced, with most pts grouped as LG (Table). OS outcomes were improved with N+I over SUN across all LIPI groups. Moreover, pts in the LG group had better OS outcomes vs pts in the LI or LP groups regardless of treatment, but with more distinct differences between LIPI groups in the SUN arm (Table). Final MVA results showed the LIPI correlated with OS for LI vs LG in the N+I arm and for LI vs LG and LP vs LG in the SUN arm (Table). Conclusions: These results from CheckMate 214 indicate the potential prognostic value of the LIPI in pts with untreated aRCC receiving N+I or SUN. Additional analyses are ongoing to further investigate the prognostic value of LIPI in this pt population and its impact on other clinical outcomes. Clinical trial information: NCT02231749. [Table: see text]
Racial differences in treatment patterns and outcomes of first-line (1L) therapies for advanced renal cell carcinoma (aRCC) in the real-world (RW) setting.
Authors: Geynisman Daniel M. , Kish Jonathan K. , Falkenstein Angelica , Huo Stephen , Del Tejo Viviana , Rosenblatt Lisa , Guttenplan Sarah , Balanean Alexandrina , Feinberg Bruce A. 
Published: June 2022

4548 Background: In 1L therapy for aRCC, nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) have demonstrated significantly improved clinical outcomes versus sunitinib in phase III trials. African American/Black (AA) patients are grossly underrepresented in all aRCC trials. Little is known about the impact of racial differences on the use of 1L therapies and clinical outcomes in the RW setting. Methods: This retrospective chart review included AA and White American (WA) patients diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) intermediate/poor (I/P)-risk aRCC who initiated on 1L NIVO+IPI, PEM+AXI, or tyrosine kinase inhibitor (TKI) monotherapy with sunitinib, pazopanib, or cabozantinib. Patients’ demographic/clinical characteristics and outcomes were abstracted from medical charts by treating oncologists. Use of 1L therapy, treatment discontinuation, and clinical outcomes including disease response, landmark progression-free survival (PFS), landmark overall survival (OS), and treatment-related adverse event (TRAE) rates were assessed descriptively by race. Results: Of 473 patients, 95 (20.1%) were AA, and 378 (79.9%) were WA patients. Median follow-up was 10.9 months. A higher proportion of AA vs. WA patients had received 1L TKI monotherapy (21.1% vs. 16.1%). Treatment discontinuation rate was higher in AA vs. WA patients (49.5% vs. 43.4%). Treatment response was lower in AA than WA patients (overall response rate [ORR]: 58.8% vs. 74.8%; complete response [CR]: 8.2% vs. 11.4%). The TRAE rate was slightly lower in AA vs. WA patients (25.3% vs. 32.5%). Stratified clinical outcomes including landmark PFS and OS rates at 6 and 9 months are shown in the Table. Conclusions: In this RW I/P-risk aRCC cohort, fewer AA patients were treated with standard of care immune-oncology (IO)-based therapy vs. WA patients, which may contribute to differences in therapy discontinuation and survival outcomes. Also, even with short follow-up, clinically meaningful ORR differences are noted in AA and WA patients. [Table: see text]
Association of antibiotic therapy and treatment efficacy in patients with renal cell carcinoma receiving immune checkpoint inhibitors.
Authors: Braun Avery , Deng Mengying , Handorf Elizabeth A. , Abbosh Philip 
Published: June 2022

4556 Background: There is growing evidence indicating that gut microbiome content is associated with the effectiveness of immune checkpoint inhibitory (ICI) therapy in various cancer types. Antibiotic therapy (ABT) induces significant changes in gut microbiota; however, the effects of ABT on oncologic outcomes with ICI therapy has only been explored in small, single-institution studies. We aimed to investigate the relationship between ABT on overall survival (OS) and real-world progression free survival (rwPFS) in subjects with advanced renal cell carcinoma (RCC) treated with ICI utilizing a national database. Methods: We queried the nationwide electronic health record (EHR)-derived de-identified FlatIron Health (FIH) database after Institutional Review Board approval was obtained and included a waiver of informed consent to select 1809 subjects who received ICI therapy. Patient characteristics were described and compared between those with known ABT use and without known ABT use (in the 3 months pre/post ICI initiation) using ANOVA and Chi-square tests. rwPFS and OS were calculated from date of initiation of ICI to date of real-world progression/date of death. Three-month landmark Kaplan Meier and log-rank tests were used to compare rwPFS and OS between groups defined by ABT use (any ABT, and ABT in 3 months pre-ICI vs 3 months post-ICI initiation). Cox proportional models were used to investigate the association between rwPFS, OS, and antibiotic use, adjusting for patient characteristics. Results: Patients receiving ABT group were younger (p = 0.007) and more likely female (p = 0.024) but similar in other measured demographic variables. rwPFS (median: 9.03 vs 11.6 months; p = 0.015) and OS (median: 23.7 vs 31.8 months; p = 0.019) were significantly shorter in the with-ABT group than in the without-ABT group. When assessing ABT use 3 months prior to initiation of ICI (vs ABT during/no known ABT use), neither rwPFS (median: 9.53 vs 11.66, p = 0.38) nor OS (median: 23.7 vs 22.6 months; p = 0.38) were significantly different. However, rwPFS (median: 23.5 vs 14.0 months vs not reached; p = 0.004) and OS (median: 36.2 vs 22.5 vs 31.8; p = 0.007) were statistically significantly different when stratifying based on exposure and timing of ABT amongst pre-ICI initiation ABT, post-ICI initiation ABT and no ABT groups, respectively. Multivariable analysis identified as a significant predictor of rwPFS (HR = 0.725, CI = 0.579-0.908; p =.005) and OS (HR = 0.722, CI = 0.573-0.911; p = 0.006). Conclusions: This study identifies a significant negative prognostic association of ABT administration on survival in advanced RCC treated by ICI in the first line setting. These results are consistent with the growing body of evidence suggesting that alterations in gut microbiome secondary to antibiotics appear to blunt efficacy of ICI treatment and emphasize the importance of antibiotic stewardship.