bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single-arm, open-label, phase I study of CPI-613 (Devimistat) in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Alistar Angela Tatiana , Morris Bonny , Harrison Lawrence , Bickenbach Kai , Starker Lee , Ginder Nancy , McIlwain Laura , Luther Sanjeev , Pardee Timothy S. , Alpert Justin 
Published: May 2020

4635 Background: Glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species, such as nab-paclitaxel. CPI- 613 is a novel antimitochondrial agent developed by Rafael Pharmaceuticals that showed promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggested possible synergy of CPI-613 with nab-paclitaxel. Methods: Single arm, open-label, phase I study of CPI-613 with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer to determine MTD, safety, and preliminary efficacy of CPI-613 in combination with chemotherapy. Key eligibility criteria included: histologically documented and measurable locally-advanced or metastatic, PDAC. ECOG performance status 0-2; and first line systemic treatment. CPI-613 was infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel (100mg/m2) and gemcitabine ( 800 mg/m2) on Days 1, 8, and 15 of a 28-day cycle. The the primary endpoint, the MTD of CPI-613 was determined by a two-stage, dose-escalation schema, with 6-month treatment duration for patients exhibiting treatment response. Secondary endpoints were treatment-related adverse events, complete response (CR) and partial response (PR). Results: From February 2018 to 2020, 26 patients were screened, (23 metastatic and 3 locally advanced), 22 patients enrolled and 18 patients underwent a restaging scan. As of the time of submission 3 patients are still on active treatment. Patient demographics were: median age of 65, ECOG was 0-1, The MTD of CPI- 613 was determined to be 1500 mg/m2. The dose limiting toxicities were not achieved. Overall the treatment was well tolerated with toxicities mainly related to chemotherapy; most common grade 3 and 4 toxicities were hematologic toxicity and neuropathy. 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results demonstrate that CPI 613 can be safely administered with gemcitabine and nab-paclitaxel at doses up to 1,500 m/g2. Efficacy data suggest synergy with chemotherapy. Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Clinical trial information: NCT03435289 .
Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Ahn Eugene R , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , Calfa Carmen Julia , Alva Ajjai Shivaram , Suhag Vijay S. , Hamid Omid , Dotan Efrat , Yang Eddy Shih-Hsin , Alese Olatunji B. , Yost Kathleen J , Marr Alissa S. , Palmer Martin Clive , Thompson Forrest L. , Rygiel Andrew Lawrence , Anderson Sarah T. , Islam Samiha , Schilsky Richard L. 
Published: May 2020

4637 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pancreatic cancer pts with germline or somatic BRCA1/2 inactivating mutations treated with O are reported. Methods: Eligible pts had advanced pancreatic cancer, no standard treatment (tx) options available, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets or capsules dosed at 300 mg (n=27) or 400 mg (n=3), respectively, orally twice daily until disease progression. Simon 2-stage design tested the null disease control (DC) (objective response (OR) or stable disease at 16+ weeks (wks) (SD16+) according to RECIST) rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty pts with BRCA1/2 inactivating mutations were enrolled from Nov 2016 to Aug 2019; 20 were previously treated with platinum based therapy. Two were not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One partial response (PR) and 7 SD16+ were observed for DC and OR rates of 31% (90% CI: 18% - 40%) and 4% (95% CI: 0% - 18%), respectively. Seven pts had at least one grade 3 AE or SAE at least possibly related to O including anemia, diarrhea, fever, elevated liver enzymes, enterocolitis, increased bilirubin, and oral mucositis. Conclusions: Monotherapy O showed anti-tumor activity in heavily pre-treated pts with pancreatic cancer with germline (5/12 pts with OR or SD16+) or somatic (3/16 pts with OR or SD16+) BRCA1/2 inactivating mutations extending findings of recent studies of O in pts with advanced pancreatic cancer. Clinical trial information: NCT02693535 . [Table: see text]
IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC).
Authors: Hussain Maha H. A. , Powles Thomas , Albers Peter , Castellano Daniel , Daneshmand Siamak , Gschwend Juergen , Nishiyama Hiroyuki , Oudard Stephane , Tayama Darren , Davarpanah Nicole N. , Degaonkar Viraj , Shi Yi , Mariathasan Sanjeev , Grivas Petros , O'Donnell Peter H. , Rosenberg Jonathan E. , Geynisman Daniel M. , Hoffman-Censits Jean H. , Petrylak Daniel Peter , Bellmunt Joaquim 
Published: May 2020

5000 Background: Radical surgery ± cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti–PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled ≤ 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 < 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 ≥ 5%; n = 392). 16% of atezo-treated pts had a tx-related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331 . [Table: see text]
Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).
Authors: Atkins Michael B. , Jegede Opeyemi , Haas Naomi B. , McDermott David F. , Bilen Mehmet Asim , Drake Charles G. , Sosman Jeffrey Alan , Alter Robert S. , Plimack Elizabeth R. , Rini Brian I. , Hurwitz Michael E. , Peace David J. , Signoretti Sabina , Wu Catherine J. , Catalano Paul J. , Hammers Hans J. 
Published: May 2020

5006 Background: Nivolumab (nivo) is FDA approved for pts with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk RCC. Little information is available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to Part B. Pathology specimens will be analyzed by immunohistochemistry, quantitative immunofluorescence, WES and RNAseq with results linked to clinical outcome. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 65 (range 32-86 years); 72% male. IMDC favorable 30 (25%), intermediate 79 (65%) and poor risk 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). 117 pts are currently evaluable for response. RECIST defined ORR was: 34 (29.3%)[CR 5 (4.3%), PR 29 (24.8%)], SD 47 (40.2%), PD 36 (30.7%). ORR by irRECIST was 35%. ORR by IMDC was: favorable 12/29 (41.4%), intermediate/poor 22/87 (25.3%) and for SARC 6/22 (27.3%). Median DOR is 13.8 (10.9, NA) mo. Median PFS is 7.4 (5.5, 10.9) mo. 110 pts remain alive. 60 pts (54 PD, 6 pSD) to date were potentially eligible for salvage nivo/ipi (Part B), but 28 did not enroll due to symptomatic PD (17), grade 3-4 toxicity on nivo (8), other (3). 27 of 32 Part B pts are currently evaluable for efficacy and 30 for toxicity. Best response to nivo/ipi was PR (11%), SD (30%), PD (59%). ORR by irRECIST was 19%. Grade 3-5 Treatment-related AEs (TrAE) were seen in 35/123 (28)% on nivo with 1 death due to respiratory failure. Grade 3-4 TrAE were seen in 10/30 (33%) on nivo/ipi with 0 deaths. Correlative studies are pending. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi after nivo monotherapy was feasible in 53% of pts with PD/pSD, with 11% responding. Clinical trial information: NCT03117309 .
FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC).
Authors: Choueiri Toni K. , Kluger Harriet M. , George Saby , Tykodi Scott S. , Kuzel Timothy M. , Perets Ruth , Nair Suresh , Procopio Giuseppe , Carducci Michael Anthony , Castonguay Vincent , Folefac Edmund , Lee Chung-Han , Hotte Sebastien J. , Miller Wilson H. , Saggi Shruti S. , Gold David , Motzer Robert J. , Escudier Bernard 
Published: May 2020

5007 Background: The immuno-oncology (I-O) combination nivolumab + ipilimumab (NIVO+IPI) is approved for first-line (1L) and NIVO is approved for second-line treatment post TKI therapy in aRCC. The open-label, randomized, phase 2 Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC; NCT02996110) platform study has an adaptive design allowing rapid evaluation of I-O therapies, including NIVO+IPI or other investigational combinations. This FRACTION analysis reports preliminary outcomes with NIVO+IPI in aRCC pts after progression on checkpoint inhibitor therapy. Methods: All pts, except 1, had previously received and progressed on checkpoint inhibitor treatment. Pts received NIVO+IPI (NIVO 3 mg/kg + IPI 1 mg/kg Q3W ×4, then after 6 weeks, NIVO 480 mg Q4W), up to 2 years or until progression, toxicity, or protocol-specified discontinuation. Primary endpoints were confirmed objective response rate (ORR; per investigator using RECIST v1.1), duration of response (DOR), and progression-free survival probability at week 24. Safety outcomes were reported. Results: 46 pts were randomized to NIVO+IPI. Pts had 0 (n = 1), 1 (n = 10), 2 (n = 12), 3 (n = 10), or ≥4 (n = 13) prior lines of therapy. All pretreated pts had prior anti-PD-(L)1-, none had prior anti-CTLA-4- therapy, and 37 had prior TKI-based therapy; 45 pts progressed on anti-PD-(L)1 as the most recent therapy. Most pts had clear cell aRCC (n = 44). After a median study follow-up of 8.9 months, ORR was 15.2%; no pts achieved complete response and 7 achieved partial response. DOR ranged from 2–19+ months (n = 7); 5 pts had ongoing response. Six of 7 responders had received ≥2 prior lines of therapy. Any-grade treatment-related adverse events (AEs) were reported in 36 pts (78.3%; fatigue, rash [both 19.6%], and diarrhea [17.4%] were most common). Grade 3–4 treatment-related AEs were reported in 13 pts (28.3%; diarrhea [8.7%], ↑amylase and ↑lipase [both 6.5%] were most common). Treatment-related immune-mediated AEs of any grade were reported in 22 pts (47.8%; rash [19.6%], diarrhea [17.4%], and ↑alanine aminotransferase [8.7%]). No treatment-related deaths were reported. Updated and expanded results with an additional 3 months of follow-up will be presented. Conclusions: These results suggest that NIVO+IPI may provide durable partial response in some pts with prior progression on checkpoint inhibitors, including some heavily pretreated pts. The safety profile of NIVO+IPI in FRACTION pts was similar to historic data in aRCC with this combination. Clinical trial information: NCT02996110 .
Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial.
Authors: van der Voort Anna , van Ramshorst Mette S. , van Werkhoven Erik D. , Mandjes Ingrid A. , Kemper Inge , Vulink Annelie J. , Oving Irma M. , Honkoop Aafke H. , Tick Lidwine W. , van de Wouw Agnes J. , Mandigers Caroline M. , van Warmerdam Laurence J. C. , Wesseling Jelle , Vrancken Peeters Marie-Jeanne T.F.D , Linn Sabine C. , Sonke Gabe S. ,   on behalf of the Dutch Breast Cancer Group (BOOG)
Published: May 2020

501 Background: The multicenter phase III TRAIN-2 study showed high pathological complete response (pCR) rates after neoadjuvant chemotherapy with and without anthracylines plus dual HER2-blockade in stage II-III HER2-positive breast cancer patients (67% vs 68%, p = 0.95) (NCT01996267). Here we report 3-year efficacy and safety outcomes. Methods: Patients were randomly assigned (1:1) to receive 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (FEC-PC) or 9 cycles paclitaxel and carboplatin (PC). Both regimens were combined with trastuzumab (T; 6mg/kg, loading dose 8mg/kg) and pertuzumab (Ptz; 420mg, loading dose 840mg). Patients completed one year of trastuzumab, radiotherapy and endocrine therapy as indicated. The primary endpoint pCR was previously reported. Secondary efficacy endpoints reported here are event-free-survival (EFS) defined as time from randomization to first event (disease progression resulting in inoperability, recurrence [contralateral DCIS excluded], secondary primary malignancies, or death) and overall survival (OS), both in the intention-to-treat population. Safety endpoints are reported for patients treated with at least one dose of study medication. Results: 438 patients were randomized (219/arm) and evaluable for long-term efficacy endpoints. After a median follow-up of 48.8 months 23 EFS events occurred in the FECT-PTC-Ptz-arm and 21 in the PTC-Ptz-arm (HR 0.90; 95% CI 0.50-1.63). Three-year EFS estimates were 92.7% (95% CI: 89.3-96.2) for FECT-PTC-Ptz and 93.6% (95% CI: 90.4-96.9) for PTC-Ptz. Three-year OS estimates were 97.7% (95% CI: 95.7-99.7) for FECT-PTC-Ptz and 98.2% (95% CI: 96.4-100) for PTC-Ptz. These results were irrespective of hormone receptor and nodal status. LVEF decline ≥10% from baseline and < 50% was more common in patients who received anthracyclines than in the PTC-Ptz arm (8.6% vs. 3.2%, p = 0.021). Two patients in the FECT-PTC-Ptz arm developed acute leukemia. No other new safety concerns were seen. Conclusions: The 3-year follow-up of the TRAIN-2 study confirms the results of the primary outcome that anthracylines do not improve efficacy and are associated with clinically relevant toxicity. A neoadjuvant carboplatin-taxane based regimen with dual HER2-blockade can be considered in all stage II-III breast cancer patients, regardless of hormone receptor and nodal status. Clinical trial information: NCT01996267 .
Immunogenomic characterization of advanced clear cell renal cell carcinoma treated with PD-1 blockade.
Authors: Braun David A. , Hou Yue , Bakouny Ziad , Ficial Miriam , Sant'Angelo Miriam , Ross-Macdonald Petra , Jegede Opeyemi , Sun Maxine , Wind-Rotolo Megan , Pignon Jean-Christophe , Neuberg Donna S. , Catalano Paul J. , Freeman Gordon J. , Sharpe Arlene , McDermott David F. , Van Allen Eliezer Mendel , Signoretti Sabina , Wu Catherine J. , Shukla Sachet A. , Choueiri Toni K. 
Published: May 2020

5010 Background: Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Further, the common paradigm in solid tumor immunology that pre-existing CD8+ T cell infiltration, in combination with high numbers of nonsynonymous mutations (which, in the context of diverse HLA class I alleles, may be presented as neoantigens) drives response to PD-1 blockade, has not been thoroughly explored in ccRCC. Methods: We analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials (CheckMate 009, CheckMate 010, CheckMate 025) of treatment with PD-1 blockade (n = 362) or mTOR inhibition (as control arm; n = 230) by whole-exome (n = 454) and RNA-sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219), to uncover the immunogenomic determinants of therapeutic response and survival. Wilcoxon rank-sum test was used to compare somatic alteration burden between clinical benefit (CB) v.s no CB (NCB); Fisher’s exact test was used to compare mutations and copy number alteration by infiltration state; and hazard ratio (HR) was calculated from Cox PH model for progression-free (PFS) and overall survival (OS) endpoints. All tests were at a significance level of p < 0.05. Results: Conventional genomic markers (tumor mutation burden, p = 0.81; neoantigen load, p = 0.47 for CB vs. NCB) and degree of CD8+ T cell infiltration (p = 0.88 for PFS; p = 0.65 for OS) were not associated with clinical response or altered survival with PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 22% having an immune desert phenotype and 5% with an immune excluded phenotype. Our analysis revealed that CD8+ T cell infiltrated tumors are depleted of clinically favorable PBRM1 mutations (p = 0.013) and enriched for unfavorable chromosomal losses of 9p21.3 (p < 0.001) when compared to non-infiltrated tumors. When found within infiltrated tumors, del(9p21.3) was associated with worse CB rate (36% (9/25) for del(9p21.3) vs. 88% (7/8) for wildtype at that locus, p = 0.017) and worse survival (HR = 2.38, p = 0.01 for PFS; HR = 2.44, p = 0.01 for OS) with PD-1 blockade. Conclusions: These data demonstrate how the potential interplay of immunophenotypes with somatic mutations and chromosomal alterations impacts therapeutic efficacy in advanced ccRCC.
Tumor, immune, and stromal characteristics associated with clinical outcomes with atezolizumab (atezo) + platinum-based chemotherapy (PBC) or atezo monotherapy (mono) versus PBC in metastatic urothelial cancer (mUC) from the phase III IMvigor130 study.
Authors: Galsky Matt D. , Banchereau Romain , Hamidi Habib Rahman , Leng Ning , Harris Will , O'Donnell Peter H. , Kadel Edward Ernest , Yuen Kobe Chi Yung , Jin Dexter , Koeppen Hartmut , Tayama Darren , Grande Enrique , Arranz Jose , De Santis Maria , Davis Ian D. , Kikuchi Eiji , Shen Xiaodong , Bamias Aristotelis , Mariathasan Sanjeev 
Published: May 2020

5011 Background: Tumor mutational burden (TMB), PD-L1 expression, T-effector gene expression (GE) and a fibroblast TGF-β–response signature (F-TBRS) are associated with clinical outcomes with atezo mono in mUC (Mariathasan, Nature, 2018). Here we explore the potential predictive role of these biomarkers and APOBEC mutagenesis in IMvigor130. Methods: Pts receiving first-line (1L) mUC treatment (tx) were randomized 1:1:1 to atezo + PBC, atezo mono, or placebo + PBC. Coprimary efficacy endpoints were PFS and OS. Planned exploratory biomarker analyses included PD-L1 expression, TMB (FoundationOne), and T-effector GE (RNA-seq). Results: The 851 biomarker-evaluable pts (BEP) were representative of the 1200 ITT pts. Biomarker results are shown in Table. PD-L1 IC2/3 was associated with significantly longer OS for atezo mono vs placebo + PBC and a combination of PD-L1 IC2/3, and high TMB (> 10 muts/Mb) identified a pt subset (≈ 14% of BEP) with particularly favorable outcomes with atezo mono vs placebo + PBC; similar results for PD-L1 and TMB were not seen with atezo + PBC vs placebo + PBC. APOBEC mutagenesis was associated with improved OS with atezo-containing regimens whereas high F-TBRS was associated with inferior OS with atezo mono. Conclusions: These results reinforce the potential predictive nature of biomarkers associated with response/resistance to atezo and highlight potentially distinct biology driving benefit with atezo and atezo + PBC. These findings suggest a possible biomarker-directed approach to 1L mUC tx that warrants mechanistic interrogation and prospective validation. Clinical trial information: NCT02807636 . [Table: see text]