bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical value of atezolizumab + bevacizumab for first-line unresectable hepatocellular carcinoma (HCC): A network meta-analysis.
Authors: Vogel Arndt , Rimassa Lorenza , Sun Hui-Chuan , Abou-Alfa Ghassan K. , El-Khoueiry Anthony B. , Pinato David James , Daigl Monica , Sanchez Alvarez Javier , Orfanos Panos , Leibfried Michael , Blanchet Zumofen Marie-Hélène , Gaillard Vincent , Merle Philippe
Published: May 2020

4585

Background: The IMbrave150 pivotal study in unresectable HCC showed superiority of atezolizumab + bevacizumab (atezo + bev) vs sorafenib for OS and PFS. Based on these data supporting first-line atezo + bev for HCC, we conducted a network meta-analysis (NMA) to compare the efficacy of atezo + bev with other systemic and local therapies approved for HCC. Methods: A systematic literature review identified randomized controlled trials in adults with locally advanced or metastatic HCC and no prior systemic therapy for HCC. Studies of therapies now approved for any line of HCC treatment with data reported for first-line treatment since sorafenib approval in 2007 were eligible. Screening of 8783 records yielded 55 trials for inclusion; 9 studies were eligible for the evidence network. Reported hazard ratios (HRs) for OS and PFS were extracted from published studies. The IMbrave150, REFLECT and CheckMate-459 study populations were considered sufficiently similar to compare. A generalized linear model with random effects was used to estimate indirect treatment effects. Informative priors for the heterogeneity of treatment effects across trials were adopted given the limited number of trials to inform each pairwise comparison. HRs with 95% credible intervals (CrIs) and Bayesian posterior probability of atezo + bev being superior to other treatments were calculated for each treatment comparison. The base case NMA compared the relative efficacy of atezo + bev vs sorafenib observed in the IMbrave150 study with the relative effect of other therapies. Sensitivity analyses were performed to compare subgroup results as appropriate based on disease etiology, extrahepatic spread and geography. Results: NMA results suggested improved OS with atezo + bev vs lenvatinib (HR, 0.63; 95% CrI: 0.32, 1.25; probability of atezo + bev being superior to lenvatinib: 93.7%) or nivolumab (HR, 0.68; 95% CrI: 0.35, 1.38; probability of atezo + bev being superior to nivolumab: 90.3%) and improved PFS with atezo + bev vs lenvatinib (HR, 0.91; 95% CrI: 0.23, 3.65; probability of atezo + bev being superior to lenvatinib: 61.5%) or nivolumab (HR, 0.63; 95% CrI: 0.16, 2.59; probability of atezo + bev being superior to nivolumab: 85.5%). Conclusions: This NMA suggested greater OS and PFS benefits with first-line atezo + bev treatment vs other therapies approved for treatment of unresectable HCC.
Predictive value of changes in plasma vascular endothelial growth factor at eight weeks after lenvatinib administration in patients with unresectable hepatocellular carcinoma.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Kaneko Shun , Yasui Yutaka , Kirino Sakura , Sekiguchi Shuhei , Inada Kento , Yamashita Koji , Hayakawa Yuka , Higuchi Mayu , Takaura Kenta , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Itakura Jun , Izumi Namiki
Published: May 2020

4594

Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) and there is no established predictive biomarker. Previously it was reported that a plasma vascular endothelial growth factor (VEGF) concentration decrease at 8 weeks after starting sorafenib might predict favorable overall survival (OS) in patients with u-HCC (Tsuchiya, et al. Cancer, 2013). We aimed to investigate the value of changes in plasma VEGF at 8 weeks after LEN administration in patients with u-HCC. Methods: Forty-six patients with u-HCC who received LEN between April 2018 and August 2019 at our institution were enrolled. Plasma concentrations of VEGF and serum α-fetoprotein (AFP) levels were measured at baseline, 4 and 8 weeks after administration of LEN. A VEGF decrease was defined as > 5% decrease during 8 weeks after the beginning of LEN therapy. AFP response was defined as > 20% decrease during 8 weeks according to the previous reports. Results: Median overall survival (OS) was not reached and progression-free survival (PFS) was 5.9 months. Median observation period and treatment duration were 10.1 and 6.3 months. The objective response rate and disease control rate by mRECIST criteria were 43.5% and 82.6%. Median PFS in patients who had a VEGF decrease at week 8 (n = 29) was significantly longer than those who did not have a VEGF decrease (n = 17; 7.1 months vs 5.0 months; p = 0.014). AFP response was not associated with PFS. There were no significant differences in baseline VEGF, AFP, ALBI score, and extrahepatic metastasis between the patients with and without a VEGF decrease. A VEGF decrease was significantly associated with radiological objective response (p = 0.001) and 18 of 20 patients who achieved CR (n = 3) or PR (n = 17) had a VEGF response in LEN therapy. Conclusions: A decrease of plasma VEGF level at 8 weeks in patients with u-HCC on LEN was significantly associated with PFS. Changes in plasma VEGF could become a new biomarker for molecular targeted therapies including VEGF inhibitors in patients with unresectable HCC.
Immediate post-thermal ablation biopsy of colorectal liver metastases to predict oncologic outcomes.
Authors: Vasiniotis Kamarinos Nikiforos , Vakiani Efsevia , Gonen Mithat , Kemeny Nancy E. , Covey Anne M. , Brown Karen T. , Brody Lynn A , Deipolyi Amy R , Camacho Juan , Boas F. Edward , Yarmohammadi Hooman , Erinjeri Joseph , Petre Elena N , Kingham T. Peter , D'Angelica Michael Ian , Saltz Leonard B. , Solomon Stephen Barnett , Sofocleous Constantinos T.
Published: May 2020

4602

Background: Thermal ablation (TA) is used as a local cure for selected colorectal liver metastases (CLM) with minimal risk. A critical limitation of TA has been early local tumor progression (LTP). The goal of this study is to establish the role of ablation zone (AZ) biopsy in predicting LTP. Methods: This institutional review board-approved prospective study included patients with CLM of 5cm or less in maximum diameter, with confined liver disease or stable, limited extrahepatic disease. Both radiofrequency(RF) and microwave(MW) ablation modalities were used. A biopsy of the center and margin of the AZ was performed immediately after ablation. The applicators were also examined for the presence of viable tumor cells. All samples containing morphologically identified tumor cells were further interrogated with immunohistochemistry to determine the proliferative and viability potential of the detected tumor cells. Ablation margin size was evaluated on the first CT scan performed 4–8 weeks after ablation and was confirmed by 3D assessment with Ablation Confirmation Software (Neuwave™). Variables were evaluated as predictors of time to LTP with the competing-risks model (uni- and multivariate analyses). Results: Between November 2009 and February 2019, 102 patients with 182 CLMs were enrolled. Mean tumor size was 2.0 cm (range, 0.6–4.8 cm). MW was used in 95/182 (52%) tumors and RF in 87/182 (48%). Median follow-up was 19 months. Technical effectiveness was evident in 178/182 (97%) ablated tumors on the first contrast material–enhanced CT at 4–8-weeks post-ablation. The cumulative incidence of LTP at 12 months was 19% (95% confidence interval [CI]: 14, 27). Samples from 64 (35%) of the 178 technically successful cases contained viable tumor. At univariate analysis, tumor size, minimal margin size, and biopsy results were significant in predicting LTP. In a multivariate model, margin size of less than 5 mm (P < .001; hazard ratio [HR], 4.3), and positive biopsy results (P = .02; HR, 1.8) remained significant. LTP within 12 months after TA was noted in 3% (95% CI: 1, 6) of tumor-negative biopsy CLMs with margins of at least 5 mm. Conclusions: Biopsy and pathologic examination of the AZ predicts LTP regardless of TA modality used. This can optimize ablation as a potential local cure for patients with limited CLM.
Safety of 177Lu-DOTATATE in patients with advanced neuroendocrine tumors: Data from a U.S. expanded access program.
Authors: Auerbach Martin S. , Wolin Edward M. , Nassiri Val , Broberg Per , El-Haddad Ghassan
Published: May 2020

4604

Background: The NETTER-1 clinical trial showed that peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE increased progression-free survival in patients with somatostatin-receptor-positive advanced midgut neuroendocrine tumors (NETs) compared with high-dose octreotide long-acting repeatable, and was associated with few serious adverse events (AEs). To assess the safety profile of 177Lu-DOTATATE in a real-world population, we analyzed safety data from a US expanded access program (NCT02705313). Methods: Patients had inoperable, histologically proven, somatostatin-receptor-positive, locally advanced or metastatic GEPNETs (Ki-67 index ≤ 20%) that progressed after somatostatin analog therapy. Exclusion criteria were: surgery, radiotherapy or chemotherapy in the last 12 weeks; treatment with an interferon, mTOR inhibitor, or other systemic therapy in the last 4 weeks; or ongoing octreotide therapy that could not be interrupted for PRRT. Patients with impaired renal function (serum creatinine > 1.7 mg/dL or creatinine clearance < 50 mL/min) or serious coexisting conditions were excluded. The analysis included patients who received ≥ 1 cycle of 177Lu-DOTATATE between July 5, 2016 and December 21, 2018. Data were collected from the first cycle to the latest data collection point (up to October 7, 2019). Results: 299 patients received a mean 177Lu-DOTATATE cumulative dose of 552 mCi (20.4 GBq) (standard deviation [SD]: 220 mCi [8.1 GBq]) over a mean of 2.8 cycles (SD: 1.1). Mean age was 60.8 years (SD: 11.7); 38.5% of patients were men. Over a mean follow-up of 131 days (SD: 87), 48.8% of patients reported treatment-related AEs (TRAEs), with a maximum severity of grade 1, 2 and 3 for 26.8% (n = 80), 18.1% (n = 54) and 4.0% (n = 12) of patients, respectively; there were no grade 4–5 TRAEs. The most common TRAEs of any grade (≥ 5.0% of patients) were nausea (31.1%), vomiting (13.7%), fatigue (9.4%) and thrombocytopenia (6.0%). The most prevalent grade 3 TRAEs were lymphocyte count decrease (1.0%) and thrombocytopenia (0.7%). Serious TRAEs occurred in 1.0% of patients (carcinoid crisis, dehydration, syncope and vomiting). AEs led to dose modification in 1.7% of patients, dose delay in 6.4% (most commonly due to nausea [2.0%] or thrombocytopenia [2.0%]) and discontinuation in 1.3% (due to thrombocytopenia [1.0%] and extravasation [0.3%]). Conclusions: In a real-world population of US patients with advanced GEPNETs, 177Lu-DOTATATE treatment was well tolerated with few TRAEs, consistent with the safety profile in the NETTER-1 trial. Clinical trial information: NCT02705313 .
Multicenter analysis of treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3).
Authors: Apostolidis Leonidas , Dal Buono Arianna , Merola Elettra , Jann Henning , Jaeger Dirk , Wiedenmann Bertram , Winkler Eva Caroline , Pavel Marianne
Published: May 2020

4607

Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.
Landscape of DNA-damage-repair/homologous recombination deficiency (DDR/HRD) in hepatopancreaticobiliary (HPB) cancers.
Authors: Park Wungki , Sokol Ethan , Chen Jiapeng , Yu Kenneth H. , Khalil Danny , Harding James J. , El Dika Imane H. , Riaz Nadeem , Abou-Alfa Ghassan K. , Kelsen David Paul , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary
Published: May 2020

4620

Background: Biallelic HR-gene mutations (HRm) confer HRD and sensitivity to DDR-targeted therapies including platinum and PARPi in pancreatic cancer (PDAC). The landscape of DDR/HRD phenotypes in HPB cancers and their clinical implication is yet to be evaluated, the subject of this effort. Methods: Hybrid capture-based comprehensive genomic profiling was performed in a CLIA-certified, CAP-accredited lab (Foundation Medicine, Inc.) on up to 395 genes, including the HR-genes ( BRCA1/2, PALB2, RAD50/51B/C/D, MRE11, ATRX, ATR, ATM, BAP1, BRIP1, CHEK2, NBN, and FANCA). Putative DDR/HRD phenotype was assessed using percent genome under LOH (gLOH) (PMID: 28916367). Variant zygosity was assessed as previously described (PMID: 29415044). From an independent PDAC subgroup among HPB cancers, we evaluated their outcomes on first-line platinum. Results: From a total of 11,174 tumors, pathogenic DDR/HRm were identified in 18% (1980/11174) of HPB cancers, 15% (863/5941) of PDAC, 25% (744/2998) of cholangiocarcinoma, 15% (141/958) of hepatocellular carcinoma, and 17% (152/873) of gallbladder carcinoma. We observed a majority (63%) of DDR/HRm with LOH. Rigorous filtering for tumor purity and copy number quality metrics yielded 34% (4051/11774) cases evaluable. The median gLOH of any biallelic DDR/HRm was 12.9% compared to 8.8% in no DDR/HRm (p=5.7E-33). Strength of the association varied by gene, with the strongest association in BRCA1 (22.3, p=1.5E-10), BRCA2 (20.1, p=1.7E-35), RAD51C (16.7, p=7.8E-4), PALB2 (16.4, p=1.4E-5), BRIP1 (14.3, p=0.02), RAD51B (13.7, p=0.02), and ATM (13.6, p=7.7E-12) (Table). Most other DDR/HR-genes and monoallelic DDR/HRm had weak gLOH. PDAC accounted for 60% of this HPB dataset. In an independent dataset of PDAC at MSK (n=262), biallelic DDR/HRm patients (n=29, 11%) had mostly germline mutations and had significantly improved median PFS on first-line platinum vs. non-platinum (13.3 [95%CI: 9.57-NR] vs 3.8 [95%CI: 2.79-NR] months, p<0.0001). Conclusions: Biallelic DDR/HRm is a distinct population of HPB cancers beyond PDAC and may confer better phenotype in DDR-targeted treatment. Further independent validation is underway. [Table: see text]
Enrichment of alterations in targetable molecular pathways in KRAS wild-type (WT) pancreatic cancer (PC).
Authors: Philip Philip Agop , Xiu Joanne , Hall Michael J. , Hendifar Andrew Eugene , Lou Emil , Hwang Jimmy J. , Gong Jun , Khushman Moh'd M. , Sohal Davendra , Lockhart A. Craig , Weinberg Benjamin Adam , Marshall John , Grothey Axel , Shields Anthony Frank , Korn Wolfgang Michael
Published: May 2020

4629

Background: Genomic profiling has identified KRAS mutations in 88-90% of PC. KRAS WT tumors represent a molecularly heterogeneous group that may harbor targetable alterations (TA). We studied KRAS WT PC using NextGen sequencing (NGS) and whole transcriptome sequencing (WTS) to characterize the molecular landscape of this unique group and to assess the prevalence of TA. Methods: A total of 1164 PC tumors were tested at Caris Life Sciences by NGS (592 genes), WTS (NovaSeq), IHC and fragment analysis. Comparison of KRAS WT vs. mutant (MT) was done by Fisher-Exact or Chi2 and was corrected for multiple tests. Results: The KRAS WT cohort included 144 tumors (12.4%). No differences were seen in gender (female: 46% in both WT & MT) and age (median: 66 & 67) compared to KRAS MT. In KRAS WT tumors, targetable fusions tested by WTS and pathogenic mutations by NGS were seen in 22% (32 of 144) and 52% (75 of 144) respectively; potentially targetable amplifications (amp) were seen in 5 additional tumors. No TA were seen in 22% of WT tumors. Key alterations are in Table. Alterations inducing MAPK activation, including BRAF, RAF1, NF1 and GNAS changes were seen in 38 (26%) tumors. Frequent alterations were seen in FGFR genes (11 tumors), MET (4, including 1 exon 14 skip), and ERBB receptor and ligands (10). Fusions in ALK, ROS1, RET and NOTCH1 were seen (8), largely exclusive of other drivers. Wnt, PI3K, chromatin remodeling (CR) and DDR changes were common and sometimes seen concurrent with other alterations. Compared to KRAS MT, no difference of PD-L1 or TMB-H was seen. BRAF, APC, PBRM1, CTNNB1 mutations, MDM2 amp, gene fusions and MSI-H/dMMR were all more frequent in KRAS WT tumors (corrected p < 0.05). Conclusions: KRAS WT PC is enriched with TA (e.g., BRAF, ALK, ROS1, NRG1, MSI-H). The use of WTS in combination with NGS identifies activated molecular pathways in the majority of KRAS WT tumors. Based on our findings, comprehensive profiling of PC at the DNA and RNA level is recommended to provide patients with therapeutic opportunities beyond standard treatments. [Table: see text]
Outcomes and Immunogenicity of pancreatic cancer stratified by the HRDetect score.
Authors: O'Kane Grainne M. , Jang Gun Ho , Denroche Rob , Zhang Amy , Picardo Sarah Louise , Grant Robert C , Allen Michael , Wang Yifan , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Tehfe Mustapha , Biagi James Joseph , Lam Bernard , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Knox Jennifer J.
Published: May 2020

4630

Background: The HRDetect score uses whole genome sequencing (WGS) to incorporate patterns of substitution base signatures and structural variation to identify tumours deficient in homologous recombination repair (HRD). HRD-tumours, with a higher mutational burden, may be more immunogenic. Methods: We applied HRDetect to 182 resected pancreatic cancers (PDA) and 233 advanced PDA enrolled on the COMPASS trial; both cohorts underwent WGS after tumour enrichment. Patients were classified as high(hi) or low(lo) according to the published score threshold of 0.7; clinical characteristics and survival outcomes were determined. Immunogenicity of the cohorts was explored by analyzing cytolytic activity (CYT) as measured by RNA expression of perforin and granzyme A. Results: 14% of resected (25/182) and 14% of advanced cases (32/233) were considered HRDetecthi . The median age at PDA diagnosis was younger in HRDetecthi vs HRDetectlo (61 vs 66 years, p = 0.005), with no difference in sex between groups. Of the 57 cases identified, 37 (65%) were considered true HRD-PDA with inactivation of BRCA1, BRCA2, PALB2, RAD51C and XRCC2. The remaining 20 cases, were considered false positives for HRD; of these 7 had evidence of a tandem duplicator phenotype with duplications ranging from 10Kbp to 1Mbp in size and 13 had no defining genomic characteristics of the HRD-subtype. In resected PDA, the HRDetect score after adjusting for stage, was not prognostic. In contrast in a multivariable analysis of advanced cases, both HRDetect (HR 0.51, 95% CI 0.30-0.87, p = 0.01) and the Moffitt RNA classifier were highly prognostic (HR 1.99, 95% CI 1.32-3.00, p = 0.0001) with improved survival in HRDetecthi and classical PDA. Of patients receiving platinum in advanced disease (n = 128) HRDetecthi PDA had longer survival compared to the HRDetectlo (15.6 vs. 9.9 months, p = 0.02) although the interaction term between chemotherapy regimen (gemcitabine vs. platinum) and HRDetect score was not significant in this cohort. HRDetecthi tumours had increased cytolytic activity than HRDetectlo PDA; furthermore, within the cohort of HRDetecthi PDA, higher CYT scores were evident in primary lesions compared to metastatic sites sequenced. Conclusions: A high HRDetect score is prognostic in advanced PDA where patients treated with platinum have longest survival. HRDetecthi tumours have increased cytolytic activity with differences observed between primary and metastatic lesions.
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]
Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study.
Authors: Pal Sumanta K. , Agarwal Neeraj , Loriot Yohann , Suarez Rodriguez Cristina , Singh Parminder , Vaishampayan Ulka N. , Mcilvaine Elizabeth , Curran Dominic , Castellano Daniel , Necchi Andrea
Published: May 2020

5013

Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences < 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received ≥2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960 .