bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment for patients with advanced pancreatic adenocarcinoma: A retrospective analysis in China.
Authors: Wu Hongyang , Huang Nana , Zhao Chenchen
Published: January 2022

556

Background: Anlotinib, a novel small molecule multi-target tyrosine kinase inhibitor that can effectively inhibit VEGFR, PDGFR, FGFR, C-KIT et al, is proved to have anti-tumor angiogenesis and tumor growth inhibition effects. However, Anlotinib exploration on advanced pancreatic adenocarcinoma (PDAC) is still limited. The motivation of this work is to evaluate the efficacy and safety of anlotinib combined with nab-paclitaxel/gemcitabine in the first-line treatment of patients with advanced PDAC, and provide some evidence for the treatment regimens of advanced PDAC. Methods: This was a retrospective study in patients with advanced PDAC performed from Aug 17, 2019 to Apr 3, 2021. Patients who received anlotinib plus nab-paclitaxel/gemcitabine treatment were defined as Group 1, and patients who received nab-paclitaxel/gemcitabine as Group 2. The study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (P2021-13-21). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: In this work, 33 patients were included, with 17 cases in Group 1 and 16 cases in Group 2. The median PFS (mPFS) of Group 1 and Group 2 were 5.0 (95% Cl, 4.97-5.94) months and 2.7 (95% Cl, 2.4-3.3) months, respectively ( P = 0.0220). The median OS (mOS) of Group 1 and Group 2 were 9.0 (95% Cl, 6.55-11.45) months and 6.0 (95% Cl, 1.08-10.92) months, respectively ( P=0.006). The PFS rate in 3 and 6 months and the OS rate in 6 and 12 months of Group 1 were significantly higher than that of Group 2. The most common grade 3 treatment related AEs (trAEs) were hematological toxicity, with 35.29% in Group1 and 31.25% in Group 2. Non-hematological toxicity were hypertension, hand-foot syndrome and diarrhea. No grade 3 or higher non-hematologic toxicity was observed in all patients. Conclusions: Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment demonstrates encouraging efficacy and manageable AE in patients with advanced PDAC. Clinical outcomes are improved with longer PFS and OS in anlotinib plus chemotherapy group. More data are needed to confirm the long-term efficacy and safety of anlotinib plus nab-paclitaxel/gemcitabine in advanced PDAC patients.
A phase I study of pharmacokinetic (PK)-driven sequential dosing of rucaparib (RUB) with irinotecan liposome (nal-IRI) and fluorouracil (5FU) in metastatic gastrointestinal (mGI) and pancreas (PANC) cancers.
Authors: Ma Wen Wee , Zemla Tyler J. , Walden Daniel , McWilliams Robert R. , Shaib Walid Labib , Ahn Daniel H. , El-Rayes Bassel F. , Halfdanarson Thorvardur Ragnar , Hobday Timothy J. , Bruggeman Sarah , Jaszewski Brandy L. , Ou Fang-Shu , Wu Christina , Bekaii-Saab Tanios S.
Published: January 2022

563

Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received > 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.
Phase II study of SHR-1701 combined with famitinib in the treatment of advanced pancreatic cancer or biliary tract cancer.
Authors: Xie Jing , Meng Zhiqiang , Chen Lianyu , Hua Yongqiang , Li Huajun
Published: January 2022

568

Background: Pancreatic cancer (PC) and biliary tract cancer (BTC) are highly malignant cancers with limited treatment (tx) options. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. Famitinib is a multitargeted tyrosine kinase inhibitor (TKI). Many studies have proved the mutually enhanced effect of anti-angiogenesis and ICI therapy in multiple tumours. Herein, we reported the safety and efficacy of SHR-1701 in combination with famitinib in advanced PC and BTC patients (pts) who have failed previous standard tx. Methods: This is an ongoing single-site, exploratory phase II study. PC or BTC pts who have failed ≥1 prior therapy would be enrolled into PC or BTC cohort, and received SHR-1701 plus famitinib until disease progression or unacceptable toxicity. SHR1701 would be intravenously given at a fixed dose of 30mg/kg q3w. Famitinib was initially given at a dose of 20mg/d. Dose reduction of famitinib to 15mg was allowed if it was intolerable. The primary endpoint was objective response rate (ORR) as per RECIST v1.1. Simon’s two-stage minimax design was used in this trial. For each cohort, if ≥2 responses are observed among 15 patients in stage I, the study will proceed to full accrual. Results: Up to 15 Sep 2021, 15 pts and 9 pts were enrolled in PC and BTC cohorts respectively. The baseline data are shown in the table. Of 15 evaluable pts in PC cohort, one had complete response, one had partial response (PR), 6 pts had stable disease (SD). The ORR and DCR were 13% and 53%, respectively. The first stage of PC cohort had a sufficient response rate to meet full enrollment. Among 8 evaluable pts in BTC cohort, one had PR (tumor shrinkage > 80%), 4 had SD. The ORR and DCR were 13% and 63%, respectively. 22 pts (92%) experienced treatment-related adverse events (TRAEs). The most frequently reported TRAEs (any grade) were proteinuria (58%), hypertension (42%), and blood urine present (42%). The incidence of Grade 3 TRAEs was 33%, among which the most common ones were hypertension (8%), and bilirubin conjugated increased (8%). No grade 4/5 TRAEs were reported. Conclusions: SHR-1701 plus famitinib showed encouraging activity with manageable safety in pts with advanced PC or BTC. Enrollment is ongoing and updated data will be presented. Clinical trial information: ChiCTR2000037927.[Table: see text]
Ciprofloxacin plus gemcitabine-based chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma: A pilot study of microbiome manipulation.
Authors: Cheo Seng Wee , Lee Jonathan WJ , Walsh Robert John , Sundar Raghav , Choo Joan RE , Chan Gloria , Yong Wei-Peng , Meah Wee Yang , Khor Chiea Chuen , Chee Cheng Ean
Published: January 2022

570

Background: Gemcitabine-based chemotherapy is an approved therapy for treatment-naïve metastatic pancreatic ductal adenocarcinoma (PDAC). Inherent resistance to gemcitabine inevitably leads to cancer progression and shorter survival. It has been demonstrated that bacteria are a component of the PDAC tumor microenvironment and may play a critical role in mediating resistance to chemotherapy. Hence, the coadministration of an antibiotic to chemotherapy may potentiate antitumour drug responses. We conducted a pilot study to assess the efficacy and safety of ciprofloxacin plus gemcitabine-based chemotherapy in patients with treatment naïve metastatic PDAC. We also aimed to study gut microbiome changes during treatment with ciprofloxacin. Methods: This was a single arm study conducted at the National University Cancer Institute, Singapore. Patients (pts) with histologically confirmed metastatic PDAC were treated with nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks, in combination with oral ciprofloxacin 500 mg twice daily. Treatment was continued until disease progression or intolerable toxicity. DNA extraction, 16S rRNA amplification and sequencing for bacteria were performed on pre- and post-treatment stool samples. Primary endpoint of this study was response rate and safety of the treatment combination. Secondary endpoints included progression free survival (PFS), overall survival (OS) and microbiome changes after treatment with ciprofloxacin. Results: From Mar 2019 – Feb 2021, 8 pts were recruited. Median age was 71 years old. Best response was stable disease in 5 (62.5%) pts and 3 pts had progressive disease (PD). Median PFS and OS were 4.3 and 15.4 months, respectively. 2 pts developed grade 4 neutropenia and 1 pt had grade 3 febrile neutropenia. Rash was common with 50% of pts developed grade 1/2 rash. No additional toxicities from ciprofloxacin were observed. Preliminary stool analysis showed significant differences in individual bacterial strains across all timepoints in the PD vs. SD groups. There was also an increased abundance in gammaproteobacteria resistant to ciprofloxacin treatment in pts with PD. Conclusions: Gemcitabine-based chemotherapy plus ciprofloxacin demonstrated clinical activity and acceptable safety profile in PDAC. Our study also highlighted that gut microbiome may play a critical role in mediating resistance to chemotherapy. Clinical trial information: NCT04523987.
Can stereotactic ablative radiotherapy for oligometastatic pancreatic cancer help avoid perpetual chemotherapy and improve outcomes?
Authors: Elamir Ahmed , Karalis John D , Sanford Nina Niu , Polanco Patricio , Porembka Matthew R. , Timmerman Robert D. , Ligorio Matteo , Beg Muhammad Shaalan , Aguilera Todd Anthony
Published: January 2022

571

Background: The oligometastatic state is increasing recognized and improved outcomes after local regional therapies have been observed in many malignancies, however there is a paucity of data on outcomes of patients with limited extent pancreatic ductal adenocarcinoma (PDAC). We hypothesize oligometastatic pancreatic cancer (OPanc) with 1-5 metastases would benefit from stereotactic ablative radiotherapy (SABR) to all active sites of disease, can improve outcome, and offer time off chemotherapy. Here in, we report our institutional experience of treating OPanc with SABR to evaluate the outcome and feasibility of the approach and compare outcomes with other institutional cohorts. Methods: A retrospective review was conducted on patients with stage IV PDAC who received SABR after noted to have OPanc. Patients with a histological diagnosis of PDAC, number of metastases ranging between 1-5, and who received SABR to all active disease at time of treatment were included. We identified a comparable group of 16 patients with similar metastatic burden but did not receive SABR. Overall survival and time off chemotherapy were evaluated in addition to assessment of each patients’ disease course. Results: Fourteen patients met the inclusion criteria. Five patients had metastases confined to lung only and nine to the liver only. Median baseline CA 19-9 was 105 U/mL (range < 1, 921 U/mL). Eight patients had metachronous OPanc diagnosis. SABR was delivered to 22 metastatic tumors. Median progression free and overall survivals were 25 and 12.8 months, and 46 and 14.5 months for the SABR treated and the chemotherapy cohorts respectively. A total of 85.7% of patients that received SABR had a chemotherapy treatment break of greater than 6 months. Conclusions: Management of OPanc (1-5 lesions) with SABR as local regional therapy could improve outcomes in this selected population and warrants prospective evaluation.
Integrative analysis of KRAS-wildtype pancreatic ductal adenocarcinoma reveals unique similarities to extrahepatic cholangiocarcinoma.
Authors: Tsang Erica S , Topham James T. , Karasinska Joanna , Kalloger Steve , Csizmok Veronika , Williamson Laura , Wong Hui-Li , O'Kane Grainne M. , Loree Jonathan M. , Notta Faiyaz , Bathe Oliver F. , Tang Patricia A. , Goodwin Rachel Anne , Knox Jennifer J. , Gallinger Steven , Laskin Janessa J. , Marra Marco A. , Jones Steven J. M. , Schaeffer David F. , Renouf Daniel John
Published: January 2022

587

Background: Oncogenic driver mutations in KRAS represent a hallmark genomic event in approximately 90% of pancreatic adenocarcinoma (PDAC). For the remaining 10% of patients with KRAS wildtype (wt) PDAC, distinct driver mutations have been described, but their transcriptional landscape has not been reported. Here, we leverage sequencing data from the PanGen trial to provide a comprehensive characterization of advanced KRASwt PDAC. Methods: 63 patients with advanced PDAC received whole genome and transcriptome sequencing prior to treatment for metastatic disease as part of the PanGen trial (NCT02869802). Clinical features, somatic mutation data and gene expression patterns were compared between KRASwt and mutant groups. PDAC samples were contrasted with 77 other metastatic carcinoma (colorectal and cholangiocarcinoma) samples from the Personalized OncoGenomics trial (NCT0215562). KRAS wt-associated genes were further investigated using 3 additional PDAC cohorts (COMPASS NCT02750657, TCGA, and ICGC). Results: 9 of 63 (14%) samples were KRASwt, with an earlier median age at diagnosis (51.4 vs. 60.9 years; p=0.03). Clinical features, including diabetes, family history of malignancy, and location of primary tumor, were comparable. CA 19-9 at baseline was lower in the KRASwt group, with median 58 vs. 4900 U/mL in the KRAS-mutant group ( p=0.03). Patients with KRASwt PDAC showed increased overall survival in univariable ( p=0.0024) and multivariable ( p=0.0089) analyses. 6 of 9 (67%) KRASwt tumors had fusions involving NRG1 (n = 3), FGFR2 (n = 1), BRAF (n = 1) or NTRK2 (n = 1), while known actionable fusions were not observed in KRAS mutant patients. KRASwt tumors showed increased expression of genes associated with cholangiocytes and grouped with cholangiocarcinoma samples in unsupervised clustering analysis. Validation using three independent PDAC cohorts revealed a core set of 70 KRAS wt-associated genes that converge on keratinization, ion transport, and hormone metabolism pathways. Conclusions: Patients with KRASwt PDAC show potentially targetable molecular traits with actionable fusions. We also highlight novel mutation and expression-based similarities between KRASwt PDAC and cholangiocarcinoma samples. Recurrent dysregulation of genes involved in cellular structure and metastasis provide impetus for further investigation into the developmental trajectory and potential therapeutic vulnerabilities of KRASwt PDAC.
Prognostic utility of preoperative and postoperative circulating tumor DNA (ctDNA) in resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.
Authors: Alqahtani Ali , Alloghbi Abdurahman , Yin Chao , Mukherji Reetu , Weinberg Benjamin Adam
Published: January 2022

595

Background: Surgical resection offers the only chance of cure for localized pancreatic ductal adenocarcinoma (PDAC). Despite surgical resection, 80% of patients experience disease recurrence. There is growing evidence that support the prognostic role of perioperative KRAS-mutated circulating tumor DNA (ctDNA). We conducted a systematic review and meta-analysis to investigate the prognostic utility of preoperative and postoperative KRAS-mutated ctDNA testing in resected PDAC. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search of PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was performed in September 2021. We included studies that reported on the effects of preoperative and postoperative KRAS-mutated ctDNA on overall survival (OS) and/or relapse free survival (RFS) in resected PDAC. The random-effects model was used to calculate pooled OS and RFS hazard ratios (HRs) and 95% confidence intervals (CIs). Publication bias was assessed by visual inspection of a funnel plot of the included studies. Results: We identified 6,986 studies, and 13 studies were eligible for analysis. A total of 954 patients were included for the final evaluation. In the preoperative setting, positive ctDNA correlated with worse RFS in 8 studies (HR, 2.067; 95% CI, 1.346-3.174; P < 0.001) and worse OS in 10 studies (HR, 2.170; 95% CI, 1.451-3.245; P < 0.001) compared to negative ctDNA. In the postoperative setting, positive ctDNA correlated with worse RFS across 7 studies (HR, 2.986; 95% CI, 1.897-4.699; P <.001), and worse OS in 5 studies (HR, 5.812; 95% CI, 1.757-19.228; P = 0.004) compared to negative ctDNA. There was visible symmetry in the funnel plot of the studies included, suggesting no publication bias. Conclusions: In resected PDAC, preoperative and postoperative KRAS-mutated ctDNA positivity may be useful markers of poor prognosis in terms of RFS and OS. Clinically, KRAS-mutated ctDNA testing may also have implications when considering the aggressiveness and duration of adjuvant therapy in PDAC, although prospective trials are needed to assess this utility.
Plasma metabolomics to predict chemotherapy (CTX) response in advanced pancreatic cancer (PC) patients (pts) on enteral feeding for cachexia.
Authors: Muranaka Hayato , Moshayedi Natalie , Hendifar Andrew Eugene , Osipov Arsen , Placencio-Hickok Veronica , Stotland Aleksandr , Parker Sarah , Van Eyk Jennifer , Bhowmick Neil , Gong Jun
Published: January 2022

600

Background: We evaluated the potential of plasma metabolites as predictors of response to CTX in a prospective cohort of pts who received enteral feeding for cachexia and advanced PC. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for palliative CTX. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. As part of an exploratory analysis of the PANCAX-1 trial, serial blood samples were collected at 3 predefined timepoints over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. The mean AUC was used in pts with metabolites measured from > 1 timepoint of collection. Pts were stratified by stable disease (SD), partial response (PR), or progressive disease (PD) as best overall response to standard CTX. Results: Of 31 pts with advanced PC prospectively enrolled for enteral feeding, there were 55 blood samples collected from 28 pts available for plasma metabolomics. 20/28 (71%) pts received first-line CTX, the majority of whom (90%) received gemcitabine-based CTX. There were 2 PRs (7%) and 10 with SD (36%) as best response to CTX. Overall, there were statistically significant differences in levels of intermediates involved in multiple metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and nucleoside synthesis in pts with PR/SD vs. PD to CTX (all p < 0.05). When stratified by CTX regimen, PD to 5-fluorouracil-based CTX (e.g., FOLFIRINOX) was associated with decreased levels of essential amino acids (AAs, L-leucine, L-methionine, L-tryptophan) and non-essential AAs (L-arginine, L-serine, L-tyrosine, all p < 0.05). For gemcitabine-based CTX (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis (pyruvate), TCA cycle (L-glutamate), nucleoside synthesis (xanthine), and bile acid metabolism (taurocholic acid, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced PC pts on enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of response and warrant further study.
Improved survival in patients with lung only recurrence after surgical resection of pancreatic ductal adenocarcinoma.
Authors: May Michael S. , Michel Alissa , Lee Tristan , Wong Winston , Jamison Jacob K.R. , Manrique David , Pan Samuel M , Hu Jianhua , Safyan Rachael A , Raufi Alexander , Kluger Michael , Bates Susan Elaine , Chabot John A. , Manji Gulam Abbas
Published: January 2022

608

Background: Recurrence rates after resection of pancreatic ductal adenocarcinoma (PDA) can be up to 80%. Prior data suggests that initial site of recurrence influences prognosis. This study aims to compare survival of patients (pts) with resected PDA by initial site of recurrence. Methods: We retrospectively reviewed the demographics, treatments, recurrence and survival of 717 pts with PDA who underwent resection at Columbia University Irving Medical Center from 2011 to 2020 and were part of a tumor registry. Analyses were performed using Kaplan-Meier and paired T-tests. Results: Of 717 pts with resected PDA, 320 had confirmed recurrence. Median age at diagnosis was 67 years (yrs). Among pts with a single initial recurrence site, 36 recurred in lung, 97 in liver, 95 locally, and 23 in peritoneum. 58 pts had initial recurrence at 2 or more sites. Neoadjuvant treatment had been administered in 42%, 36%, 40%, 35%, and 22% of pts with lung, liver, local, peritoneal, and multiple sites at initial recurrence, respectively (p=0.21). Adjuvant treatment had been administered in 72%, 69%, 76%, 70%, and 72% of pts with lung, liver, local, peritoneal, and multiple sites at initial recurrence, respectively (p=0.88). Pts with initial lung recurrence had a significantly longer median overall survival (mOS), 4.39 yrs, compared to initial recurrence in the liver (1.98 yrs, p=0.02), peritoneum (2.19 yrs, p=0.0002), and at multiple sites (2.66 yrs, p=0.03). A significantly longer time from diagnosis to recurrence was observed in pts who had initial lung recurrence, compared to pts who had initial hepatic, peritoneal or multiple site recurrences. Pts with initial lung recurrence had a significantly longer time from first recurrence to death compared to pts with initial peritoneal recurrence. See Table for summary. Conclusions: Pts with resected PDA with initial pulmonary recurrence experience improved survival compared to those who recur at other distinct or multiple sites. The underlying pathways contributing to this improved survival need to be investigated further.[Table: see text]
Rural-urban disparities in mortality from gastrointestinal (GI) cancer.
Authors: Hussaini Syed , Blackford Amanda L. , Gupta Arjun
Published: January 2022

644

Background: There are notable economic, social, and political challenges to rural healthcare delivery in the US. Patients with GI cancer have high symptom burden and complex needs, challenging healthcare infrastructure. We investigated U.S. rural-urban disparities in age-adjusted mortality rates (AAMRs) from GI cancers. Methods: We utilized the CDC Wonder database to analyze deaths from GI cancer from 1999 to 2019. Per the 2013 US Census classification, we created population categories using the NCHS Urban-Rural Classification Scheme: large metropolitan (population, ≥1 million), small-or-medium-sized metropolitan (50,000-999 999), and rural (<50,000) areas. We calculated AAMRs and stratified results by age, sex, and race/ethnicity. We estimated annual percentage change (APC) in AAMR using a linear regression model of the log-scale with interactions between subgroup and year to examine differential changes over time. Results: We identified 3,020,133 deaths from GI cancers. The overall APC in AAMR was -0.9%, 95%CI, -0.8 to -1.0%. Rural areas noted least improvement in AAMR (APC, -0.6%; 95% CI, -0.4 to -0.6%, interaction p < 0.001) compared to large (APC, -1.2%; 95% CI, -1.1 to -1.3%) and small-or-medium-sized (APC, -0.8%; 95% CI - 0.7 to -0.9%) metropolitans. AAMR in rural areas decreased from 49.2/100,000 in 1999 to 43.8/100,000 in 2019 (p < 0.001; 2019 rural AAMR was highest across all areas) (Table). Across all areas, men had greater AAMRs (p<0.001) and lower reduction in APC (interaction p < 0.001) than women. Non-Hispanic Black individuals (NHBs) had highest AAMRs among all racial/ethnic groups and across all areas (p<0.001). Among those with age≥65 years, NHBs had the highest AAMRs; 367.3/100,000 in 1999 and 266.7/100,000 in 2019, and NHBs living in rural areas had the lowest APC. All racial/ethnic groups saw reductions in AAMRs across all areas. Conclusions: In this national analysis over 2 decades, rural residents with GI cancer experienced greater mortality, and the least improvement in mortality over time. Our findings support ongoing congressional policy to urgently develop infrastructure and improve cancer care access in rural areas. [Table: see text]
Preferences and attitudes of cardiologists in the management of cancer patients.
Authors: Azar Ibrahim , Wang Stephani , Kenitz Jacqueline , Lombardo Dawn , Deaño Roderick , Shields Anthony Frank , Mahmood Syed S. , Philip Philip Agop , Al Hallak Mohammed Najeeb , Schulman-Marcus Joshua
Published: January 2022

651

Background: With recent improvements in survival of cancer patients and emphasis on high-value care at end-of-life, the management of cardiovascular disease in patients with cancer is increasingly important. To our knowledge, there is no current US data examining how the presence and extent of cancer influence cardiologists’ decision-making for common cardiovascular conditions. Methods: An anonymous online vignette-based survey of cardiologists was conducted at five US institutions investigating how the extent of gastrointestinal and thoracic malignancies (prior/localized, metastatic) would influence treatment recommendation for atrial fibrillation (AF), aortic stenosis (AS), unstable angina (UA) and obstructive coronary artery disease (CAD). Results: Thirty-three percent (86/259) of cardiologists completed the survey between September and November 2019. Participants were 67% male, 51% below age 40, and 58% had five or more years of clinical experience. Majority of cardiologists practiced at teaching hospitals (72%) and were non-interventional (63%). Cardiologists were more likely to recommend procedural interventions in patients with localized cancer than with metastatic disease: AF (LAAO: 20% vs 8%), AS (AVR: 83% vs 11%), UA (LHC: 70% vs 27%) and obstructive CAD (PCI: 81% vs 38%) (Table). In patients with metastatic cancer, most cardiologists sought an oncology (82%) or a palliative care (69%) consult. Conclusions: Cardiologists were less likely to recommend invasive cardiovascular therapies to patients with metastatic cancer. This preference pattern likely reflects the influence of comorbidities and quality of life expectation on cardiologists’ treatment recommendations but may also be related to the stigma of advanced cancer. Better communication between cardiologists and oncologists is necessary to a personalized care of patients with cancer and cardiovascular disease that would maximize treatment benefit with least morbidity.[Table: see text]
Prognostic significance of exosomal programmed death-ligand 1 in advanced gastric cancer patients treated with first-line chemotherapy.
Authors: Shin Kabsoo , Kim Joori , Park Juyeon , Kim Ok Ran , Kang Nahyeon , Kim In-Ho
Published: January 2022

Retraction

The abstract by Shin et al entitled, “Prognostic significance of exosomal programmed death-ligand 1 in advanced gastric cancer patients treated with first-line chemotherapy,” ( Journal of Clinical Oncology 40, no. 4, suppl 665) published on February 1, 2022, has been retracted due to statistical errors that significantly changed the results and conclusion of the abstract.

This abstract was retracted on November 4, 2022.

665

Background: Recent studies have found that exosomal PD-L1 could be associated with prognosis in several malignancies by its potential immunosuppressive role. Prognostic role of exosomal PD-L1 in advanced gastric cancer patients treated with systemic chemotherapy has not been well explored. The aim of the present study was to explore prognostic and predictive significance of exosomal PD-L1 in advanced gastric cancer patients. Methods: We prospectively collected plasma samples of patients with advanced gastric cancer receiving first-line chemotherapy at pre and post treatment. Combined ultracentrifugation with polymer-based precipitation was applied to isolate exosome and enzyme-linked immunosorbent assay(ELISA) was applied to measure exosomal PD-L1. The correlation between exosomal PD-L1 and circulating immune cells in the plasma was evaluated. Patients were divided into two groups according to pretreatment exosomal PD-L1 level. Survival analysis was performed using Kaplan-Meier method and multivariate analyses based on Cox-proportional hazards regression model. Results: A total of 99 patients were enrolled in the study, and serum samples collected at pre-treatment and post-treatment were pooled. Median value of the pre-treatment exosomal PD-L1 was 0.42 pg/ml (range 0.01 ̃3.75). Patients with pre-treatment exoPD-L1 < 0.42 pg/mL (exoPD-L1low) showed significantly better overall survival than those with exoPD-L1 ≥ 0.42 pg/mL(exoPD-L1high) (p = 0.033). Progression-free survival was not different between the groups (p = 0.754). exoPD-L1lowgroup showed significantly higher percentages of CD8+T cells than exoPD-L1high group. (p = 0.024). In multivariate analysis, pretreatment exosomal PD-L1, poorly differentiated tumors and No. of metastatic sites(≥2) were independent prognostic factors for overall survival. Conclusions: In summary, the level of pre-treatment exosomal PD-L1 could be used as a prognostic marker for patients with advanced gastric cancer receiving systemic chemotherapy.
An observational study to evaluate RAS mutations in circulating tumor DNA after standard chemotherapies for metastatic colorectal cancer patients with tumors harboring RAS mutation: RASMEX study (JACCRO CC-17).
Authors: Izawa Naoki , Kagawa Yoshinori , Satake Hironaga , Sunakawa Yu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi
Published: January 2022

TPS230

Background: RAS status in tumor tissue is a predictive factor for the efficacy of anti-epidermal growth factor receptor (EGFR) antibodies therapy in patients (pts) with metastatic colorectal cancer (mCRC). In mCRC pts with tumors harboring RAS mutation, anti-EGFR antibodies therapy has the lack of clinical benefit; thus, the survival of RAS mutant mCRC pts is shorter compared to RAS wild mCRC pts. Recently, several studies have shown that colorectal cancer tissue had heterogeneity of gene profiling, and the analysis of circulating tumor DNA (ctDNA) in blood samples could detect the change of gene alterations in tumors which were caused by chemotherapy. Bouchahda et al., demonstrated that nearly half of the pts with RAS mutant mCRC had no detectable RAS mutation in ctDNA after first-line chemotherapy; moreover, some of the pts had clinical benefits from post-anti-EGFR antibodies therapy. Therefore, anti-EGFR antibodies therapy might become a novel treatment option for RAS mutant mCRC pts without RAS mutations in ctDNA after chemotherapies. Other report also showed the frequency of no RAS mutations in ctDNA was about 1%. There have been few studies to prospectively evaluate the RAS status in ctDNA for mCRC pts with RAS mutant tumors treated with standard chemotherapies. We, therefore, conducted an observational study to evaluate RAS mutations and the mutation allele frequency in ctDNA for mCRC pts with RAS mutant tumors who were treated with first- or second-line chemotherapy. Methods: This study is a multi-center observational/translational study in 67 facilities. The key eligibility criteria are as follows: 1) Eastern Cooperative Oncology Group Performance status 0-1, 2) histologically proven unresectable mCRC, 3) RAS mutation in tumor tissue, 4) refractory or intolerable after response to prior fluoropyrimidine-containing regimen. OncoBEAM RAS CRC kit is used to investigate RAS status in ctDNA just after first- or second-line treatment in enrolled pts. The primary endpoint is the frequency of pts without RAS mutations in ctDNA. Secondary endpoints include mutation allele frequency of RAS in ctDNA and clinical outcomes of pre- and post-treatments (overall response rate, disease control rate, overall survival, and progression-free survival). As the exploratory analysis, gene alterations related to the resistant mechanism of anti-EGFR antibodies (BRAF, PIK3CA, ERBB2, MET) are analyzed in pts without RAS mutations in ctDNA. We assume that no RAS mutations are observed in ctDNA in at least 1 % pts. We expect that one patient with no RAS mutations in ctDNA is detected in 100 pts; thus, the sample size of 300 pts is set for our study. Accrual is starting in April 2021. Clinical trial information: UMIN000043442.
Prospective study of the co-relation of ctDNA with pathologic complete remission (pCR) and other efficacy outcomes in rectal cancer patients undergoing neoadjuvant chemotherapy and radiation.
Authors: Xue RuoBing , Sharma Vivek R. , Farmer Russell Ware , Rai Shesh , Wu Xiaoyong , Krainock Michael , Drummond Bridgette , Olshan Perry , Billings Paul R. , Aleshin Alexey
Published: January 2022

TPS235

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker for non-invasive longitudinal monitoring of tumor progression in cancer management. Through the recent advances in next generation sequencing (NGS) technologies and personalized assays, ctDNA has been heralded as a promising tool to detect residual disease, relapse, and monitor treatment response in hematologic malignancies and solid tumors. Our study aims to determine whether treatment related ctDNA dynamics can be used as a reliable indicator to predict pathologic complete response (pCR) in patients with rectal cancer receiving neoadjuvant treatment. Methods: This is a prospective observational cohort study. The primary aim is to estimate the sensitivity and specificity of ctDNA clearance in predicting pCR in patients undergoing neoadjuvant therapy. The secondary aim is to evaluate the feasibility of using ctDNA as a surveillance method to detect progression of rectal cancer during neoadjuvant therapy and relapse in the subsequent follow up period. ctDNA levels are collected from newly diagnosed rectal cancer patients at 7 discrete time points: at diagnosis or screening, during neoadjuvant therapy, after completion of neoadjuvant therapy and 1 month, 2 months, 4 months, 6 months after surgery. This will be followed by every 3 months ctDNA testing for surveillance for up to 2 years. We expect to enroll approximately 30 patients at our institution. The subjects will be sorted into two groups: responders and non-responders based on whether they achieve pCR. ctDNA level between two groups will subsequently be compared. The use of ctDNA to predict pCR in rectal cancer patients may allow for many of these patients to safely avoid surgery if undetectable ctDNA at the end of neoadjuvant therapy strongly correlates with pCR. We are actively enrolling patients into this prospective observational study and expect to report the data in the near future. The data we obtain will be combined with those from several institutions around the US doing similar studies with the same test. Data analysis will subsequently be conducted. [Table: see text]
A phase 3 randomized, double-blind, placebo-controlled, multicenter, global study of durvalumab with and after chemoradiotherapy in patients with locally advanced, unresectable esophageal squamous cell carcinoma: KUNLUN.
Authors: Wang Luhua , Chen Ming , Kato Ken , Wyrwicz Lucjan , Smyth Elizabeth Catherine , Jiang Anastasia , Zhang Di , Robbins Scott H. , He Philip , Negro Alejandra , Saba Nabil F.
Published: January 2022

TPS373

Background: Esophageal cancer is the eighth most common cancer type and the sixth leading cause of cancer-related death worldwide, and esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. For patients with locally advanced, unresectable ESCC (AJCC 8th Stage II–IVA), definitive chemoradiotherapy (dCRT) is the current standard of care; however, up to half of patients will experience disease progression within two years of dCRT, and overall survival rates remain suboptimal. The combination of immune checkpoint inhibitors with CRT has demonstrated synergistic antitumor activity in pre-clinical models, and recent clinical data has demonstrated clinical benefit of combined programmed cell death-1 inhibition and preoperative CRT in patients with locally advanced ESCC. KUNLUN (NCT04550260) is a Phase 3, multicenter, global study evaluating the efficacy and safety of durvalumab, a programmed cell death ligand-1 (PD-L1) inhibitor, given concurrently with, and after, dCRT in patients with locally advanced, unresectable ESCC. Methods: Approximately 600 patients will be randomized 2:1 to receive either durvalumab with dCRT (cisplatin plus fluorouracil or cisplatin plus capecitabine, with a total dose of 50–64 Gy radiation), followed by durvalumab for up to approximately 24 months, or placebo with dCRT, followed by placebo for up to approximately 24 months. Eligible patients will have histologically or cytologically confirmed ESCC, and present with locally advanced, unresectable ESCC that is deemed suitable for dCRT. Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1, and have not received prior anti-cancer treatment. The co-primary endpoint of the study is progression-free survival according to RECIST v1.1 as assessed by blinded independent central review in all randomized patients and in patients with PD-L1-high tumors. Additional endpoints include overall survival and safety. Study enrollment is ongoing. Funding: This study was sponsored by AstraZeneca. References: Hong MH, et al. J Clin Oncol 2019;37(15 suppl). Abs 4027. Clinical trial information: NCT04550260.
AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC).
Authors: Fan Jia , Ren Zhenggang , Hsu Chiun , Guo Yabing , Song Tianqiang , Wang Wentao , Chao Yee , Gao Yujuan , Li Bai , Ferro Salvatore , Yen Chia-Jui
Published: January 2022

TPS488

Background: Treatment with PD-1/programmed death-ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all investigator-assessed overall survival), safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.
Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: The DEMAND randomized phase II clinical trial.
Authors: De Toni Enrico N. , Kubisch Ilja , Ben Khaled Najib , Ricke Jens , Mayerle Julia , Ehmer Ursula , Waldschmidt Dirk , Rössler Daniel Christoph , Oehrle Bettina , Bitzer Michael , Kandulski Arne , Reuken Philipp A. , Wege Henning , Seidensticker Max
Published: January 2022

TPS492

Background: Atezolizumab and bevacizumab is the first approved immunotherapeutic regimen for first-line treatment of patients with advanced hepatocellular carcinoma (HCC). The efficacy and tolerability of this regimen suggests that its use could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The effect of TACE combined with atezolizumab and bevacizumab could improve response and tumor control as well as prevent disease progression in non-responders to TACE. Response to the early use of immunotherapy could also reduce the number and extent of TACE cycles needed to achieve tumor control, thereby contributing to the prevention of collateral damage to the liver parenchyma and preservation of liver function. Initiating immunotherapy first may also promote the access of circulating lymphocytes into tumor lesions. The DEMAND study investigates the efficacy and ideal sequence of TACE and immunotherapy in intermediate stage HCC. Methods: This investigator-initiated, multi-center, randomized, open-label phase 2 trial is the first study to evaluate the safety and efficacy of atezolizumab and bevacizumab prior to, or in combination with TACE in patients with unresectable HCC. 106 patients (Barcelona Clinic Liver Cancer Stage A not amenable to curative therapy or B, Child-Pugh A or B7, Eastern Cooperative Oncology Group performance status 0 or 1, no prior TACE) will be randomized in a 1:1 ratio to receive either up-front atezolizumab and bevacizumab followed by TACE selectively directed against progressive lesions (Arm A, 53 patients), or TACE and synchronous treatment with atezolizumab and bevacizumab (Arm B, 53 patients). Patients receive study treatment until loss of clinical benefit or unacceptable toxicity for up to 24 months. The use of local ablation is allowed for the treatment of lesions which cannot be targeted sufficiently selectively by TACE, or of de-novo lesions. The primary endpoint is the 24-month survival rate; secondary endpoints include objective response rate, progression-free survival, safety and quality of life. Translational analyses aim at identifying predictive biomarkers and focus on immune cell phenotyping in tumor and peripheral blood, circulating tumor DNA and changes in the diversity of the gut microbiome. Recruitment is ongoing in 15 German centers with 21 of 106 patients randomized. Clinical trial information: NCT04224636.
LEAP-012 trial in progress: Transarterial chemoembolization (TACE) with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma (HCC)
Authors: El-Khoueiry Anthony B. , Llovet Josep M , Vogel Arndt , Madoff David C. , Finn Richard S. , Ogasawara Sadahisa , Ren Zhenggang , Mody Kalgi , Li Jerry J. , Siegel Abby B. , Dubrovsky Leonid , Kudo Masatoshi
Published: January 2022

TPS494

Background: Limited treatment options are available for patients with intermediate HCC. Lenvatinib, a potent multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, are approved first- and second-line therapies for advanced HCC, respectively. The LEAP-012 study (NCT04246177) is investigating lenvatinib plus pembrolizumab in combination with TACE versus placebo plus TACE in patients with intermediate-stage HCC. Methods: LEAP-012 is a randomized, double-blind, phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥1 measurable lesion per RECIST v1.1, Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to receive lenvatinib 8 mg (body weight < 60 kg) or 12 mg (body weight ≥60 kg) orally once daily plus pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) plus TACE or placebo orally once daily plus placebo IV Q6W plus TACE. Response will be assessed by imaging every 9 weeks; safety will be assessed throughout the study and up to 90 days after the end of treatment. Dual primary end points are overall survival and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified RECIST by BICR; ORR, DCR, DOR, and TTP per RECIST v1.1 by BICR; and safety. Exploratory end points are PFS, ORR, DCR, DOR, TTP, and time from randomization to second/subsequent disease progression after initiation of new anticancer therapy or death from any cause, whichever occurs first, per RECIST v1.1 by investigator review, identification of molecular biomarkers, and health-related quality of life. Recruitment began in April 2020, and the planned sample size is 950 patients. The results of the LEAP-012 study will show the clinical benefit of adding lenvatinib plus pembrolizumab to the current standard of care TACE for patients with intermediate-stage HCC not amenable to curative treatment. Clinical trial information: NCT04246177.