bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary analysis of a phase II study of atezolizumab plus bevacizumab for TACE-unsuitable patients with tumor burden beyond up-to-seven criteria in intermediate-stage hepatocellular carcinoma: REPLACEMENT study.
Authors: Ueshima Kazuomi , Kudo Masatoshi , Tsuchiya Kaoru , Kato Naoya , Yamashita Tatsuya , Shimose Shigeo , Numata Kazushi , Kodama Yuzo , Tanaka Yasuhito , Kuroda Hidekatsu , Itoh Shinji , Aikata Hiroshi , Hiraoka Atsushi , Moriguchi Michihisa , Wada Yoshiyuki , Nakao Kazuhiko , Tateishi Ryosuke , Ogasawara Sadahisa , Yamamoto Kouji , Ikeda Masafumi
Published: June 2023

4125

Background: Intermediate-stage hepatocellular carcinoma (HCC) is a heterogeneous disease; therefore, the efficacy of transarterial chemoembolization (TACE) is affected by tumor burden, resulting in a wide range of survival outcomes. Multiple recent guidelines suggest that systemic therapy is preferable for patients with intermediate-stage HCC who are TACE unsuitable because of high tumor burden, such as beyond up-to-seven criteria. The Phase III IMbrave150 study established atezolizumab plus bevacizumab (atezo+bev) as the standard of care in patients with unresectable HCC. Here, we investigated whether atezo+bev is potentially superior to TACE in efficacy and safety in TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria. Methods: In this multicenter, phase II study, atezo 1200 mg + bev 15 mg/kg q3w were administered to eligible patients (as defined above plus having Child-Pugh A liver function) enrolled from Dec 2020 to Sep 2021 until discontinuation due to disease progression, adverse events (AEs), or other reasons. Overall survival (OS) follow-up continued for 2.5 years after enrolment. The primary endpoint was progression-free survival (PFS) assessed by mRECIST by investigator; secondary endpoints were objective response rate (ORR), PFS by RECIST v1.1, OS, and safety. In an exploratory analysis, we conducted propensity score matching (PSM) analysis to compare the efficacy between atezo+bev and TACE, the data of which were retrospectively collected in patients treated with TACE in each participating center from Jan 2017 to Dec 2017. Results: In total, 74 patients were enrolled (male, 87.8%; mean age, 73.7 years; median [range］maximum tumor diameter by pre-treatment CT, 4.8［1.0,13.0］cm). Median (min, max) follow-up was 15.0 (1.6, 21.6) months. Median PFS was 9.1 (95%CI: 7.1, 10.2) months (by mRECIST; primary endpoint). ORR was 45.9 (95%CI: 34.3, 57.9) % by mRECIST. Median OS was not reached (NR) (95%CI: NR, NR). 12-month OS rate was 84.6 [95%CI: 74.0, 91.2]%. The most frequent AEs (any grade ≥10% of patients) were hypertension, proteinuria, malaise, anorexia, edema, pruritis, and diarrhea. Conclusions: Atezo+bev provides clinical benefits to TACE-unsuitable patients with intermediate-stage HCC beyond up-to-seven criteria. Results of the exploratory PSM analysis will be presented. Clinical trial information: jrcts071200051 .
The efficacy of radical hepatectomy versus stereotactic body radiotherapy for primary hepatocellular carcinoma: A propensity score matching analysis.
Authors: Hu Yulin , Kong Feng-Ming Spring , Ji Ren
Published: June 2023

4130

Background: Recent international guidelines have included stereotactic body radiotherapy (SBRT) which outstanding tumor control as a treatment option for hepatocellular carcinoma (HCC) in several settings. However, data evaluating surgery and SBRT are limited, and results published were controversial. The retrospective study aims to compare the efficacy of hepatectomy and SBRT for HCC. Methods: The study population started with patients in databases of primary HCC, treated with curative hepatectomy or SBRT, regardless of tumor number, tumor size, cirrhosis and portal vein thrombosis. Patients with prior cancer treatment other than transarterial chemoembolization were excluded. In order to reduce the potential confounding effect of treatment and selection bias, 3-to-1 propensity score models were constructed based on each patient’s estimated propensity score. The variables significant for overall survival were considered for the match, including age, sex, Child-Pugh score, ECOG performance status score, maximum diameter, BCLC stage, prothrombin time, total bilirubin, albumin, and white blood cell. Overall survival and progression-free survival were compared. Results: A total of 174 patients, 154 in hepatectomy group and 20 in SBRT group, were analyzed. 125 men and 29 women, mean 56.2 years of age, in hepatectomy group. 12 men and 8 women, mean 70.5 years of age, in SBRT group. ECOG was a significant favorable factor for overall survival. Maximum diameter, portal vein embolization, aspartate transferase and albumin was significant favorable factors for disease-free survival of patients with primary hepatocellular carcinomas. Before PSM, patients in the hepatectomy group tended to be younger, had better performance status, less cirrhosis, less tumor number and had better hepatic function than those in the SBRT group ( P < .05). The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 77.9% vs 35.4 (P = .003) and 30 vs 20 month (P = .486), respectively. After PSM, 80 patients, 60 in hepatectomy group and 20 in SBRT group, were analyzed. The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 71.9% vs 56.6 (P = .92) and 17 vs 26 month (P = .656), respectively. The patients of hepatectomy group had less cirrhosis, better liver function and less tumor number than those in 20 with SBRT. Conclusions: For primary HCC, regardless of tumor size and tumor number, stereotactic body radiotherapy can provide similar result on overall survival and tumor control compared to hepatectomy. Stereotactic body radiotherapy can also be less invasive and provide less inpatient time. So stereotactic body radiotherapy can be a effective treatment for patients with primary HCC.
Racial disparities in the outcomes of liver transplantation in the treatment of hepatocellular carcinoma.
Authors: Kamal Syeda Ashna Fatima , Vikash Sindhu , Sohail Haris , Kilani Yassine , Vikash Fnu
Published: June 2023

4131

Background: According to the National Comprehensive Cancer Network (NCCN), liver transplantation (LT) is currently the treatment of choice for patients with early hepatocellular carcinoma (HCC). A retrospective study in 2016 showed a difference in mortality among races in patients undergoing treatment for HCC. Our study is the first to compare the outcomes of mortality, morbidity and hospital utilization of HCC patients undergoing LT among races in the US. Methods: This is a retrospective longitudinal study of patients with a primary diagnosis of HCC. We retrieved data from the Nationwide Inpatient Sample (NIS) databases from the years 2016 to 2020 using ICD-10 codes. Multivariate regression analysis was applied to compare the outcomes in races, adjusted for patient and hospital confounders. A T-Test and Chi Square test were performed to compare baseline characteristics. We used STATA Version 17.0 Software for analysis. The p-value was set at p < 0.05 for statistical significance. Results: Among a total of 112,110 adults with HCC, 2.8% (n=3,150) underwent LT. Blacks had lower rates of LT. Blacks and Hispanics were found to have a lower income (p= 0.000). No difference in the Charlson Comorbidity index was noted among races (p=0.5519), however, Blacks had more smokers (p=0.0149). Hispanics had a significant increase in THC compared to Whites (coefficient: 102,058 US Dollars, p=0.033, CI95%: -109,404 - 119,787), with no difference in the length of stay among races. Blacks had higher rates of mortality (p=0.004), acute kidney injury (AKI) (p=0.001), and similar rates of transplant complications. Conclusions: Our study showed that while Blacks have lower rates of LT, they have a higher rate of mortality and morbidity following LT. Large scale studies are necessary to help determine factors associated with these findings.
ACTION-1 phase Ib/3 trial of RYZ101 in somatostatin receptor subtype 2–expressing (SSTR2+) gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Initial safety analysis.
Authors: Morris Michael , Ulaner Gary A. , Halperin Daniel M. , Strosberg Jonathan R. , Mehr Samuel H. , Li Daneng , Soares Heloisa P. , Anthony Lowell Brian , Kotiah Sandy Diana , Jacene Heather , Pavel Marianne E. , Kunz Pamela L. , Ferreira Denis Vasconcelos , Li Joanne , Ma Kimberly , Rearden Jessica , Moran Susan , Hope Thomas A. , Singh Simron
Published: June 2023

4132

Background: RYZ101 (225Ac-DOTATATE) is a first-in-class, highly potent alpha-emitting radiopharmaceutical in development for treating SSTR2+ solid tumors. Alpha-particles (as emitted by 225Ac) have a shorter path length (40–100 μm) and higher linear energy transfer (80–100 keV/μm) than beta-particles, causing more frequent double-strand DNA breaks and potentially higher cancer cell kill rates and less damage to healthy tissues. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in patients (pts) with advanced well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Part 1 (phase 1b) aims to determine safety, pharmacokinetics, and recommended phase 3 dose (RP3D) of RYZ101. Methods: Part 1 is an uncontrolled dose de-escalation study with a Bayesian optimal interval design. Escalation (0.197) and de-escalation (0.298) boundaries based on a target dose-limiting toxicity (DLT) rate of 25% were applied. Pts received RYZ101 IV every 8w for up to 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose), 120 kBq/kg (3.2 µCi/kg); if necessary, Level –1, 90 kBq/kg (2.4 µCi/kg); Level –2, 60 kBq/kg (1.6 µCi/kg). No dose escalation above starting dose was permitted. DLT was assessed for 56d after the first RYZ101 treatment. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions and safety data review were overseen by a Data Review Committee. Data cut-off: 26 Oct 2022. Results: At data cut-off, 9 pts had received RYZ101 at 120 kBq/kg (median dose 8.9 MBq); 7 pts were DLT-evaluable. No DLTs occurred and no dose de-escalation steps were implemented. Baseline characteristics: median age 70y; male (n=6)/female (n=3); ECOG PS 0 (n=4)/1 (n=5); median disease duration 6.9y; primary tumor site GI (n=6)/pancreas (n=3). A safety summary is shown. No treatment-related serious AEs were observed. TEAE requiring dose reductions occurred in 2 pts (Grade 2 platelet count decreased, n=1; Grade 2 thrombocytopenia, n=1). Grade 3 or 4 TEAEs occurred in 3 pts (lymphocyte count decreased, n=2; skin infection, n=1; weight decreased, n=1). One serious adverse event (skin infection) was unrelated to treatment. Conclusions: RYZ101 was well tolerated at 120 kBq/kg, which was declared the RP3D. Part 2 (Phase 3) will commence after Part 1 and will compare RYZ101 at the RP3D with standard of care in pts with advanced SSTR2+ GEP-NETs with disease progression following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 . [Table: see text]
Novel use of alternate (Alt) response (Rp) criteria (Cr) for early prediction of outcomes in pancreatic (P) neuroendocrine tumors (NETs): Utilizing banked imaging data from the ECOG-ACRIN E2211 study.
Authors: Vijayvergia Namrata , Handorf Elizabeth A. , Kunz Pamela L. , Alkim Emel , Burke Lauren M.B. , Catalano Paul J. , Graham Noah , Levin Laura , Li Weier , Meeker Caitlin R. , Rubin Daniel L , Narasimhan Sridharan Anush , O'Dwyer Peter J. , Wong Terence Z. , Anaokar Jordan
Published: June 2023

4133

Background: The evaluation of treatment (Tx) Rp in NETs using CT/MRI scans can be difficult. Previous studies, including the E2211, have shown improved progression-free survival (PFS) but no significant difference in Rp as measured by RECIST 1.1 (R1.1) Cr. Thus, making it difficult to determine Tx effectiveness with short-term imaging, further complicated by differences in imaging protocols and inter-reader variability. Incorporating tumor density, using smaller threshold changes in tumor size, and novel quantitative features may be more sensitive and precise than R1.1 (e.g. CHOI in GIST) but they have not been studied for NETs. Methods: Banked CT images from the E2211 trial were repurposed to study novel Cr. Three radiologists provided a R1.1 assessment. Density and radiomic features were calculated from a 2D region of interest in the portal venous phase (as per CHOI Cr). Patients were classified as responders (PR), stable disease (SD), or progressive disease (PD) based on R1.1 and CHOI and compared with PFS to determine the best predictor. Radiomic features were analyzed using pyradiomics. Wilcoxon tests were used to compare scan quality by center type, agreement was measured using Cohen’s Kappa, and predictive value was quantified using the c-statistic and AUC for time-varying outcomes. Results: 67 patients had their scans repurposed for the study. Inter-reader agreement for overall imaging studies was fair, with only 5 of 9 PD cases noted by reviewer 1 being agreed upon by reviewer 2 (proportional agreement for PD = 0.56) and a Kappa of 0.6 (95% CI 0.41 – 0.79). The CHOI Cr showed improved prediction of PFS compared to R1.1 (12-month AUC 0.75 for CHOI vs 0.69 for R1.1, c-statistic 0.66 vs 0.64, p=0.22), and was able to predict improved PFS for PR versus SD at the first interval scan. This was not seen with R1.1 (table). Radiomics and texture analysis as a potential adjunct to CHOI is being studied and results will be presented. Conclusions: This study using repurposed banked imaging from an NCTN trial, found that there was significant variability in the interpretation of images, and that the R1.1 Cr had a poor correlation with Rp in PNETs. The CHOI Cr emerged as a better alternative as it may have a better correlation with PFS and the ability to predict outcomes at the point of first disease assessment. Importantly, CHOI Cr can be easily applied in clinical practice to inform treatment decisions. Further research is needed to confirm these findings and define the therapeutic importance. [Table: see text]
Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.
Authors: Coveler Andrew L. , Reilley Matthew , Zalupski Mark , Macarulla Teresa , Fountzilas Christos , Castanon Alvarez Eduardo , Nagrial Adnan , Uboha Nataliya Volodymyrivna , Frentzas Sophia , Overman Michael J. , Noonan Anne M. , Messersmith Wells A. , Pavlakis Nick , Mettu Niharika B. , Smith Paul , Murtomaki Elina , Bragulat Veronique , Cooper Zachary A. , Kumar Rakesh , Spigel David
Published: June 2023

4136

Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]
Nationwide implementation of best practices in pancreatic cancer care (PACAP-1): Stepped-wedge cluster randomized trial.
Authors: Mackay Tara , Latenstein Anouk EJ , Augustinus Simone , van der Geest Lydia G. , Bogte Auke , Bonsing Bert A. , Bos Hendrik , Bosscha Koop , Brosens Lodewijk , Cirkel Geert A. , Hol Lieke , Busch Olivier R.C. , Creemers Geert-Jan , Curvers Wouter L. , Derks Sarah , van Hooft Jeanin E. , Van Eijck Casper H.J. , Wilmink Johanna , Van Laarhoven Hanneke W.M. , Besselink Marc G. ,   for the Dutch Pancreatic Cancer Group
Published: June 2023

4152

Background: Implementation of new treatment strategies in cancer care is often inadequate and slow. We aimed to implement best practices in pancreatic cancer care using a nationwide stepped wedge design and assess the impact on overall survival. Methods: Nationwide multicenter stepped-wedge cluster randomized controlled trial comparing implementation of best practices with usual care (May 22, 2018 – May 29, 2020). Best practices included adequate use of perioperative and palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), and metal biliary stents. The 6-week implementation period in all 17 Dutch pancreatic centers and their regional referral networks included monitoring, return visits, and provider feedback in combination with education and reminders. Primary outcome was one-year overall survival for all disease stages and secondary outcomes included guideline compliance and quality of life. Results: Overall, 5580 patients diagnosed with pancreatic cancer were included; 2939 after implementation of best practices versus 2641 before. One-year survival did not differ among the groups (HR 0.98, 95 CI 0.88-1.08). Overall use of perioperative chemotherapy (neoadjuvant and adjuvant) did not significantly differ, but use of palliative chemotherapy significantly increased (23.9% to 30.3%, OR 1.38, 95 CI 1.10-1.74). Also the use of PERT (34.2% to 45.2%, OR 1.64, 95 CI 1.28-2.11); and metal biliary stents (74.1.% to 83.3%, OR 1.78, 95 CI 1.13-2.08) significantly increased. The Global Health Score did not differ (AUC 43.8 to 42.7, median difference -1.12, 95 CI -3.13-0.80, n=655). Conclusions: This nationwide population-based trial to enhance implementation of best practices in pancreatic cancer care showed successful implementation of most best practices, but no increase in one-year survival and quality of life. Clinical trial information: NCT03513705 .
First in class TLR7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiation therapy in patients with advanced pancreatic adenocarcinoma: Results from the AGADIR study.
Authors: Pernot Simon , Sargos Paul , Rochigneux Philippe , Ghiringhelli François , Palmieri Lola Jade , Cousin Sophie , Guégan Jean Philippe , Fumet Jean David , Bourbonne Vincent , Bessede Alban , Metges Jean Philippe , Italiano Antoine
Published: June 2023

4153

Background: Pancreatic adenocarcinoma is refractory to immune checkpoint inhibitors such as PD1/PDL1 antagonists. Investigating alternative immunotherapeutic approaches is a crucial need for this devastating disease. The potent immunostimulatory effects of Toll-like receptor (TLRs) have spurred efforts aimed at the development of TLR agonists as new immune-oncology agents. Radiation therapy combined with TLRs agonists has been shown to enhance antitumor immunity in the preclinical setting. Methods: AGADIR is a multi-cohort, phase 2, multicenter, open-label study investigating the novel TLR 7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced cancers. Cohort A enrolled patients with advanced pancreatic adenocarcinoma. BDB001 was administered IV at the dose of 0.75 mg/m² on days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 on day 1 every 3 weeks. Atezolizumab was given at the dose of 1200 mg every 3 weeks. SBRT of at least one metastatic lesion was started at least one week after the first administration of atezolizumab and at the latest before the Cycle 2 Day 1. The primary endpoint is disease control rate defined as the proportion of participants with complete response, partial response or stable disease, as per adapted RECIST v1.1, observed within 24 weeks of treatment onset. Secondary endpoints include objective response, progression-free survival, overall survival and safety. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 32 pts were enrolled in 3 centers (14 male, 18 female). Median age was 64 years (range 38 – 78). Median number of previous treatment lines was 1 (range 1 – 5). The most common treatment related adverse events were grade 1/2 asthenia, chills and fever. No death was related to the treatment. Among the 21 patients for whom central review was performed at the time of this writing, best tumor response was confirmed partial response, stable disease and progressive disease in 2 (9.5%), 6 (28.5%) and 13 (62.0%) patients respectively. The disease control rate was 38.0% (95%CI 18.1-61.5). Conclusions: The AGADIR study met its first endpoint for disease control rate in patients with advanced pancreatic cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03915678 .
Chemotherapy dose density and effect on prognosis for patients with resectable pancreas cancer: A secondary analysis of SWOG S1505.
Authors: Patel Sameer H. , Colby Sarah , Sohal Davendra , Guthrie Katherine A , Kachnic Lisa A. , Chiorean E. Gabriela , Lowy Andrew M. , Rocha Flavio G , Philip Philip Agop , Ahmad Syed
Published: June 2023

4158

Background: Chemotherapy is an integral part of multimodality treatment for resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose reductions or missed cycles on survival is difficult as few trials prospectively address the prognostic value of this important metric. Methods: SWOG S1505 (NCT02562716) was a randomized, phase II study of perioperative (12 weeks neoadjuvant and 12 weeks adjuvant) chemotherapy with mFOLFIRINOX or gemcitabine/nab-paclitaxel for resectable PDAC. Dose density (DD) was defined as the estimated percent of chemotherapy dose received of the total planned per protocol. Thresholds were based on published analyses and balance in sample size across treatment arms. Cox regression analysis of overall survival (OS) according to DD was performed in patients alive at two landmark time points: after surgery (among those who completed surgery) and at 40 weeks (when protocol therapy was to be completed). Results: Of the 103 eligible patients enrolled, median age was 64 years, 81% underwent pancreaticoduodenectomy, 15% distal pancreatectomy, and 3% a total pancreatectomy. In the 73 patients who underwent surgery, median neoadjuvant chemotherapy DD was 89%. Patients with ≥ 85% DD had higher median OS from surgery (38.1 v. 17.2 months, p = 0.039) compared to patients with < 85% DD. Of the 82 patients who survived to 40 weeks post randomization, 67 underwent surgery and 58 started adjuvant chemotherapy. The median DD for all perioperative chemotherapy was 67%; DD was significantly higher for neoadjuvant compared to adjuvant therapy (83% vs. 58%, p < 0.001). In this cohort, DD ≥ 70% was associated with better median OS from 40 weeks post randomization (32.2 v. 14.0 months, p = 0.017). DD was not significantly associated with pathologic response, margin status, or lymph node negativity. There were no significant differences in DD between the mFOLFIRINOX and gemcitabine/nab-paclitaxel arms. Conclusions: This is the first study to identify a prognostic role for chemotherapy DD in patients undergoing perioperative chemotherapy for resectable PDAC. Patients who received ≥ 85% DD preoperatively and/or ≥70% DD perioperatively had significantly higher mOS than those receiving a smaller proportion of protocol therapy. With greater survival benefit in patients who received higher chemotherapy DD, and higher DD being likelier in preoperative vs. postoperative treatment, these data support use of neoadjuvant chemotherapy for resectable PDAC. Moreover, these findings suggest that DD should be considered in prospective studies for localized PDAC to optimize therapy to be received.
Meta-analyses of factors associated with long-term survival after resection of pancreatic ductal adenocarcinoma.
Authors: Fatimi Asad Saulat , Javed Ammar Asrar , Mahmud Omar , Habib Alyssar , Grewal Mahip , He Jin , Wolfgang Christopher Lee , Besselink Marc G.
Published: June 2023

4165

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Long-term survival (>5 years, LTS) is rarely seen even after ‘curative-intent’ resection. With improved systemic control via effective systemic therapies, LTS is now being reported more frequently. However, our understanding of LTS in PDAC remains limited. The aim of the current study was to perform a systematic review and meta-analysis to quantify the associations between various clinicopathological factors and LTS following resection of PDAC. Methods: The PubMed, Embase, Scopus, and Cochrane CENTRAL databases were systematically searched for articles reporting actual patient survival data. Two reviewers independently screened and reviewed articles, extracted relevant data, and assessed the risk of bias in included studies using the Newcastle-Ottawa scale (NOS). Data that compared patients who achieved LTS after resection with those who did not were extracted from the included studies. Meta-analyses using a random effects model were conducted to identify associations between LTS and various patient, tumor, and treatment related factors. Results: Overall, 33 studies with 46,981 patients after resection of PDAC were included. Most articles received a ‘good’ NOS assessment, indicating acceptable risk of bias. The median rate of LTS was 15.27% (IQR: 9.47-20.72). Multiple clinicopathological factors were found to be associated with LTS, including tumor grade (OR: 0.40, 95%CI: 0.31-0.52), tumor stage (OR: 0.36, 95%CI: 0.31-0.41), and margin status (OR: 0.43, 95%CI: 0.36-0.50). Factors that were not associated with LTS included patient age, tumor size, tumor location, or genetic mutations. Notably, adjuvant therapy (OR: 1.68, 95%CI: 1.24-2.28) but not neoadjuvant therapy (OR: 1.08, 95%CI: 0.62-1.87) were associated with LTS. Conclusions: This meta-analysis revealed that 15% of patients achieved LTS after resection of PDAC. Multiple clinicopathological factors are associated with LTS whereas presence of ‘traditional’ negative prognostic factors does not rule out LTS. Further studies are required to identify robust predictors of LTS in resected PDAC. [Table: see text]
Mutation-site localized non-B DNA burden and survival heterogeneity in early-stage pancreatic cancer.
Authors: Xu Qi , Kowalski-Muegge Jeanne
Published: June 2023

4166

Background: Pancreatic cancer is a highly aggressive disease with a poor prognosis, and one in which most measure of genomic instability (e.g., tumor mutation burden (TMB), fraction of genome altered (FGA)) have thus far, not proven informative in differentiating survival. Non-B DNA are alternative DNA forms that deviate from the canonical B-DNA structure with potential to increase susceptibility to mutations, leading to the development of cancer. The role of non-B in pancreatic cancer has not been fully explored. Herein, we investigate the relationship between gene mutation sites co-localized with non-B DNA motifs in terms of survival and B-DNA features. Methods: Using TCGA data, we derived a genome-wide mutation signature on 104 early-stage pancreatic patients. We introduced a metric, mutation-localized non-B burden (MLNB) by the number of non-b motifs containing mutation sites, normalized to the number of mutations and motif library size. We applied MLNB to patient-specific mutation signatures to derive an MLNB burden for non-B DNA structure motifs: G-quadruplexes (G4), Z-DNA, inverted repeats (IR), mirror repeats (MR), direct repeats (DR), and short tandem repeats (STR). We performed a cluster analysis on MLNB and compared groups based on overall survival (OS) in months (mos) using a log-rank test. Comparisons of B-DNA-derived molecular features among clusters were performed using a Kruskal-Wallis and Fisher Exact test. Results: Among the 104 early-stage pancreatic patients with a mutation signature, MLNB clustering resulted in six patient clusters that differentiated by non-B DNA structure, with DR burden the longest OS cluster (n=23, median OS=30mos), significantly (p < 0.05) differing as compared to IR (n=23, median OS=15 mos), STR (n=20, median OS=16mos), MR with lack of IR (n=14, median OS=13mos) and MR with IR (n=16, median OS=8mos). A mix of Z-DNA and G4 burden defined a cluster with shorter OS (n=22, median OS=14mos) as compared to DR, though not significant. Patients with the longest OS, MLNB-DR burden cluster had mutation signatures enriched in MAPK and Notch signaling pathways, as compared to the other clusters enriched with double-stranded break and mismatch repair (IR), hedgehog and WNT signaling (STR), and interleukin-4 signaling (MR) pathways. Among all clusters, CDKN2A deletion was most prevalent except for MLNB-DR burden cluster. No Significant differences were found between the MLNB clusters with age, race gender, KRAS and TP53 mutations, FGA, TMB, tumor purity, Bailey and Moffit subtypes. Conclusions: Our results point towards the potential use of MLNB as an emerging marker of site-structure genomic instability. Considering that triplex DNA is emerging as a marker genomic instability, and that we distinguish between two MR groups based on IR burden, our results may provide insights into various instability mechanisms associated with poor survival in pancreatic cancer.
The five periampullary cancers: Not just different siblings but different families—An international multicenter cohort study.
Authors: Uijterwijk Bas , Cabus Santiago , Mavroeidis Vasileios K. , Pessaux Patrick , Korkolis Dimitris , Berger Adam C. , Björnsson Bergthor , Suárez Miguel , Vladimirov Miljama , Kleeff Jorg , Boggi Ugo , Soonawalla Zahir , Zaniboni Alberto , Serradilla Mario , Mazzola Michele , Ghorbani Poya , Wellner Ulrich , Besselink Marc G. , Abu Hilal Mohammed
Published: June 2023

4167

Background: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC) and ampullary adenocarcinoma (AAC). Based on histopathology, the AAC is currently subdivided in the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype. Despite close anatomical resemblance, it is unclear how the ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. Methods: This is an international multicenter cohort study, including patients after curative intent resection for periampullary cancer retrieved from 45 centers (from Europe, USA, Asia and Canada) between 2010 and 2021. Pre-operative CA19-9, differences in pathology and postoperative pancreatic fistula (POPF, grade B/C), 8-year overall survival (OS) and disease-free interval (DFI) were compared between DAC, AmpIT, AmpPB, dCCA and PDAC. Results: Overall, 3809 patients were included of which 348 DAC, 774 AmpIT, 848 AmpPB, 1036 dCCA and 803 PDAC. The best 8-years overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, p<0.001), dCCA (26.4%, p=0.020) and last, PDAC (12.9%, P<0.001). The best 8-years DFI was measured for AmpIT (62.7%) and the worst for both dCCA and PDAC (24.9% and 21.8%). This pattern correlated with the height of the pre-operative CA19-9 but not with the pathology, in which the largest and most progressed tumors were found in DAC. The incidence of POPF was lower in the pancreas-related tumor types (AmpPB 18.5%, PDAC 8.3%) compared to the non-pancreas related types (DAC 27.3%, AmpIT 25.5%, dCCA 27.6%). Conclusions: Despite the close anatomic relation of the five periampullary cancers, this study shows that there are prognostic and clinically relevant differences in terms of preoperative blood markers, pathology, complications, long-term survival, and recurrence. More characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for “periampullary cancers”, this study emphasizes the need for individual evaluation of each histopathological periampullary subtype with the ampullary subtypes as individual entities in future studies.
Tumour factors and the variation in non-muscle invasive bladder cancer recurrence after transurethral resection surgery between sites: Results from the RESECT study.
Authors: Gaba Fortis , Gallagher Kevin M. , Bhatt Nikita R. , Clement Keiran D. , Zimmermann Eleanor F. , Khadhouri Sinan , Kulkarni Meghana , Anbarasan Thines , Ng Alexander , Light Alexander , Asif Aqua , Chan Vinson W. , Nathan Arjun , Ross Sabrina H. , O'Brien Tim , MacLennan Steve , Nielsen Matthew E. , Mariappan Paramananthan , Kasivisvanathan Veeru ,   RESECT Study Global Collaborators (BURST)
Published: June 2023

4510

Background: To determine if there is significant variation in early recurrence after transurethral resection (TURBT) surgery between sites taking part in the RESECT study (NCT05154084) after accounting for tumour characteristics. Methods: An international, multi-centre, observational study. A mixed effects logistic regression model with tumour size, tumour number, tumour grade, tumour stage as fixed effects and site as a random effect was fitted. Cases with first, presumed non-muscle invasive bladder cancer (NMIBC) undergoing TURBT were included. Cases were excluded if first check follow up had not been completed. Sites were excluded if they did not have at least 10 cases with first check follow up. Local and/or national approvals or ethical exemptions were obtained prior to commencing the study at participating sites. Results: After exclusions, 186 sites (UK: 80; Europe: 59; North America: 18; Asia: 17; Africa 7; South America: 3; Oceania: 2), contributing a total 4597 cases (average 25 cases) were included. Median recurrence rate per site was 12% (IQR 0-22) for low grade tumours and 27% (IQR 13-42) for high grade tumours. After controlling for tumour size, number, stage and grade (all significantly and independently associated with early recurrence) there was significant residual variation attributable to site (p<0.0001, intra-class correlation, 0.1). Adjustment for sites improved the regression model from an area under the receiver operating characteristic curve of 0.66 to 0.74. Initial analysis of surgical and peri-operative practice showed wide variation, mean 75% (IQR 66-92) cases per site had detrusor muscle resection and 42% (IQR 17-58) had use of single instillation of intravesical chemotherapy. Other differences in operative and perioperative practice were identified through surveys. Conclusions: There is significant variation in the early recurrence rate of NMIBC after TURBT surgery between sites that could not be explained by currently understood tumour features. We have identified differences in surgical technique and perioperative practice that may impact this and further investigation is warranted to understand how these factors impact recurrence rates. Clinical trial information: NCT05154084 . [Table: see text]
The impact of surgery on patients with VHL-associated tumors: An international patient survey.
Authors: Sundaram Murali , Atkinson Christian , Mann Joshua , Cooper Charley , Taylor-Stokes Gavin , Iliopoulos Othon
Published: June 2023

4517

Background: Von Hippel-Lindau syndrome (VHL) is a rare hereditary neoplastic disorder caused by mutations in the VHL gene. Treatment (tx) options for patients are limited to multiple surgeries dispersed between regular scans, watchful waiting and txs that preserve organ function. Methods: An international, cross-sectional survey comprising patients in the United States (US), Canada (CA), the United Kingdom (UK), France (FR), and Germany (DE) was conducted. Patients were recruited via the VHL Alliance; data were collected between Dec 2021 and May 2022. For inclusion, patients must have renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET), and/or central nervous system hemangioblastoma (CNS-Hb). Data collected included demographics, impact of most recent surgery on aspects of condition (1-7 scale 1 being greatly worsened and 7 being greatly improved), tx goals (top 3 goals from a list of 11), and patient preference in treatment. Patients were presented two scenarios “watch and wait” and potentially need surgery, or “take a once-daily pill” to delay a potential surgery. Results: 220 patients (68.2% female, median age 40.0, median disease duration 15.8 years) in the US (n=108), CA (n=37), the UK (n=21), FR (n=3), and DE (n=51) completed the study. 146 patients reported RCC (66.4%), n=122 reported pNET (55.5%), and n=190 reported CNS-Hb (86.4%). Among the top 4 symptoms experienced by patients were kidney cysts (n=82, 37.3%), numbness (n=59, 26.8%), dizziness (n=56, 25.5%), and fatigue/low energy (n=54, 24.5%). 205 (93.2%) patients had experienced surgery; n=171 (77.7%) had experienced multiple surgeries (median number of surgeries, 4.0). 166 patients recorded data on their most recent surgery. Of these, patients reported that their most recent surgery worsened (scored 1-3) their fatigue (51.8%), mental health (51.2%), and ability to go about daily life (45.2%). 47.3% of patients selected reduce the number of surgeries as a top tx goal, 46.4% selected being able to go about life as usual, 36.8% delay the need for surgery, and 33.2% improved quality of life. 73% of patients indicated they would prefer to take a pill which would possibly delay the time until surgery, rather than watch and wait to see if the tumor would grow. Conclusions: Surgery negatively impacts the lives of patients, leading to a worsening in their fatigue, mental health, and ability to go about daily life. Almost half of patients would like a treatment that reduces the number of surgeries, and over a third would like a treatment that delays the need for surgery. Nearly three quarters of patients would prefer to take a pill that might delay the need for surgery. Tx options that reduce the need for surgery would benefit this patient group.
First-line lenvatinib + pembrolizumab treatment across non-clear cell renal cell carcinomas: Results of the phase 2 KEYNOTE-B61 study.
Authors: Lee Chung-Han , Gurney Howard , Atduev Vagif , Suárez Cristina , Climent Duran Miguel A , Pook David William , Tomczak Piotr , Barthelemy Philippe , Lee Jae-Lyun , Nalbandian Taron , Stus Viktor , Ferguson Thomas , Wiechno Pawel , Gokmen Erhan , Lacombe Louis , Gedye Craig , Burgents Joseph , Sharma Manish , Peng Xiang , Albiges Laurence
Published: June 2023

4518

Background: Lenvatinib (lenva) + pembrolizumab (pembro) is a first-line treatment for advanced clear cell renal cell carcinoma (RCC). Initial results of the single-arm, phase 2 KEYNOTE-B61 (NCT04704219) study showed antitumor activity of lenva + pembro in patients (pts) with advanced non-clear cell RCC who had opportunity for ≥24 wk of follow-up (n=82). We report results from the complete cohort of pts enrolled in KEYNOTE-B61 (N=158) with extended follow-up. Methods: Adults with previously untreated advanced non-clear cell RCC and measurable disease per RECIST v1.1 received lenva 20 mg PO QD + pembro 400 mg IV Q6W for up to 18 cycles (~2 y). The primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DOR, DCR, and PFS per RECIST v1.1 by BICR; OS; and safety. Histology was assessed by investigator (assessment by central review is planned). Results: Of 158 treated pts, 93 (59%), 29 (18%), and 21 (13%) had papillary, chromophobe, and unclassified histology, respectively. Additionally, 6 pts (4%) had translocation and 9 (6%) had other histology. 70 pts (44%) had IMDC favorable risk and 88 (56%) had intermediate/poor risk. Median follow-up was 14.9 mo (range 8.7-19.7). ORR was 49% (95% CI, 41-57; 9 CRs [6%]; 69 PRs [44%]). DCR was 82% (95% CI, 75-88). Median DOR was not reached (NR; range, 1.5+ to 15.3+ mo). By Kaplan-Meier estimate, 75% of responders had a response for ≥12 mo. ORR and DCR by histology are shown in the table. For the IMDC favorable risk group, ORR was 51% (95% CI, 39-64) and DCR was 87% (95% CI, 77-94). For the IMDC intermediate/poor risk group, ORR was 48% (95% CI, 37-59) and DCR was 78% (95% CI, 68-86). In all pts, median PFS and OS were 17.9 mo (95% CI, 13.5-NR) and NR (95% CI, NR-NR), respectively; 12-mo rates were 63% and 82%. Treatment-related AEs (TRAEs) occurred in 149 pts (94%) and were consistent with results from other studies. The most common (≥30%) TRAEs were hypertension (n=90; 57%), diarrhea (n=69; 44%), and hypothyroidism (n=58; 37%). Grade 3-4 TRAEs occurred in 81 pts (51%). Overall, 17 pts (11%) discontinued pembro, 14 (9%) discontinued lenva, and 5 (3%) discontinued both drugs because of TRAEs. No deaths occurred because of TRAEs. Conclusions: In pts with advanced non-clear cell RCC enrolled in KEYNOTE-B61, lenva + pembro showed antitumor activity with no new safety signals. These data support the use of lenva + pembro as first-line treatment for pts with non-clear cell RCC, regardless of histology. Clinical trial information: NCT04704219 . [Table: see text]
Efficacy of first-line (1L) immunotherapy (IO)-based regimens in patients with sarcomatoid and/or rhabdoid (S/R) metastatic non-clear cell renal cell carcinoma (nccRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Labaki Chris , Bakouny Ziad , Lemelin Audreylie , Ernst Matthew Scott , Takemura Kosuke , Wells J Connor , Pal Sumanta Kumar , Szabados Bernadett , Beuselinck Benoit , McKay Rana R. , Lee Jae-Lyun , Yuasa Takeshi , Parnis Francis , Bjarnason Georg A. , McGregor Bradley Alexander , Braun David A. , Xie Wanling , Xu Wenxin , Heng Daniel Yick Chin , Choueiri Toni K.
Published: June 2023

4519

Background: Patients with advanced RCC with S/R components exhibit poor clinical outcomes. IO-based combination therapies demonstrated substantial efficacy among patients with metastatic S/R ccRCC, compared to VEGF targeted therapy (VEGF-TT). Recent trials showed promising activity of IO-based regimens in patients with advanced nccRCC. We sought to assess the efficacy of IO regimens among patients with S/R nccRCC. Methods: Patients with advanced nccRCC treated with 1L IO regimens (IO/IO or IO/VEGF-TT) or 1L VEGF-TT monotherapy (sunitinib or pazopanib) were included. Cases were categorized as S/R or non-S/R. The primary outcomes were overall survival (OS) and time to treatment failure (TTF) in patients with S/R nccRCC receiving 1L IO or VEGF-TT. Overall response rate (ORR) was a secondary outcome. OS and TTF were compared between groups (IO vs. VEGF-TT) using Cox regression models adjusted for age, IMDC risk groups, and nccRCC subtype. ORR was compared between groups (IO vs. VEGF-TT) using a logistic regression adjusted for the same confounders. Results: Overall, 103 patients with S/R nccRCC were included, of whom 33 (32%) received 1L IO regimens. Median follow-up was 31 months. After adjustment for confounding factors, patients with S/R nccRCC treated with IO regimens presented with significantly improved survival outcomes as compared to those receiving VEGF-TT (median OS [mOS]: NR vs. 7.1 and mTTF: 9.4 vs. 2.9 mos for IO regimens and VEGF-TT, respectively). Similarly, a higher ORR was seen in patients with S/R nccRCC receiving IO regimens versus VEGF-TT (34.1 vs. 10.9%, respectively). Among 430 patients with non-S/R nccRCC (IO regimens: n=44), no significant differences in survival outcomes between regimen classes were seen (mOS: 24.4 vs. 14.8 and mTTF: 4.2 vs. 5.0 mos for IO regimens and VEGF-TT, respectively). Conclusions: To our knowledge, this represents the largest effort to characterize the outcomes of patients with S/R nccRCC treated with IO regimens. Patients with S/R nccRCC appear to derive a substantial and selective benefit from IO regimens (vs. VEGF-TT). These data support the use of IO-based regimens in patients with S/R nccRCC. [Table: see text]
Phase II study of cabozantinib (Cabo) with nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma with variant histologies (RCCvh).
Authors: McGregor Bradley Alexander , Huang Jiaming , Xie Wanling , Xu Wenxin , Bilen Mehmet Asim , Braun David A. , Zhang Tian , McKay Rana R. , McDermott David F. , Hammers Hans J. , Choueiri Toni K.
Published: June 2023

4520

Background: New therapeutic approaches in RCCvh are needed. Herein, we report on treatment intensification with the combination of Cabo/Nivo/Ipi in patients with metastatic RCCvh in a multi-institutional prospective single arm phase II trial. (NCT04413123). Methods: Eligible patients (pts) had metastatic RCCvh with ECOG performance status of 0-1 and may have received one line of prior therapy excluding immunotherapy or Cabo. Pts underwent a baseline biopsy and received treatment with Nivo 3 mg/kg and Ipi 1 mg/kg intravenously Q3 weeks (W) for 4 cycles followed by Nivo 480 mg IV Q4W. Cabo was given continuously at dose of 40 mg daily; reductions to 20 mg daily and 20 mg every other day were allowed. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Safety was a secondary endpoint. Results: 40 pts have been enrolled. At the time of data cut-off (Dec 9, 2022), 38 pts received at least 1 study drug. 11% (n=4) pts received prior systemic therapy. 45% (n=17) received all 4 doses of Nivo and Ipi; 18% (n=7) received 3 and 37% (n=14) received ≤ 2 doses. 61% (n=23) (15 of whom received 4 cycles Nivo/Ipi) received Nivo maintenance (median number of cycles, 5 (range, 1-21)). 71% (n=27) and 13% (n=5) required Cabo dose reduction to 20 mg and 20 mg every other day, respectively. Median follow-up was 8.4 (range, 2.1-23) months. Objective response was achieved in 8 pts (ORR 21%, two-sided 80% CI, 13%-32%). Median duration of response was not reached with 5 pts maintaining response > 6 months. Median progression-free survival was 8.9 (95% CI, 4.2-12.7) months. 74% (n=28) developed treatment-related grade 3 or higher toxicities; 37% (n=14) developed ≥ grade 3 elevation in AST or ALT. 29% (n=11) required high dose steroids (prednisone ≥ 40 mg daily or equivalent). 13% (n=5) discontinued all study drugs due to toxicity. No grade 5 toxicity has been reported. Conclusions: The study suggests activity for this combination in patients with RCCvh particularly among those without chromophobe histology. An additional cohort of 20 pts is enrolling with Cabo starting dose of 20 mg daily. Clinical trial information: NCT04413123 . [Table: see text]