bluuebunny/crossref_metadata_2025 huggingface dataset:
IMbrave151: A phase 2, randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer.
Authors: El-Khoueiry Anthony B. , Ren Zhenggang , Chon Hongjae , Park Joon Oh , Kim Jin Won , Pressiani Tiziana , Li Daneng , Zhukova Lyudmila , Chen Ming-Huang , Hack Stephen Paul , Wu Stephanie , Liu Bo , Wang Yulei , Macarulla Teresa
Published: January 2023

491

Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .
A multicenter, single-arm, phase II study of nivolumab in patients with biliary tract cancer with a PD-L1 combined positive score ≥ 1.
Authors: Furukawa Masayuki , Ueno Makoto , Sakai Daisuke , Ouchi Kota , Hamamoto Yasuo , Aikata Hiroshi , Ozaka Masato , Tsumura Hidetaka , Tsuji Kunihiro , Kubo Shoji , Nishina Tomohiro , Katanuma Akio , Morizane Chigusa , Ikeda Masafumi , Mizuno Nobumasa , Inagaki Takashi , Shioji Kazuhiko , Furuse Junji
Published: January 2023

533

Background: Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and high unmet medical needs still exist for the treatment of this disease. Nivolumab has shown its effectiveness against multiple cancer types, especially those with PD-L1 expression. This study assessed the efficacy and safety of nivolumab in BTC patients with a combined positive score (CPS) ≥ 1 who were refractory or intolerant to the standard of care (SOC): gemcitabine, cisplatin and tegafur/gimeracil/oteracil (S-1). Methods: This was a single-arm, multicenter, open-label, prospective phase II study. Key eligibility criteria were as follows: having unresectable or recurrent BTC (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer); being refractory or intolerant to SOC; having adequate hepatic, renal and hematological function; and having a CPS ≥ 1 in central assessment. Patients received nivolumab (480 mg, every 4 weeks) until disease progression, clinical deterioration, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the central review according to RECIST 1.1. The secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled between Mar 11, 2020 and Mar 15, 2021, of them 12 received one regimen and 72 received two or more regimens. The median follow-up period was 6.90 months. ORR per central assessment was 10.7% (CR: 3.6%, PR: 7.1%), and ORR per investigator assessment was 15.5% (CR: 2.4%, PR: 13.1%). The median PFS per central and investigator assessment was 1.02 (95% CI 0.95–1.77) months and 2.48 (95% CI 1.87–2.83) months, respectively. The median OS was 6.90 (95% CI 5.26–9.20) months. The median duration of response per central and investigator assessment was not reached (range 2.8–13.0+) and 10.15 (range 2.0–12.8+) months, respectively. The 1-year survival rate was 25.3% (95% CI 15.4–36.4). The most frequent treatment-related adverse events were pyrexia (19.0%), pruritus (16.7%), and decreased appetite (13.1%). Conclusions: Nivolumab may have some activity with a durable response and a manageable safety profile in heavily treated BTC patients with CPS ≥ 1. Clinical trial information: JapicCTI-205097 .
Downstaging locally advanced hepatocellular carcinoma with selective internal radiation therapy.
Authors: Hoang Marjorie , Chow Pierce K. H.
Published: January 2023

536

Background: Locally advanced HCC (beyond BCLC A, including PVT but without extra-hepatic metastases) that are unresectable because of inadequate future liver remnant may be downstaged by selective internal radiation therapy (SIRT) with Yttrium-90 to subsequently receive interval surgical resection. We hypothesized that HCC that required downstaging before resection will have some disparity in overall survival (OS) and recurrence-free survival (RFS) compared to HCCs that were resected upfront. Methods: We reviewed all patients who underwent surgical resection for HCC between 1st January 2000 and 31st December 2019 and identified those that had locally advanced HCC and were downstaged with Y90-SIRT and referred for consideration of surgical resection. OS and RFS of patients resected upfront for early and locally advanced HCC and those resected after downstaging were obtained using the Kaplan Meier method and compared using Log-rank (Mantel-Cox) test after propensity score matching. Results: 1141 patients had surgical resection for HCC within the study period. 245 patients were excluded for other primary cancers or metastatic disease at diagnosis. 875 were resected upfront (473 early, 402 locally advanced) and 23 locally advanced HCC were downstaged with SIRT before resection. Locally advanced HCC patients downstaged with Y90 before resection have significantly better OS and RFS than locally advanced HCC with upfront resection (5-year OS of 69.0% versus 47.5% p = 0.048; 5-year RFS of 53.5% vs 27.0%, p = 0.047) and similar OS and RFS with resected early HCC (5-year OS of 69.0% versus 62.6% p=0.475; 5-year RFS of 53.5% vs 39.0%, p = 0.736). Conclusions: In addition to downstaging HCC to resection, Y90-SIRT also produces a change in tumour biology that favours better prognosis. A randomised controlled trial to the role of SIRT as neoadjuvant therapy in locally advanced HCC is justified and can potentially change practice.
Gunagratinib, a highly selective irreversible FGFR inhibitor, in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR pathway alterations: A phase IIa dose-expansion study.
Authors: Guo Ye , Yuan Chunwang , Ding Weimin , Gao Yi , Zhu Xu , Ying Jieer , Sun Meili , Zhang Jingdong , Zhuang Zhixiang , Huang Yangqing , Deng Lichun , Chen Ping , Bai Yuxian , Niu Zuoxing , Li Wei , Yin Xiaoyu , Xu Aibing , Cheng Yufeng , Li Jin
Published: January 2023

572

Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]
Phase II study of cobolimab in combination with dostarlimab for the treatment of advanced hepatocellular carcinoma.
Authors: Acoba Jared David , Rho Young , Fukaya Erin
Published: January 2023

580

Background: Immunotherapy is the backbone of hepatocellular cancer (HCC) systemic treatments. Preclinical studies have shown that the combination of anti-TIM-3 antibody and anti-PD-1 antibody is more effective than either therapy alone. Early clinical experience shows that the combination of cobolimab (anti-TIM-3) and dostarlimab (anti-PD-1) can be safely administered. Herein we report an interim update to this phase II, single arm study of cobolimab and dostarlimab in patients with untreated advanced HCC. We hypothesize that this combination immune checkpoint inhibitor therapy will increase the overall response rate (ORR) of patients from 20% (historical control) to 35%. Methods: In total, 42 patients with histologically confirmed, Barcelona Clinic Liver cancer (BCLC) stage B or C HCC will be enrolled on to this trial. Patients receive cobolimab 300 mg and dostarlimab 500 mg on day 1 of each 21-day cycle for up to two years or until disease progression, unacceptable toxicity, or patient withdrawal. CT or MRI is performed every 9 weeks to assess clinical response. The primary objective is to assess ORR. Results: At the cutoff date of September 1, 2022, 16 patients had been enrolled and received at least one dose of cobolimab and dostarlimab. The median age was 68 years (range 44 – 84); most were male (n=15); 5 were White, 5 Native Hawaiian, 4 Asian, and 2 other races. 3 patients had stage BCLC B and 13 had stage BCLC C disease; 1 had Hep B and 5 had Hep C; and 14 were Child Pugh A and 2 Child Pugh B. This interim analysis for efficacy includes 13 patients who had at least one post-baseline tumor assessment (or clinical progression or died). Complete response was seen in 1 patient, partial response in 5 patients (ORR 46%), stable disease in 3 patients (23%), and disease progression in 4 patients (31%). Of the 7 patients with an elevated AFP at baseline, 4 (57%) had a decrease in AFP level by greater than 50%. There was one grade 4 treatment-related adverse event (AE) of neutropenia. Grade 1/2 AEs included pruritus, rash, fatigue, hypothyroidism, and elevated AST and ALT. Conclusions: Interim results indicate that the combination of cobolimab and dostarlimab has acceptable safety with encouraging clinical activity as first line treatment in patient with advanced HCC. To our knowledge, this is the first report of clinically meaningful efficacy of a TIM-3 antibody in combination with a PD-1 antibody in patients with HCC. Clinical trial information: NCT03680508 .
Management (mgmt) of futibatinib-associated adverse events (AEs) in patients (pts) with advanced cancers: Results of a pooled analysis.
Authors: Meric-Bernstam Funda , Hollebecque Antoine , Furuse Junji , Oh Do-Youn , Bridgewater John A. , Shimura Masashi , Anderson Bailey , Hangai Nanae , Wacheck Volker , Goyal Lipika
Published: January 2023

586

Background: Futibatinib, a covalently binding FGFR1–4 inhibitor, showed a 42% objective response rate with a 9.7 mo median duration of response in pts with advanced intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions/rearrangements in the phase 2 FOENIX-CCA2 trial. Futibatinib treatment (tx) was safe and tolerable with a predictable and manageable side effect profile. This pooled retrospective analysis examined mgmt of futibatinib-associated AEs in pts with advanced tumors, including iCCA. Methods: Pts from a global phase 1/2 study (NCT02052778) and a Japanese phase 1 study (JapicCTI-142552) who received futibatinib 20 mg QD (recommended dose) were included. Futibatinib dose modifications and supportive medications (meds) for AE mgmt were analyzed for futibatinib-associated AEs of clinical interest (group terms: hyperphosphatemia, hepatic AEs, retinal disorders, nail disorders, rash, palmar plantar erythrodysesthesia [PPE], cataract). The Kaplan-Meier method was used for time-to-resolution (TTR) analysis. Results: As of October 1, 2020, 318 pts with advanced solid tumors (60% CCA; 98% with ≥1 prior tx) had received ≥1 futibatinib 20 mg QD dose (median tx duration, 3.6 mo). Table includes incidence and mgmt of key AEs of clinical interest. Hyperphosphatemia was the most frequent cause of futibatinib dose modifications; 85% and 30% of pts with hyperphosphatemia received phosphate binders and/or phosphaturic agents, respectively, with no obvious TTR differences. Other common supportive meds included analgesics (in 55% of pts with nail disorders; 71% with PPE) and corticosteroids (37% of pts with rash). Retinal disorders occurred in 8% of pts (all grade [gr] 1-2 and resolved). Cataract, a late-onset AE on continued tx, occurred in 12 (4%; 4 [1%] gr ≥3) pts, leading to dose modifications in 3 pts. One pt underwent cataract surgery and resumed futibatinib tx the next day. Discontinuations due to tx-related AEs were rare (2.5%) and included 1 pt each with retinal detachment, onycholysis, and cataract. Conclusions: This analysis of AE mgmt showed a consistent and manageable safety profile for futibatinib in pts with pretreated advanced tumors. Commonly observed AEs with futibatinib were well managed with dose adjustments and supportive meds and rarely led to tx discontinuation. Clinical trial information: NCT02052778 /JapicCTI-142552. [Table: see text]
Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer.
Authors: Peng Chengwei , Saffo Saad , Shusterman Michael , Becker Daniel Jacob , Berlin Jordan , Oberstein Paul Eliezer , Nagar Anil , Yu Shun
Published: January 2023

59

Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p < 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were > 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.
Correlation of high serum interleukin-6 with clinical outcome and T cell response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.
Authors: Chon Hongjae , Kim Chan , Yang Hannah , Cheon Jaekyung , Ha Yeonjung , Lee Sung Hwan , Kang Beodeul , Kim Ilhwan , Kim Hyeyeong , Lee Won Suk , Jung Sanghoon , Gaillard Vince
Published: January 2023

596

Background: We elucidated the clinical and immunologic implications of serum interleukin (IL)-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (Discovery cohort: 84 patients from three centers; Validation cohort: 81 patients from one center). Baseline blood samples were analyzed using a flow cytometric bead array. The tumor immune microenvironment was analyzed using RNA sequencing. Results: In the Discovery cohort, clinical benefit (CB) was defined as a complete or partial response or stable disease for ≥ 6 months. Among various blood-based biomarkers, the serum IL-6 level was significantly higher in patients without CB than in those with CB (mean 11.56 vs. 5.05 pg/mL, P=0.02). The optimal cutoff value for high IL-6 was determined as 18.49 pg/mL using maximally selected rank statistics, and 15.2% of patients were identified to have high IL-6 levels at baseline. In both the Discovery and Validation cohorts, patients with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev compared with that of patients with low IL-6 levels. In the multivariable Cox regression analysis, the clinical implication of high IL-6 levels persisted even after adjustment for various confounding factors. Patients with high IL-6 levels showed reduced interferon-γ and tumor necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and CD8+ T-cell proliferation. Finally, patients with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumor microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: A sub-analysis of the phase III IMbrave150 study.
Authors: Fulgenzi Claudia A.M. , Murphy Cian , D'Alessio Antonio , Scheiner Bernhard , Pinter Matthias , Cortellini Alessio , Pinato David J. James
Published: January 2023

597

Background: The combination of atezolizumab plus bevacizumab (A+B) is the standard of care for patients (pts) with unresectable/advanced hepatocellular carcinoma (HCC). Emerging evidence suggest a detrimental role of early antibiotics (ATB) exposure in immunotherapy recipients. However, it is unclear whether ATB affect outcomes of pts receiving A+B. Methods: We conducted a patient-level analysis of subjects receiving either A+B or Sorafenib (Sor) within the IMbrave150 trial to assess the impact of early ATB exposure (ATB+, i.e. +/-30 from treatment initiation) on overall (OS) and progression-free survival (PFS). Differences in median (m) OS and mPFS were estimated by the Kaplan-Meier method. Cox proportional regression models were used to assess the prognostic impact of ATB+ adjusting for race, age, baseline AFP, baseline ALBI grade, continent of origin and neutrophil-to-lymphocyte ratio, a measure of systemic inflammation. Results: Data of 420 IMbrave150 participants were made available by Vivli. Among them, 278 received A+B and 142 Sor. Most pts were of ECOG performance status 0 (65%); 47% had extrahepatic spread, 40% had macrovascular invasion and 35% had AFP>400 ng/mL. Viral aetiology (39% HBV and 24% HCV) was the most common risk factor for HCC. Overall, 60 pts in the A+B arm (21.5%) and 31 (21.8%) in the Sor group were ATB+. Baseline characteristics were well balanced across ATB groups, except for region of origin, with a higher proportion of Asian pts in ATB+ (60% vs 45%; p=0.01). After a median follow-up of 10.38 months (95%CI:8.6-12.5), OS and PFS rates at 12 months were 72.3% and 9.7% in A+B; 64.8%, and 1.4% in Sor, respectively. ATB+ exposure was associated with increased risk of death both in univariate (HR 1.67; 95%CI 1.04-2.69) and multivariate models (HR 1.62; 95%CI 1.40-1.89) in the A+B (p for interaction <0.001), but not in the Sor arm (univariate HR 0.63; 95%CI 0.32-1.25; multivariate HR 0.70; 95%CI 0.31-1.60). Similarly, the risk of progression was increased for ATB+ pts in the A+B arm (univariate HR 1.68; 95%CI 1.03-2.71; multivariate HR 1.59; 95%CI 1.40-1.81), but not in the Sor arm (univariate HR 0.51;95%CI 0.26-1.01; multivariate HR 0.53; 95%CI 0.21-1.30) with positive p for interaction (p=0.002). Objective response rate (ORR) according to RECIST v.1.1 did not differ between ATB+ (28.0%) and ATB- (30.0%) in A+B (p=0.68). Conclusions: In a post-hoc sub-analysis of IMbrave150 we demonstrate for the first time the negative impact of early antibiotics exposure on outcomes of patients receiving A+B but not in those treated with Sor. Prospective translational studies should evaluate the role of ATB-mediated gut dysbiosis as a proposed mechanism underlying the adverse outcome in immunotherapy-recipients.
Use of FOLFOXIRI plus bevacizumab in metastatic colorectal cancer (mCRC): An age-stratified analysis.
Authors: Vassilev Zdravko , Fan Xiaozhou , Ostojic Helene , Xu Julie , Barzi Afsaneh
Published: January 2023

64

Background: As the incidence of early-onset mCRC continues to rise, evidence is emerging for the use of more aggressive treatment in the front-line setting in patients aged < 50 years (yrs). Although the superior efficacy of the multiagent chemotherapy FOLFOXIRI+bevacizumab (triplet+bev) over doublet regimens (FOLFOX or FOLFIRI+bev) is well documented, it is commonly associated with increased toxicity. Contemporary data are needed on triplet+bev use by age group in the US, which may help tailor treatment in patients with early-onset mCRC. Methods: This was a retrospective, observational cohort study using Optum Oncology Electronic Health Records data between 2010 and 2021. Use of triplet+bev and subsequent treatments were reported by age group (18–49, 50–64, ≥65 yrs) among newly diagnosed patients with mCRC. Baseline demographic and clinical characteristics data for patients receiving triplet+bev and regorafenib as a subsequent treatment were collected. Results: Among 36,053 eligible patients with mCRC diagnosed between 2010 and 2021, 13.8% were aged 18–49 yrs, 36.4% 50–64 yrs, and 49.8% ≥65 yrs at the time of diagnosis. The proportion of patients receiving triplet+bev was higher in age groups 18–49 yrs (4.0%) and 50–64 yrs (3.4%) vs ≥65 yrs (1.5%). Between 2010 and 2020, the proportion of patients receiving triplet+bev changed from 1.5% to 4.2% in age group 18–49 yrs, from 3.1% to 2.6% in 50–64 yrs, and from 1.1% to 1.2% in ≥65 yrs. Over a median 20-month follow-up period, 58.0% of patients in age groups 18–49 and 50–64 yrs, and 53.7% of patients in age group ≥65 yrs, received a new treatment after triplet+bev. In the overall cohort, the most common new treatment after triplet+bev was regorafenib (20.7%), received by 18.2% of patients in age group 18–49 yrs, 22.7% in 50–64 yrs, and 19.2% in ≥65 yrs. Other new subsequent treatments in the overall cohort included trifluridine/tipiracil (17.1%) and cetuximab (16.3%), with a similar trend seen among all age groups. Across age groups, triplet+bev recipients were more likely to be male, obese, resident in the Midwest or Northeast, and have distant metastases, and less likely to have colorectal surgical resection prior to mCRC diagnosis. Patients in age group 18–49 yrs subsequently receiving regorafenib were more likely to be obese and less likely to have Charlson Comorbidity Index ≥3, distant metastases, and colorectal surgical resection before mCRC diagnosis vs those who did not receive regorafenib. Conclusions: Our study shows that, recently, triplet+bev use has increased in patients with mCRC, particularly in those aged < 50 yrs. Chemotherapy-free treatments may be an option for these patients beyond the first-line setting. While regorafenib is typically used in third or later lines, these real-world data suggest it is often a preferred option following triplet+bev treatment.
The tumor mutation burden in gastro-entero-pancreatic-neuroendocrine tumors.
Authors: Jeong Sun Young , Kim Seung Tae , Jang Jae Yeon
Published: January 2023

654

Background: Neuroendocrine tumors (NET) are rare tumors with limited treatment options. Tumor mutation burden (TMB) has been known as a novel biomarker in various tumor types. However, there has been little study of the role of TMB-high in gastro-entero-pancreatic (GEP)-NETs. Methods: We analyzed 31 metastatic GEP-NET patients who were newly diagnosed between 2013 to 2022. Next-generation sequencing (NGS) including TMB analysis, as a routine clinical practice was performed. The TruSight Oncology 500 assay from Illumina was used as a cancer panel. Results: Among a total of 31 patients, the median TMB was 4.7 mutation/Mb (3.10-6.3). Primary origin was stomach in 4 (12.9%), small bowel in 2 (6.5%), rectum in 7 (22.6%), pancreas in 21 (38.7%), bile duct in 1 (3.2%), gall bladder in 4 (12.9%), liver in 1 (3.2%) patient. 17 (54.8%) patients were diagnosed with well-differentiated NET with grade 1 in 3 (9.7%), and grade 2 in 14 (45.2%) patients. Grade 3 NET (neuroendocrine carcinoma) was confirmed in 14 (45.2%) patients. The median number of metastases was 2.7 (1.0-4.0). The most common metastatic site was the liver (26 patients, 83.9%). All tumors were classified as type of micro-satellite stable (MSS). Only one patient had the tumor with high TMB (266.4 mutation/Mb). This tumor was classified as the grade 3 neuroendocrine carcinoma and the primary tumor site was pancreas. Conclusions: This analysis revealed that the GEP-NETs were generally considered as tumor-type of low TMB. However, uncommonly, GEP-NET with high-TMB could be found. For the precision medicine, the NGS test is needed as a routine clinical practice in this tumor type.
Guideline compliance and outcomes of genetic testing in pancreatic cancer patients.
Authors: Klatte Derk C.F. , Hardway Heather D. , Starr Jason S. , Riegert-Johnson Douglas L. , Clift Kristin E. , Potjer Thomas P. , van Leerdam Monique E. , Presutti R. John , Wallace Michael B. , Bi Yan
Published: January 2023

688

Background: Guidelines recommend patients with pancreatic ductal adenocarcinoma (PDAC) undergo genetic testing for germline pathogenic variants (PV). The aim of this study was to evaluate compliance with recently updated guidelines (May 2019) and assess subsequent uptake and outcomes of genetic testing in PDAC patients. In addition, social and clinical factors associated with genetic testing were assessed. Methods: A retrospective chart review of patients diagnosed with PDAC between May 2018 and August 2020 was performed. Discussion and subsequent uptake of genetic testing was reviewed and compared between a 12-month period before (pre-guideline) and a 12-month period after (post-guideline) guidelines were updated, accounting for a three-month transition period. Univariate and multivariate logistic regression analysis was used to assess factors predictive of undergoing genetic testing. Results: In total, 534 patients with PDAC were identified; 321 (60.1%) in the pre-guideline period and 213 (39.9%) in the post-guideline period. The mean age at diagnosis was 68 years and 47% were female. Genetic testing was discussed in 34% (109/321) of pre-guideline and in 39% (84/213) of post-guideline patients ( P = .23). Of those, 82% (89/109) of patients in pre-guideline and 75% (63/84) in post-guideline groups underwent subsequent genetic testing ( P = .71). In 26 (17.1%) of 152 tested patients, a PV was identified, of which 17 (11.2%; 17/152) had a PDAC-associated PV. Age, cancer stage at diagnosis, length of survival, and having a first-degree relative with pancreatic cancer were significant predictors of genetic testing on multivariate analysis. Conclusions: Adherence to recently updated guidelines is poor and germline genetic testing in PDAC patients remains insufficient. Efforts to increase awareness of benefits of testing, which include personalized therapies for patients and cascade testing in family members for subsequent enrollment in pancreatic cancer surveillance programs, could improve future uptake.[Table: see text]
Phase I study of trifluridine/tipiracil in combination with gemcitabine (gem) and nab-paclitaxel (nab-P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Turk Anita Ahmed , Helft Paul R. , Sehdev Amikar , Shahda Safi , Loehrer Patrick J.
Published: January 2023

731

Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]
The identification of reversion mutations in patients with advanced pancreatic cancer and germline or somatic BRCA or PALB2 variants who were treated with maintenance rucaparib.
Authors: Brown Timothy J , Yablonovitch Arielle , Yen Jennifer , Kiedrowski Lesli A. , Carpenter Erica L. , Nathanson Katherine , Domchek Susan M. , Reiss Kim Anna
Published: January 2023

734

Background: Maintenance PARP inhibition (PARPi) extends progression-free survival and improves quality of life for patients (pts) with advanced, platinum-sensitive pancreatic cancer (PC) and BRCA or PALB2 variants. However, most will experience progression. PARPi resistance mechanisms are poorly defined in PC. Cell-free (cf)DNA analysis can detect some known classes of resistance mechanisms, like reversion mutations, and other potentially prognostic and predictive genomic features. Methods: Pts with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2, or PALB2 variants were treated with maintenance rucaparib on clinical trial. cfDNA was collected at baseline and progression and analyzed with the GuardantOMNI 500-gene liquid biopsy. Time to event analysis was performed from index date of enrollment until endpoint (PFS, OS, and PFS2). Associations were tested by the log-rank test with adjustment. Results: The trial enrolled 42 pts, of whom 31 have progressed. cfDNA was available for 41 pts at baseline and 30 pts at progression; 88% had baseline detectable cfDNA. Two pts had baseline reversion mutations, 5 had new reversion mutations at progression. Of 21 pts who had tissue NGS, 17 pts had a KRAS variant in the tumor, 12 of whom had detectable cfDNA at either baseline or progression. Of the 41 patients with cfDNA samples, 10 pts had baseline KRAS mutations detected in plasma; an additional 10 pts had a detectable plasma KRAS mutation at progression. Outcomes are shown. Of those who had progressed, pts with acquired reversion mutations had shorter OS (p<0.001) and PFS (p = 0.018) on rucaparib than those without reversion mutations. Of those who received chemo after progression (n=23), PFS2 was shorter for pts with acquired reversions compared to those with no reversions (p = 0.038). KRAS mutation detection at baseline was observed with higher overall somatic allele fraction in cfDNA and a trend toward shorter PFS and OS. Conclusions: Acquired reversion mutations were infrequent but associated with worse outcomes. Other causes of resistance may be dominant. Detection of KRAS mutation in the peripheral blood may be associated with disease burden and clinical outcome. [Table: see text]
Genomic profiling of rare undifferentiated sarcomatoid subtypes of pancreatic carcinomas for potential response to immunotherapy.
Authors: Faber Erik , Krause Harris , Walker Phillip , Hosein Peter Joel , Shields Anthony Frank , Lenz Heinz-Josef , Prakash Ajay , Goel Sanjay , Korn Wolfgang Michael , Oberley Matthew James , Luchini Claudio , Lou Emil
Published: January 2023

741

Background: While pancreatic adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, the highly aggressive PDAC subtype of undifferentiated sarcomatoid carcinoma (USC) remains poorly characterized as it comprises only 2-3% of all PDAC histology. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy for USC, but the prevalence of established predictive biomarkers of response are largely unknown in this unique subpopulation. We identified PDAC USC patient samples from a large dataset and performed comprehensive genomic profiling to determine the prevalence of biomarkers associated with response to immunotherapy. Methods: PDAC USC patient samples (N=43) underwent central pathology review to confirm this diagnosis and were compared to non-USC PDAC patient samples (N=5562). Next-generation sequencing of DNA and RNA was performed at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142; Positive (+): ≥ 2+, ≥%5). A combination of IHC, NGS, and fragment analysis was used to assess deficient mismatch repair/microsatellite instability high (dMMR/MSI). High tumor mutational burden (TMB-High) was defined as ≥10 mutations/MB. Immune cell fractions of the tumor microenvironment were estimated by RNA deconvolution analysis using quanTIseq. Chi-square tests with Bonferoni correction for multiple comparisons were used to determine significance. Results: Among PDAC USC samples, KRAS (86% USC vs 90% non-USC, p = 0.31, q = 1), TP53 (86% vs 77%, p = 0.16, q = 1), and CDKN2A (18% vs 23%, p = 0.45, q = 1) were the most commonly mutated genes with a similar prevalence compared to non-USC histologies; however, KRAS was amplified more frequently (7% USC vs <1% non-USC, q = 0.006). Furthermore, more USC tumors were PD-L1+ (63% vs 16%, q < 0.001), while few USC samples were dMMR/MSI (2% USC vs 1% non-USC, p = 0.45, q = 1) or TMB-High (2% vs 2%, p = 0.89, q = 1). All USC tumors were deplete of lymphocytes, but many were differentially enriched (>5%) with neutrophils (85% vs 57%, q = 0.03) or M2 macrophages (52% vs 28%, p = 0.006, q = 0.06). Conclusions: This work represents the largest molecular analysis of PDAC USC samples to date. Our analysis uncovered a different prevalence of amplified KRAS and PD-L1 expression in USC as compared to other PDAC histologies amidst an immune desert lacking lymphocytes in the USC tumor microenvironment. These findings provide evidence for further investigation into combination therapy of KRAS inhibitors with immune checkpoint inhibitors to target these immune-imbalanced microenvironment landscapes.
Patient-specific tumor-informed circulating tumor DNA (ctDNA) assay to predict cancer recurrence in patients with resected pancreatic cancer.
Authors: Wang Xiuchao , Wang Hongwei , Chen Xinyun , Liu Yuxiao , Zhao Tiansuo , Gao Song , Wang Jian , Ma Weidong , Gao Chuntao , Hao Jihui
Published: January 2023

744

Background: Pancreatic cancer (PC) is one of the leading causes of cancer death. Identifying molecular residual disease (MRD) with tailored tumor-informed ctDNA-based next-generation sequencing (NGS) assays after curative surgery could facilitate the individualized management of patients with resected pancreatic cancer (PC). Here, we prospectively evaluated the clinical performance of tumor-informed ctDNA mutation analysis using a novel Burning Rock Patient Specific Prognostic and Potential Therapeutic Marker Tracking (brPROPHET) approach for assessing MRD in patients with resected PC. Methods: The prospective cohort study recruited patients (n = 20) diagnosed with resectable stage I-III PC. Plasma samples (n = 63) were collected before surgery (baseline), 7-days after surgery (landmark), 30-days after surgery (before any adjuvant therapy), during the adjuvant therapy and follow-up. Individual tumors and matched white blood cells (WBCs) were whole-exome sequenced and somatic mutations were identified. Serial plasma samples were analyzed by a personalized, tumor-informed ctDNA-based NGS assay (brPROPHET) designed to target up to 50 variants per patient. Results: A total of 20 patients (stage I/II 10 [50%]/9[ 45%]) were analyzed. Patients were followed for a median of 190 days (range: 158 days to 396 days). Preoperative ctDNA was detected in 100% (20/20) of the patients. MRD status was analyzed postoperatively on day 7 and day 30 with a positivity rate of 11% (2/18) and 17% (2/12), respectively. Of the 4 patients with known recurrences, 2 had detectable ctDNA (50%, 2/4) at 7 days after surgery, whereas all disease-free patients were ctDNA-negative (100%, 13/13) at this time point. Detection at the landmark timepoint 7 days after surgery was associated with shorter recurrence-free survival (hazard ratio [HR]: 16.87, p=0.00363). The landmark negative predictive value (NPV) and positive predictive value (PPV) were 87.5% and 100%, respectively. When integrating all timepoints, 100% (4/4) of relapse patients were ctDNA positive before relapse, with the median leading time by brPROPHET assay to radiological recurrence was 126 days, whereas all of the patients with constant ctDNA negative status were disease-free (longitudinal PPV 80%, NPV 100%). In one relapsed patient who had elevated preoperative carbohydrate antigen (CA) 19-9 and constant normal postoperative CA19-9 (<27 U/ml), ctDNA was detected prior to radiological relapse, with a lead time of 211 days. Conclusions: Patient-specific tumor-informed ctDNA-based postoperative monitoring predicts disease recurrence at earlier postoperative settings better than the clinical parameter CA19-9, which paves an alternative strategy in the individualized management of patients with resected PC.
Circulating tumor DNA–based genomic landscape of KRAS wild-type pancreatic adenocarcinoma.
Authors: Fusco Brendon , Tsai Jill , Clemens Keelia , Gulhati Pat
Published: January 2023

747

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths. KRAS is a primary oncogenic driver in the majority of PDAC patients. KRAS wild-type (wt) PDAC (~10%) is a molecularly heterogeneous subgroup that may harbor alternate drivers and targetable alterations. In this study, we sought to characterize the circulating tumor DNA (ctDNA) landscape of alterations in PDAC patients harboring KRAS mutations ( KRAS mut) compared to KRAS wt. Methods: We analyzed ctDNA samples from 2000 patients ( N= 1000 each for KRAS mut and KRAS wt) collected prospectively between 2019-2022 using a 74-83 gene next generation sequencing panel (Guardant360). KRAS mutation not detected was used as a proxy for KRAS wt. To limit bias from low tumor shed, samples were excluded if they did not have maximum variant allele fraction (VAF) > 0.34% and if the only maximum VAF > 0.34% was within putative germline range (40-60%). Statistical analyses were performed using Fisher’s exact test or t-test. Results: No significant gender differences were noted between KRAS wt and KRAS mut patients. Median age was 72yo in KRAS wt and 69yo in KRAS mut patients. Overall, KRAS wt patients had higher frequency of alterations in ATM, BRAF, ERBB2, FGFR2, JAK3, MET and NOTCH1 compared to KRAS mut (all p < 0.05). Meanwhile, KRAS wt patients had lower frequency of alterations in CDKN2A, SMAD4, CDK6, ARID1A, and TP53 compared to KRAS mut (all p < 0.05). The most frequently mutated gene in KRAS wt PDAC was TP53 (46%), followed by ATM (26%) and EGFR (11%). The most common currently targetable alterations identified in KRAS wt patients were ATM (26%), BRCA1/2 (12%), EGFR (11%; 70% mutations, 30% amplifications), FGFR1/2 (9%), BRAF (8%; 91% mutations, 9% amplifications), PIK3CA (7%), MET (7%; 80% mutations, 20% amplifications) and ERBB2 (5.8%; 79% mutations, 21% amplifications) among others. Median tumor mutational burden for KRAS wt patients was higher than KRAS mut (10.0 vs. 7.77 mut/Mb, p = 0.035). There were no significant differences in rates of MSI-H between KRAS wt and KRAS mut patients (1.9% vs. 1.3%, p = 0.37). KRAS wt patients harbored higher number of oncogenic gene fusions compared to KRAS mut (1.6% vs 0.2%, p = 0.0013). The most common fusion partners among KRAS wt patients included FGFR2 (0.4%), BRAF (0.4%), ALK (0.2%), NTRK (0.2%), RET (0.2%), FGFR3 (0.1%) and EGFR (0.1%). Potential germline variants (pathogenic/likely pathogenic) were detected in both KRAS wt and mut patients, most commonly in the DNA-damage repair genes, including ATM (3.5%), BRCA2 (1.8%) and BRCA1 (0.6%). Conclusions: Targetable alterations and oncogenic rearrangements are enriched in KRAS wt PDAC compared to KRAS mut. These analyses provide additional therapeutic options and may improve outcomes for KRAS wt patients, warranting blood-based ctDNA genomic profiling in PDAC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.
A phase II clinical trial of toripalimab in advanced solid tumors with POLE/POLD1 mutation.
Authors: Jin Ying , Huang Run-jie , Mai Zong-jiong , Wang Zhi-qiang , Shi Yan-xia , Li Yu-hong , Xiao Jian , Zhang Xing , Zhao Qi , Liu Ming , Xu Rui-hua , Wang Feng
Published: January 2023

802

Background: Prior studies indicated that polymerase epsilon/polymerase delta (POLE/POLD1) exonuclease domain mutations (POL-EDMs) was associated with the efficacy of immune checkpoint inhibitor (ICI). However, there remains controversy about whether patients with POLE/POLD1 non-exonuclease domain mutations (POLE-non-EDMs), which occupied the majority of POLE/POLD1 mutations, could benefit from ICI. Currently, few prospective clinical trials have evaluated the predictive value of POLE/POLD1 mutation in ICI. Methods: We initiated a phase II clinical trial for non-microsatellite instability-high (non-MSI-H) patients with POLE/POLD1 mutant advanced solid tumors to investigate the treatment efficacy of toripalimab, an anti-PD-1 antibody. Eligible patients received one dose of 240mg toripalimab every three weeks for up to two years until disease progression or intolerable toxicity occurred. The primary endpoint was overall response rate, and secondary endpoints included disease control rate, overall survival, progression-free survival, and safety. Treatment responses were assessed using the RECIST v1.1 after each six-week treatment cycle. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. This study is registered on ClinicalTrials.gov, NCT03810339. Results: A total of 15 patients were enrolled to receive treatment, of whom 14 underwent response assessment. The overall response rate was 21.4%, and the disease control rate was 57.1%. The median overall survival and median progression-free survival were 2.5 months and 28.2 months, respectively. The overall response rate of the patients with POL-EDMs and POL-non-EDMs were 66.7% and 7.1%, while the disease control rates were 66.7% and 54.5%, respectively. Grade three or four treatment-related adverse events occurred in 20% of patients. Conclusions: This study showed that patients with POL-EDMs had a good response to ICI therapy, and those with POL-non-EDMs could clinically benefit from anti-PD-1 antibody monotherapy, urging the need for more investigations on immunotherapy combined with chemotherapy in patients with POL-non-EDMs. Clinical trial information: NCT03810339 .