bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of combined positive score of PD-L1 expression and clinical efficacy for advanced esophageal squamous cell carcinoma treated with nivolumab monotherapy.
Authors: Mikuni Hayato , Yamamoto Shun , Sawada Ryoichi , Honma Yoshitaka , Sekine Shigeki , Oguma Junya , Saruta Masayuki , Daiko Hiroyuki , Kato Ken , Ishiyama Koshiro
Published: January 2022

289

Background: Based on the results of the ATTRACTION-3 trial, nivolumab has shown superiority compared to taxane monotherapy as second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) patients (pts). However, the PD-L1 expression by tumor proportion score (TPS) did not obviously correlate to the efficacy. In contrast, PD-L1 expression by combined positive score (CPS) was used as a companion diagnosis for pembrolizumab in ESCC. There are little data on CPS with nivolumab in ESCC. Methods: We retrospectively reviewed the medical records of the pts with ESCC who received nivolumab monotherapy in our hospital. The CPS before nivolumab was evaluated by 22C3 antibody. We evaluated the correlation of CPS and clinical efficacy of progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) by using Cox proportional regression model and Fisher’s exact test. Results: Eighty-seven pts were selected for this analysis with a median follow-up time of 7.9 (1.2-84.1) months. Thirty pts (34.5%) had CPS < 10, and 57 patients (65.5%) had CPS≥10. Between two groups, the characteristics were as follows; median age (range): 62 (35-85) and 66 (46-85) years, PS 0: 20.0/36.8%, prior taxane: 50.0/40.4%, prior radiotherapy: 86.7/77.2%, respectively. The median PFS (95%CI) were 1.8 (1.2-2.8)/2.6 (1.8-33.8) months (HR: 0.85 [0.52-1.38], p = 0.50). The ORR/DCR were 21.1/31.6% in CPS < 10 group, and 22.2/57.8% in CPS≥10 group, and there was no statistical significance, respectively (p = 1.0/0.10). In multivariate analysis, only higher age was the favorite factor for PFS. From the result with another cut-off level of CPS, the proportion of CPS≥1/CPS≥20 was 90.8/36.8%. The HR of multivariate analysis with CPS≥1/CPS≥20 was 1.24/0.73, respectively. Conclusions: There was a trend toward better PFS with a higher cut-off point of CPS. CPS had the potential to be a biomarker even for nivolumab for advanced ESCC pts.
Perioperative sintilimab combination with SOX for resectable locally advanced gastric/gastroesophageal junction cancer(GC/GEJC): Initial findings of a single-arm phase II trial.
Authors: Ding Xuewei , Li Bin , Xue Qiang , Cai Mingzhi , Cui Jingli , Wang Baogui , Ke Bin , Zhang Rupeng , Liang Han
Published: January 2022

294

Background: Perioperative treatment is very important to improve long-term survival for gastric/gastroesophageal junction cancer(GC/GEJC), The RESOLVE study showed that perioperative-SOX have a clinically meaningful improvement in patients with locally advanced GC/GEJC who had D2 gastrectomy. Adding PD-1 inhibitor to the chemotherapy have shown significant clinical benefits in first-line treatment of GC/GEJC. This trial was designed to assess the feasibility and efficacy of this combination in perioperative treatment of resectable locally advanced GC/GEJC. Methods: This is a prospective, single-arm, single-center phase II study. Patients of histopathology confirmed locally advanced GC/GEJC, with clinical stage II-IV A per AJCC8th, ECOG PS 0-1, were enrolled and treated with 3 cycles of preoperative sintilimab (200mg, iv, d1) and SOX (oxaliplatin 130mg/m2, iv, d1 and S-1 40-60mg, po, bid, d1-14) every 3 weeks, and 12 months of postoperative sintilimab (200mg, iv, d1) and S-1 (40-60mg, po, bid, d1-14) every 3 weeks. The primary endpoint was 2-year DFS rate. The second endpoints were pCR, MPR, R0 resection rate, safety and 3-year OS. Results: As of June 2021, 21 patients were enrolled, with median age 56 years (range 31-72 years), males 10 (47.6%), cT2/3/4a/4b 2(9.5%)/0/16(76.2%)/3(14.3%), cN1/N2 7(33.3%)/14(66.7%) and GC/GEJC 14(66.7%)/7(33.3%). All 21 patients had completed gastrectomy. 7 patients (33.3%) achieved pathological complete response (pCR), 8 patients (38.1%) had major response (TRG 0-1) and 21 patients (100%) achieved R0 resection. Common TRAEs were anemia (38.1%), lymphopenia (28.6%), neutropenia (19.0%), leukopenia (14.3%), ALT increase (9.5%), AST increase (4.8%), thrombocytopenia (4.8%). Grade 3 or more TRAEs included anemia (9.5%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 10 days (range 7-41 days). Conclusions: Adding sintilimab to the chemotherapy resulted in an encouraging pCR and MPR as perioperative treatment for resectable locally advanced GC/GEJC, and safety was manageable. A Phase II randomized study is ongoing. Clinical trial information: ChiCTR2100043572.
A phase Ib/II, multicenter, open-label study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (chemo) as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer.
Authors: Ji Jiafu , Shen Lin , Gao Xiangyu , Ji Ke , Chen Ye , Xu Nong , Liu Tianshu , Yang Nong , Zhong Haijun , Li Ziyu , Li Changzheng , Guo Zengqing , Fan Qingxia , Lin Xiaoyan , Yao Zhifang , Liu Wei , Li Baiyong , Xia Yu
Published: January 2022

308

Background: Anti-PD-1 agent plus chemo as first-line therapy for advanced G/GEJ cancer (Checkmate-649) yields OS and PFS benefits compared to chemo alone, indicating synergistic activity between immune checkpoint inhibitors and chemo. The combination of anti-PD-1 and anti-CTLA-4 has consistently demonstrated higher response rate compared to PD-1 monotherapy but higher toxicity. Here, we performed this phase Ib/II study to evaluate the efficacy and safety of AK104, a PD-1/CTLA-4 bispecific antibody, combined with XELOX (capecitabine combined with oxaliplatin) or modified XELOX (mXELOX) in the first-setting of G/GEJ cancer cohorts. This study is registered on ClinicalTrials.gov (NCT03852251). Methods: Pts with unresectable advanced G/GEJ adenocarcinoma and no prior systemic therapy, regardless of PD-L1 status were enrolled, excluding known HER2-positive pts. Enrolled patients received AK104 (4 mg/kg, 6 mg/kg, 10 mg/kg, Q2W or 10 mg/kg, 15mg/kg Q3W) + chemo (mXELOX Q2W or XELOX Q3W). The primary endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 13 Aug 2021, 96 pts were enrolled with median age 62.7 years (range: 29–75), 70.8% male, 62.5% ECOG PS 1, 44.8% liver metastasis. The median follow-up was 9.95 months (range, 0.4-26.8). 88 patients (92%) had at least one post-baseline tumor evaluation. The ORR was 65.9% (58/88) with 2 (2.3%) complete responses and 56 (63.6%) partial responses. The disease control rate (DCR) was 92.0% (81/88). The median duration of response (DoR) was 6.93 months (95%CI, 4.60 to 11.20). The median PFS was 7.10 months (95%CI, 5.55 to 10.48). The median OS was 17.41 months (95%CI, 12.35 to NE). In pts with PD-L1 CPS≥1 vs CPS＜1, median OS was 17.41 months and 14.65 months, respectively. Treatment-related adverse events (TRAEs) occurred in 97.9% of pts, and the most frequent were platelet count decreased (60.4%), white blood cell count decreased (58.3%), neutrophil count decreased (56.3%), anaemia (47.9%), nausea (30.2%), vomiting (30.2%), aspartate aminotransferase increased (30.2%). Grade ≥3 TRAEs occurred in 62.5% pts. No new safety signals were identified. Conclusions: AK104 in combination with mXELOX/XELOX showed promising activity and manageable safety in previously untreated pts with advanced G/GEJ adenocarcinoma. AK104 + chemo represents a potential new first-line treatment option for these pts. A phase III study of AK104 combined with chemo as first-line therapy for G/GEJ cancer is underway. Clinical trial information: NCT03852251.
Productivity loss outcomes and indirect costs among patients (Pts) with cholangiocarcinoma (CCA).
Authors: Teschemaker Anna , Thiel Ellen , Park Julie , Parasuraman Shreekant
Published: January 2022

392

Background: CCA pts, often diagnosed at older age with advanced disease, face poor prognoses and economic burden. Despite increasing CCA incidence in working age pts, little is known on financial impact on working pts. This study describes the impact of CCA on productivity loss and indirect costs due to workplace absence, short-term disability (STD), and long-term disability (LTD). Methods: Retrospective claims data from IBM MarketScan Commercial and Health and Productivity Management (HPM) databases between 7/1/2010 to 12/31/2019 were used. Eligible pts were ≥18 years, had ≥1 non-ruleout claim for CCA ( ICD-9/ -10: intrahepatic [iCCA]: 155.1/C221; extrahepatic [eCCA]: 156.1, 156.9/C240, C249) in the index period (1/1/2011 – 12/31/2019), and had ≥6 months of continuous medical and pharmacy benefit enrollment before and ≥1 month of follow-up and full-time employee eligibility after index date. Productivity loss as absenteeism, STD, and LTD among iCCA and eCCA was reported per pt per month (PPPM) for a work month of 21 days. Absenteeism was defined as absence days for illness; STD and LTD were defined as days on disability leave. Indirect cost was estimated using wage equivalent to median hourly wage rate and salary replacement rate of 70% from US Bureau of Labor and Statistics. Results: A total of 1065 CCA pts (iCCA, n=624 [58.6%]; eCCA, n=380 [35.7%]) were identified. The number of productivity benefit–eligible pts for analysis in absenteeism, STD, and LTD were 107, 617, and 549, respectively. Across cohorts, mean age ranged from 51.9 to 53.9 years; >60% were men. Mean (SD) follow-up time (days) was 725.0 (730.4) for absenteeism, 639.7 (587.0) for STD, and 614.4 (583.2) for LTD. The most notable comorbidities across cohorts were moderate/severe liver disease (58–63%) and pain (67–71%). Among pts with productivity claims, more CCA-related absences and higher related indirect costs were observed in iCCA than eCCA pts. The trend in all-cause disability outcomes of STD, LTD, and related costs was less clear between iCCA and eCCA pts; however, medical costs were higher in iCCA pts. Conclusions: CCA pts had high productivity loss and indirect costs, which is pt costs due to days missed from work in addition to medical costs; iCCA pts incurred substantially more absences, related indirect costs, and medical costs than eCCA pts.[Table: see text]
Patient report outcomes: Financial toxicity in cholangiocarcinoma.
Authors: Keilson Jessica M. , Lindsey Stacie , Bachini Melinda , Medin Caroline , Berk Alexandra , Cornew Sophia , Maithel Shishir K.
Published: January 2022

394

Background: While surgery is the only curative option for cholangiocarcinoma (CCA), it is amenable only in a minority of patients and has high recurrence rates. Numerous experimental and targeted therapies are under investigation; however, objective health-related quality of life (HRQoL) data for patients receiving these therapies are currently not available. Methods: Pts engaged in the Cholangiocarcinoma Foundation completed two validated HRQoL surveys: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary and COmprehensive Score for financial Toxicity (COST). Subscales (Physical Well-Being, PWB; Social Well-Being, SWB; Emotional Well-Being, EWB; Functional Well-Being, FWB; Hepatobiliary Cancer Subscale, HCS; Financial Toxicity Scale, FTS) and composite scores (FACT-Hep, composite for PWB, SWB, EWB, FWB, HCS) were calculated according to the FACIT-Manual, with higher values indicating improved HRQoL. Results: 208pts completed the surveys. 75% (n = 156) had intrahepatic CCA, 57% (n = 119) underwent resection, of which 48% (n = 56) had disease recurrence. 22% (n = 45) enrolled in a clinical trial and 80% (n = 167) underwent molecular profiling, of which 29% (n = 48) received targeted therapy. While pts enrolled in a clinical trial reported similar HRQoL compared to those not enrolled in a clinical trial, they also reported lower FTS (effect size 0.33, p = 0.05), suggesting higher financial burden. Pts who received targeted therapy reported equivalent HRQoL and lower FTS compared to those who did not (effect size 0.43, p = 0.01). Conclusions: Our data suggest that enrollment in a clinical trial does not affect a patient’s physical, emotional, social, or functional well-being. However, despite these treatments being paid for through trial enrollment, patients still report higher financial burden. This is also seen among patients who received targeted therapy. For patients with CCA, clinical trials and personalized therapy are mainly offered late in the advanced disease setting, at which point a significant financial toll has already been endured. Further, they are often only available at large academic centers, creating a physical barrier to access. These findings underscore the need to increase clinical trial availability and eliminate physical and financial barriers that threaten access and utilization of personalized and progressive therapies.[Table: see text]
Multi-target blood test to improve the performance of hepatocellular carcinoma surveillance programs: A modeling-based virtual trial.
Authors: Chhatwal Jagpreet , Samur Sumeyye , Yang Ju Dong , Roberts Lewis R. , Nguyen Mindie , Ozbay A. Burak , Ayer Turgay , Parikh Neehar , Singal Amit G.
Published: January 2022

405

Background: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer mortality in the United States. Although clinical guidelines recommend ultrasound (U/S), with or without the serum biomarker alpha fetoprotein (AFP) for HCC surveillance in at-risk patients, only 24% of patients adhere to surveillance and only one-third of HCCs are detected before developing symptoms. A multi-target HCC blood-based test (mt-HBT) was recently shown to have promising sensitivity for early HCC detection and may help improve surveillance adherence given its blood-based nature. Our objective was to evaluate the comparative clinical effectiveness of mt-HBT with the current standard-of-care surveillance strategy in patients with cirrhosis. Methods: We simulated a virtual trial by developing a microsimulation model of the natural history of HCC in patients with compensated (Child Pugh A) cirrhosis over a 30-year horizon. To inform model parameters, we used published data on tumor progression, competing risks of mortality, and real-world HCC surveillance adherence. Test performance characteristics were informed by a network meta-analysis. We simulated the life course of 51-year-old patients with cirrhosis and compared no surveillance with biannual surveillance using (1) AFP only, (2) U/S only, (3) U/S+AFP, (4) mt-HBT, and (5) mt-HBT with improved adherence. We assumed a blood-based test—without U/S—would improve surveillance adherence by 10% compared with current adherence (̃4% absolute improvement). Results: Per 100,000 cirrhosis patients, mt-HBT detected 6,220 more early-stage HCC than no surveillance, 2,250 (+57%) more than AFP, 1080 (+21%) more than U/S, and 200 (-3%) less than U/S+AFP. mt-HBT with improved adherence detected 210 (+3%) more early-stage HCC than U/S+AFP (Table). The remaining HCC cases were either symptomatic or the patients died per other competing causes prior to detection. The number of screening tests needed to detect one HCC were 296 for AFP, 287 for U/S, 253 for U/S+AFP, 254 for mt-HBT and 262 for mt-HBT with improved adherence. The number of diagnostic MRI/CT needed to detect one HCC were 40 for AFP, 38 for U/S, 45 for U/S+AFP, 37 for mt-HBT, and 38 for mt-HBT with improved adherence. Conclusions: mt-HBT detects more early-HCC cases than U/S and similar number of early-HCC cases with U/S+AFP. By decreasing surveillance barriers and increasing adherence, mt-HBT could improve early HCC detection and could be promising option for HCC surveillance in patients with cirrhosis. [Table: see text]
A phase Ib, multicenter, open-label study to assess the safety, tolerability, and preliminary efficacy of sintilimab plus IBI310 (anti-CTLA4 mAb) in patients with advanced hepatocellular carcinoma.
Authors: Zhou Jian , Shi Ying-Hong , Liu Baorui , Jia Wei-Dong , Gu Shanzhi , Qin Yanru , Liu Ying , Han Zhengxiang
Published: January 2022

421

Background: Immune checkpoint inhibitors (ICI) targeting PD-1/L1 or in combination with CTLA-4 have shown therapeutic benefit in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to evaluate the safety, tolerability, and preliminary efficacy of IBI310, an anti-CTLA-4 monoclonal antibody (mAb), combined with sintilimab, in patients with aHCC who failed or intolerant to previous systemic therapy. Methods: Three cohorts were pre-designed to explore recommended dose of IBI310 in de-escalation order: sintilimab 200 mg plus IBI310 3, 2 or 1 mg/kg every 3 week (q3w). Patients will receive the combined treatment up to 4 cycles, followed by sintilimab 200 mg q3w up to 24 months. Primary endpoint was safety. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), progress free survival (PFS) and overall survival (OS) by RECISTv1.1 per investigators. Results: 9 subjects were initially treated with sintilimab 200 mg plus IBI310 3 mg/kg q3w without predefined adverse event (AE) observed. 3 mg/kg was determined as recommended dose of IBI310 and no subject was assigned to other cohorts. As of the data cut-off of August 30, 29 subjects were enrolled (median age 51.4 years, 86.2% male, 96.6% BCLC C, 24.1% ICI treated). The average treatment cycles of IBI310 and sintilimab were 2.8 and 5.7. The most frequent treatment related adverse events (TRAEs) of any grade were alanine transaminase increases (34.5%), aspartate transaminase increases (34.5%), thrombopenia (24.1%), and lipase increases (24.1%). Grade ≥3 TRAEs occurred in 34.5% of subjects (including one grade 5 immune-mediated pneumonitis). Dose interruption and discontinuation rates due to AE were 55.2% and 6.9%. With a median follow-up of 9.89 months, investigator confirmed ORR and DCR were 17.2% (all partial response, including one anti-PD1 mAb failed) and 72.4%. The median PFS was 3.9 months (95% CI: 2.6, NR) and median OS not reached (95% CI: 11.4, NR). The 6-month PFS and OS rates were 45.8% (95%CI 25.2%, 64.2%) and 93.1% (95%CI 75.1%, 98.2%) respectively. 6 patients remain on treatment at cutoff date. Conclusions: The combination of sintilimab and IBI310 shows promising efficacy and managable safety profile in aHCC patients. Our results are comparable to that have been published in the same setting. This regimen is currently being evaluated in phase II study. Clinical trial information: NCT04401813.
Cyclin dependent kinase 9 inhibition as a potential treatment for hepatocellular carcinoma.
Authors: Shao Yu Yun , Hsu Hung-Wei , Wo Rita Robin , Wang Han-Yu , Cheng Ann-Lii , Hsu Chih-Hung
Published: January 2022

425

Background: Composite cyclin dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. Methods: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, on cell viability and apoptosis in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. Results: Both BAY1143572 and AZD4573 exhibited potent antiproliferative activities in HCC cell lines including HuH7, HLE, and HepG2, regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1, survivin, BimEL, and the X-linked inhibitor of apoptosis protein. Reduction of CDK9 expression through siRNA knockdown also reduced the phosphorylation of RNA polymerase II and the colony formations of HuH7 and HLE cells. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited a significantly lower tumor growth rate than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving BAY1143572 also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Conclusions: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.
Sintilimab plus lenvatinib as conversion therapy in patients with unresectable locally intermediate to advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase 2 study.
Authors: Wang Lijun , Wang Hongwei , Cui Yong , Jin Kemin , Liu Wei , Wang Kun , Xing Baocai
Published: January 2022

449

Background: Most patients (pts) with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combining a PD-1 inhibitor with tyrosine kinase inhibitors (TKIs)has achieved a high response rate for advanced HCC in first- and second-line settings. This study aimed to explore the efficacy and safety of conversion therapy with sintilimab (PD-1 inhibitor) plus Lenvatinib (TKI) in pts with unresectable locally intermediate advanced HCC. Methods: This was a phase 2, single-arm study (NCT04042805). Eligible pts were adults who were newly diagnosed with HCC, not amenable to curative resection, no extrahepatic metastasis, with an ECOG PS 0-1 and Child-Pugh class A/B. Pts received 12mg or 8mg oral Lenvatinib daily plus 200mg intravenous sintilimab every 3 weeks until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was tumor objective response rate (ORR) RECIST version 1.1. Secondary endpoints included conversion resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between August 1, 2019, and September 1, 2021, 26 pts were enrolled with a median age of 60 years (range, 30-78). The study population was predominantly male (92%), and 92% were HBV-positive. Patients were classified as BCLC stage B (46%) and stage C (54%). Twenty-six pts were evaluable for response, with an ORR of 35% (95%CI, 0.15-0.54) and a DCR of 92% (95%CI, 0.81-0.99). Seven (27%) pts received hepatectomy, and 1 (4%) patient received radical ablation and stereotactic radiotherapy. With a median follow-up of 9 months (range, 2-24), the median PFS and OS were not reached. All pts were evaluable for toxicity, and 20 (77%) pts had at least one treatment-related AE (TRAE). TRAEs occurring in ≥20% of pts were hypothyroidism (38%), proteinuria (31%), and hypertension (23%). Five pts had grade 3 TRAEs. Conclusions: In view of the encouraging response rate observed and the acceptable safety profile, the lenvatinib plus sintilimab regimen may achieve a favorable conversion rate and be a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. Clinical trial information: NCT04042805.
Galectin-9 expression and decreased survival in advanced biliary tract cancers.
Authors: Keilson Jessica M. , Ruggieri Amanda , Hammons Jacklyn , Chen Helen X. , Sharon Elad , Yarchoan Mark , Azad Nilofer Saba , Medin Caroline , Henry Curtis , Robinson Brian , Maithel Shishir K. , Lesinski Gregory B.
Published: January 2022

465

Background: Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies often refractory to chemotherapeutic or targeted therapies, carrying an overall poor prognosis and high mortality. Identifying prognostic biomarkers and effective therapeutic targets for this disease therefore remains a high priority. T-cell immunoglobulin mucin domain-containing protein 3 (TIM-3), a negative regulatory immune checkpoint receptor, is known to induce immune tolerance and inhibit T-cell antitumor immunity. Its ligand, galectin-9 (Gal-9), has been shown to play a paradoxical role in tumorigenesis in a number of disease states. However, the role of Gal-9 in the setting of BTCs is not completely understood. Methods: We examined expression patterns of total cellular Gal-9 and TIM-3 in a panel of human BTC cell lines with diverse molecular profiles via immunoblot. Soluble Gal-9 (sGal-9) was measured by enzyme-linked immunoassay (ELISA). Tetrazolium-based MTT assay was utilized to evaluate cell viability following Ab-mediated Gal-9 neutralization. Pre-treatment peripheral blood was obtained from patients with metastatic BTCs enrolled in a randomized phase II clinical trial (NCI10139) and sGal-9 levels were measured. ROC curve analysis was employed to identify an optimal concentration cut-point value. Kaplan-Meier models were used to assess the association between sGal-9 levels and overall survival. Results: Human BTC cells demonstrate detectable and differential expression levels of total Gal-9 and TIM-3 proteins in vitro, with greater expression among intrahepatic cell lines (HUCCT-1, HUH28, SNU478). TIM-3 expression was not detected among extrahepatic (MzChA-1) and gallbladder cancer (WITT) cell lines. sGal-9 is secreted at variable levels between cell lines and its neutralization does not affect viability. Pre-treatment peripheral blood was obtained from 73 patients with metastatic BTCs (53% (n = 39) intrahepatic cholangiocarcinoma, 22% (n = 16) extrahepatic cholangiocarcinoma, 25% (n = 18) gallbladder cancer). There was no significant difference in sGal-9 levels between disease sites (p = 0.08). Patients were dichotomized by low and high sGal-9 levels. High baseline plasma levels of sGal-9 were associated with worse overall survival among patients with advanced BTCs (p = 0.03). Conclusions: Biliary tract cancer cells differentially express galectin-9 and its ligand, TIM-3, in vitro. Higher plasma levels of soluble galectin-9 are associated with worse overall survival, suggesting galectin-9 expression may be related to a more aggressive disease state. Additional work is needed to better inform the mechanistic role of the galectin-9/TIM-3 axis on disease progression and how best to leverage this pathway as a therapeutic target in the management of biliary tract cancers.
Randomized phase III study of etoposide plus cisplatin versus irinotecan plus cisplatin in advanced neuroendocrine carcinoma of the digestive system: A Japan Clinical Oncology Group study (JCOG1213).
Authors: Morizane Chigusa , Machida Nozomu , Honma Yoshitaka , Okusaka Takuji , Boku Narikazu , Kato Ken , Nomura Shogo , Hiraoka Nobuyoshi , Sekine Shigeki , Taniguchi Hirokazu , Okano Naohiro , Yamaguchi Kensei , Sato Takuji , Ikeda Masafumi , Mizuno Nobumasa , Ozaka Masato , Kataoka Tomoko , Kitagawa Yuko , Terashima Masanori , Furuse Junji ,   Japan Clinical Oncology Group（JCOG）
Published: January 2022

501

Background: Neuroendocrine carcinoma (NEC) arising in the digestive system is a rare and high-grade malignant tumor. Treatment guidelines for advanced NEC recommend platinum-based chemotherapy regimens. Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for NEC. However, it is unknown which is more effective. This phase III study aimed to identify more effective regimen between EP and IP in terms of overall survival (OS) for patients with advanced NEC. Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable, histologically confirmed NEC (WHO2010) arising from the gastrointestinal tract (GI), hepatobiliary and pancreas (HBP), ECOG PS of 0-1, age of 20–75 years. In the EP arm, etoposide (100 mg/m2 on days 1, 2 and 3) and cisplatin (80 mg/m2 on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2 on days 1, 8 and 15) and cisplatin (60 mg/m2 on day 1) were repeated every 4 weeks. The primary endpoint was OS. Total of 140 patients (114 events) were required to detect a hazard ratio (HR) of 0.67 (median OS; 8/12 months in inferior/superior arms) with a two-sided alpha of 10% and power of 70%. Due to a rapid accrual, the sample size was increased to 170 (power of 80%). Pathology was centrally reviewed after the start of treatment. Results: Of all enrolled 170 patients (GI: 100, HBP: 70) from Aug 2014 to March 2020, median OS was 12.5 months in EP and 10.9 months in IP (HR 1.043 [a ratio of EP to IP], 90% CI, 0.794-1.370, p= 0.797). Median progression-free survival (PFS) was 5.6 months in EP and 5.1 months in IP (HR 1.060, 95% CI, 0.777-1.445). Response rate (RR) was 54.5% (42/77) in EP and 52.5% (42/80) in IP among patients with target lesions. No interactions with OS, PFS, or RR were seen in pre-planned subgroup analyses including primary organs or pathological findings. The common Grade 3-4 AEs (EP/IP) was neutropenia (91.5%/53.7%), leukocytopenia (61.0%/30.5%), and febrile neutropenia (26.8%/12.2%). Conclusions: A superiority was not demonstrated, which indicates that both EP and IP remain standard first-line chemotherapy. Clinical trial information: UMIN000014795.
Long-term outcomes of rectal neuroendocrine tumors according to the risk after endoscopic resection: A multicenter study.
Authors: Lee Hyun Jin , Lee Han Hee , Kim Ilsoo , Seo Yun , Jung Hana , Oh Chang Kyo , Lee Ji Min , Choi Hyun Ho , Gweon Tae-Geun , Lee Sung Hak , Cheung Dae Young , Kim Jin Il , Park Soo-Heon
Published: January 2022

505

Background: The detection of rectal neuroendocrine tumors has increased with advances in diagnostic endoscopy. Endoscopic resection (ER) is highly effective treatment option for small rectal neuroendocrine tumors (NETs) confined to submucosa. However, there was no risk classification for evaluating the clinical outcomes. In this study, we analyzed long-term outcomes of rectal neuroendocrine tumors after ER. Methods: In this multicenter retrospective study, we analyzed the medical records of patients who underwent ER of rectal NETs from 2009 to 2018 and were followed for ≥ 12 months at five university hospitals under the Catholic Central Medical Center in Korea. Data were collected through Catholic Medical Center Clinical Data Warehouse. We classified patients into three risk groups (low, intermediate, an high) according to clinicopathologic status of rectal NETs. The high-risk group was defined if the tumors have any of the followings: size ≥ 10mm, lymphovascular invasion, muscularis propria or deeper invasion, positive resection margins, or mitotic count ≥ 2/10. Results: A total of 346 patients were included in our study, with 144 (41.6%), 121 (35.0%), and 81 (23.4%) patients in the low-, intermediate-, and high-risk groups, respectively. Among the high-risk group, only seven patients (7/81, 8.6%) received salvage treatment at 2.1 ± 4.1 months after initial treatment. Of them, three patients underwent endoscopic submucosal dissection and the other four patients underwent surgery. There was no extracolonic metastasis in all 7 patients. During follow-up period of all included patients, although there was no local recurrence, four patients (4/346, 1.1%) had extracolonic metastasis (2 liver, 2 perirectal lymph node) at 70.5 ± 33.9 months after initial treatment. Three of them (75%) were high-risk patients without salvage treatment. The risk of extracolonic metastasis is significantly higher in the high-risk group compared with the others (P=0.041, Fisher exact test). Conclusions: Although the prognosis of the patients who underwent ER of rectal NETs showed favorable outcomes, physicians should be concerned with the possibility of metastasis during long-term follow-up of high-risk patients and consider salvage treatment.
Race, sex, age, and geographic disparities in pancreatic cancer incidence.
Authors: Moshayedi Natalie , Escobedo Anna Loraine , Thomassian Shant , Osipov Arsen , Hendifar Andrew Eugene
Published: January 2022

520

Background: Pancreatic cancer has a poor prognosis and a 5-year survival rate of 10%. A population-risk level analysis of pancreatic cancer will identify epidemiologic risk factors including geographic, racial, ethnic, and sex inequities which could lead to improved prevention strategies. Methods: Incidence data for invasive pancreatic cancer from 2009 through 2018 was obtained from the Surveillance, Epidemiology, and End Results Research (SEER) Plus Limited-Field database (SEER 21) that covers about 37% of the US population. Age-adjusted incidence rates (AAIR) and trends were estimated by race, sex, age categories (ten-year age groups starting from age 30), and county-level rural-urban classification developed by the United States Department of Agriculture (USDA). Trends over the period are described using the annual percent change (APC) calculated using weighted least squares method. Results: Overall pancreatic cancer incidence (per 100,000 population) for all ages during 2009-2018 was 13.0. Rates were highest among Black (15.4), followed by non-Hispanic white (13.2) and Hispanic (11.6) groups in both men and women. Males carries a higher rate of incidence (14.8) than females (11.6) in pancreatic cancer although both sexes experienced a 0.6% increase in incidence yearly. Incidence of pancreatic cancer increased with age across all ethnicities in men and women. The highest rate of incidence was found in ages 80 and above (99.5) and the lowest in age group 30-39 (1.0). Pancreatic cancer rates increased by 0.6% yearly and increased in every racial/ethnic group for both males and females, except Black males (0.0) and American Indian/Alaska Native females (-0.2). Although incidence in urban counties (13.1, n = 321) and rural counties (12.8, n = 411) was comparable, rural countries observed a faster increase in rates between 2009 and 2018 (p < 0.05). Conclusions: Incidence of pancreatic cancer has increased from 2009 to 2018 across all ethnicities and in both men and women. Minorities, males, and individuals living in rural counties are disproportionately affected by pancreatic cancer. Additionally, older individuals have a higher incidence of pancreatic cancer, suggesting an increased risk in this patient population. This data will inform strategies to identify high-risk populations and implement preventative care, screening, and surveillance.[Table: see text]
Feasibility and utility of synthetic control arms derived from real-world data to support clinical development.
Authors: Lyman Jaclyn Paige , Doucette Abigail , Zheng-Lin Binbin , Cabanski Christopher R. , Maloy Molly A. , Bayless Nicholas L. , Xu Jingying , Smith William , Karakunnel Joyson Joseph , Fairchild Justin P. , Ibrahim Ramy , O'Reilly Eileen Mary , Vonderheide Robert H. , Gabriel Peter Edward
Published: January 2022

528

Background: ‘Synthetic’ control arms (SCAs), created using electronic health records (EHRs), have immense potential to augment clinical trial findings and provide a rich context of real-world evidence (RWE) while reducing patient (pt) and sponsor burden (Gottlieb 2019). PICI0002 (PRINCE) is a ph1b/2 study evaluating APX005M with gemcitabine (gem) and nab-paclitaxel (NP) ± nivolumab for the treatment of metastatic pancreatic adenocarcinoma (mPDAC; NCT03214250). PRINCE pts were enrolled from select US academic cancer centers and a global, ph3 study was utilized for an historical reference control (Von Hoff 2013). To address the perceived limitations of this design, we explored the feasibility and utility of developing a contemporary SCA using real-world data (RWD). Methods: The SCA was derived using retrospective pt data from the two highest enrolling participating centers on PRINCE. Pts meeting key PRINCE eligibility criteria, who received gem/NP in the two years preceding the trial start date, were identified using an electronic phenotyping algorithm applied to cancer registry and EHR data, followed by manual review. Baseline characteristics, treatment exposure, efficacy and survival data were extracted electronically and via manual chart abstraction. Data were stored in a REDCap database built and housed by the Parker Institute for Cancer Immunotherapy. SCA pt characteristics were compared with PRINCE and overall survival (OS; time from initiation of gem/NP to death) was compared to historical reference controls (Table). Results: N=68 pts treated with gem/NP meeting PRINCE eligibility criteria were identified. All pts were deceased at the time of analysis. SCA pts had comparable baseline characteristics to PRINCE pts; key differences included inferior performance status and a higher proportion of pts presenting with a de novo mPDAC diagnosis. Median time on gem/NP was 4.8 months (mos; range 0-39). Median OS was 11.5 mos (95% CI 9.0-13.6) and 1-year OS was 43% (95% CI 31-55), in line with historical controls (Table). Conclusions: This study confirms the feasibility and utility of generating a control arm via a semi-automated approach. Current limitations entail manual oversight requirements as well as the known constraints of RWD, including associated biases and lack of available RECIST data. These limitations stand to evolve alongside EHR technologies. SCAs using RWD may help inform the value of prospective data by providing a contemporary reference of RWE. In some circumstances, SCAs may also serve as an alternative to traditional control arms, particularly for well-characterized standard therapies.[Table: see text]
Real-world clinical outcomes and molecular features of lung-specific and liver-specific metastases in pancreatic ductal adenocarcinoma (PDAC).
Authors: Osipov Arsen , Blais Edik Matthew , Davelaar John , Moshayedi Natalie , Nikravesh Nima , Gresham Gillian , Zheng Lei , McRee Autumn Jackson , Chuy Jennifer W. , Shroff Rachna T. , Wadlow Raymond Couric , Gregory Gary Lee , DeArbeloa Patricia , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Thomassian Shant , Gong Jun , Hendifar Andrew Eugene
Published: January 2022

532

Background: PDAC remains one of the most lethal malignancies following metastatic presentation, typically to the liver or lung. Previous studies have observed that advanced PDAC patients have variable outcomes depending on site of involvement. Here, we aim to understand survival outcomes and molecular features for PDAC based on involvement of lung vs liver. Methods: We retrospectively analyzed longitudinal clinical outcomes across 787 patients with PDAC with next generation sequencing (NGS) from Perthera’s Real-World Evidence database whose tumors first metastasized to either the lung or the liver. Median overall survival (mOS) was measured from either the date of initial diagnosis (resectable cases only, stage I-III) or advanced diagnosis (stage IV) until death. Differences in survival and frequencies of mutations were evaluated between patients with lung-specific and liver-specific metastases using Cox regression and Fisher's exact test, respectively. Results: Among resectable PDAC, mOS from initial diagnosis was significantly shorter in patients that developed liver only metastasis (Table, left) compared to those patients that developed lung only metastasis (p=2.4e-08, HR=3.04 [2.06-4.49]). In the advanced PDAC cohort, mOS from diagnosis of advanced disease was also significantly shorter (Table, right) in liver only versus lung only metastasis (p=0.0013, HR=1.62 [1.21-2.18]). Differences in treatment-specific outcomes were not significant supporting a potential prognostic role for lung only metastases. PDAC tumors presenting to the liver first were modestly enriched (unadjusted p<0.05) for TP53 mutations (81.4% in liver vs 69.2% in lung), MYC amplifications (8.6% vs 3.0%), and inactivating CDK2NA alterations (51.5% vs 39.1%) whereas lung-specific mutation frequencies were higher for STK11 mutations (2.4% in liver vs 7.5% in lung), CCND1 amplifications (0.5% vs 3.0%), GNAS alterations (2.0% vs 8.5%). No differences in KRAS mutations nor specific isoforms were noted between lung vs liver only metastasis. Conclusions: Lung only metastasis in both resectable and advanced PDAC confers a significant survival advantage compared to liver only metastasis. Deeper investigation into the molecular drivers of site-specific metastases is warranted.[Table: see text]
A pilot study of liposomal irinotecan plus 5-FU/ LV combined with paricalcitol in patients with advanced pancreatic cancer which progressed on gemcitabine-based therapy.
Authors: Grierson Patrick , Suresh Rama , Tan Benjamin R. , Pedersen Katrina Sophia , Amin Manik A. , Park Haeseong , Trikalinos Nikolaos , Liu Jingxia , Lim Kian-Huat , wang-gillam Andrea
Published: January 2022

566

Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m2)/LV (400mg/m2)/liposomal irinotecan (70mg/m2) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Between 8/29/2019 to 5/6/2021, a total of 20 patients were enrolled in the study. No DLTs or grade 4 adverse events were observed in either paricalcitol cohort. The most common toxicities were gastrointestinal (nausea, diarrhea), fatigue and anemia and were similar in both cohorts. Only one grade 3 adverse event was possibly due to paricalcitol (spinal fracture). 2/10 patients experienced an objective response, one of which was confirmed. Median follow up was 6.1 months. At the time of analysis, one patient remains on liposomal irinotecan and 5-FU/LV and mPFS of all patients is 3.57 months and mOS is 6.15 months. The mPFS is 3.55 months for dose level 1 and 5.34 months for dose level 2 (p = 0.3). The mOS is 6.15 months for dose level 1 and 6.66 months for dose level 2 (p = 0.4). Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer, however does not appear to improve response rate or survival outcomes. Correlative analyses are ongoing. Clinical trial information: NCT03883919.
Molecular precision medicine in pancreatic cancer: A single-center experience.
Authors: Tarabay Anthony , Hollebecque Antoine , Smolenschi Cristina , Antoun Leony , Klotz Caroline , Fuerea Alina , Perret Audrey , Gouriou Claire , Burtin Pascal , Belkhodja Hichem , Boige Valérie , Malka David , Ducreux Michel
Published: January 2022

605

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack for treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of them considered as actionable with molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years, with histologically confirmed PDAC, who underwent tumor molecular profiling between 2010 and 2020 in our institution as part of personalized medicine trials. Overall survival was the primary study endpoint (minimal follow-up after molecular profiling, 6 months). Results: Of 115 eligible patients, molecular profiling was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Actionable GAs were found in 29 patients (28%), involving mainly BRCA1/2 (5 [18%]), HER2 (5 [18%]), MTAP (5 [18%]), and FGFR (3 [11%]). Only 12 of these 29 patients (41%, or 10% of the whole population) could receive MTTs accordingly, with a median progression-free survival of 1.6 months. Median OS was 17 months in patients with actionable GAs treated with MTTs (n = 12 [11.8%]), 14 months in patients with actionable GAs not treated with MTTs (n = 17 [16.7%]), and 19 months in patients without actionable GAs treated with standard therapies (n = 73 [71.5%]; p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The longest duration of response with MTTs was observed in patients with BRCA mutations treated with olaparib. Conclusions: Actionable GAs are found in more than the quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study. However, selected GA/MTT duets (e.g., BRCA mutations/olaparib) were associated with better outcome.
Disparities in place of death (PoD) in patients with gastrointestinal (GI) cancers.
Authors: Hussaini Syed , Arora Nivedita , Sedhom Ramy , Beg Muhammad Shaalan , Gupta Arjun
Published: January 2022

645

Background: PoD is an important determinant of patient and caregiver experience. Differences in PoD may reflect disparities in care, including aggressive end-of-life (EOL) care, and access to palliative care/hospice services and caregiver support/resources. We sought to describe sociodemographic disparities in PoD in patients dying from GI cancers between 2003-2019. Methods: We used deidentified death certificate data via the CDC Wonder database. We included decedents with an underlying cause of death of GI cancer (identified through ICD codes) from 2003-2019. We stratified findings by ethnicity, race, gender, and age (< or ≥ 65 years). We classified PoD as (1) medical facility (2) nursing home, (3) home, or (4) hospice facility. We estimated Annual Percentage Change (APC) in PoD across sociodemographic groups. Results: We included 2,347,754 decedents in the analysis (43.6% women, 68.4% ≥65 years, 7.6% Hispanic, 12.7% non-Hispanic Black [NHB], 75.4% non-Hispanic White [NHW]). From 2003– 2019, across all groups, deaths in medical facility reduced from 45,046 (33.4% of all deaths in the year) to 38,673 (23.3%) (APC -2.2%), and deaths in hospice increased from 871 (0.6%) to 24,092 (14.8%) (APC 26.1%). In 2019, men more frequently died in a medical facility than women (25.5% vs. 21.1% of deaths), and women were more likely to die in a nursing home facility than men (12.6% vs. 9.8%). In 2019, individuals aged<65 years died in a medical facility more frequently than those aged ≥65 years (29.8% vs. 21.0%), and also had lower APC for medical facility deaths from 2003– 2019 (APC -1.8% vs. -2.4%). Among groups, NHWs were least likely to die in a medical facility in (21.0% of deaths in 2019) and most likely to die in a hospice facility (15.5% of deaths in 2019). Hispanic individuals (vs. non-Hispanic individuals) had higher rates of home deaths, and lower hospice and nursing home deaths. Conclusions: Despite overall reductions in deaths in medical facilities for people with GI cancers over time, there remain significant sociodemographic disparities. Targeted interventions for care access, economic stability, and social communities are needed to address these findings. PoD for patients with GI cancer.[Table: see text]