bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive genomic profiling (CGP) of fibrolamellar oncocytic hepatoma (FLO) and conventional hepatocellular carcinomas (HCC): An observational study.
Authors: Shreenivas Aditya V. , George Ben , Thomas James P. , Puckett Lindsay , Chakrabarti Sakti , Awan Musaddiq , Straza Michael Wayne , Hall William A. , Loy Veronica , Rilling William S. , Hong Johnny , Kamgar Mandana , Tsai Susan , Gamblin T. Clark , Smolock Amanda , Christians Kathleen K. , Dougherty Kali , Danziger Natalie , Durazo Francisco , Ross Jeffrey S.
Published: January 2022

474

Background: FLO is a rare variant of liver cancer that disproportionately affects young adults and is frequently progressive and fatal as it is often detected in a clinically advanced stage. It is seldom associated with cirrhosis of liver, viral hepatitis or other risk factors associated with conventional HCC. Treatment options are largely limited to surgical resection, and there is dearth of effective targeted therapies for FLO. Methods: Comprehensive genomic profiling (CGP) was performed using the Foundation Medicine Inc. (FMI) data base on 63 FLO and 1,793 HCC clinically advanced cases between 6/2013-12/2020 using a hybrid capture-based assay of up to 324 genes a to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: The FLO patients (pts) were significantly younger than HCC pts (median age 20 vs. 64, respectively) and the male preponderance was similar. The HCC group featured significantly more GA/tumor than FLO group (3.74 vs 1.31 p<.0001). In the currently untargetable GA group, CTNNB1, TERT and TP53 GA were significantly more frequent in HCC than FLO. GA in potentially targetable genes were extremely uncommon in both FLO and HCC with HCC featuring slightly more MTOR pathway targets ( PTEN, TSC2, NF1). GA in DNA damage and repair (DDR) pathway including BRCA2 were infrequent in both groups. GA in targetable kinases including EGFR, ERBB2, ALK, RET and PIK3CA were extremely uncommon in both groups. GA associated with intrahepatic cholangiocarcinoma (IDH1, FGFR2) were extremely uncommon in these tumors. Although the mean TMB was significantly higher in HCC than FLO, overall TMB was low with very few cases having TMB > 10 mutations/Mb. PD-L1 expression was relatively low in both groups. GA in genes associated with immune checkpoint inhibitors (ICPI) drug response like PBRM1, CD274, MDM2, STK11 were rarely identified in both groups. Additional details are illustrated in the table. Conclusions: Comparison of CGP of FLO with HCC illustrates the multifarious nature of these cancers. In HCC, there is a high prevalence of GA in TERT, CTNNB1 and TP53. CGP identified certain targetable GA in the MTOR and DDR pathways and TMB was higher in HCC. These findings warrant further evaluation of clinically advanced FLO and HCC pts by CGP to identify possible targetable genomic pathways. [Table: see text]
The role of serial analysis of hepatocellular carcinoma via circulating tumor DNA in identification of new actionable alterations.
Authors: Hsieh David , Bucheit Leslie A. , Kasi Pashtoon Murtaza , Beg Muhammad Shaalan , Zhu Hao , Dada Hiba I. , Yang Dong
Published: January 2022

478

Background: Molecular profiling using circulating tumor DNA (ctDNA) is advantageous in cancers where tissue biopsies are not routinely obtained such as in hepatocellular carcinoma (HCC). We hypothesize that due to the expected evolution of cancer clones during treatment, serial analysis of ctDNA at the time of progression may identify additional actionable alterations. This study analyzed serial testing patterns and results for patients with HCC in a large laboratory database. Methods: Analysis of genomic results from blood samples prospectively collected between January 1, 2016-March 31, 2021 for clinical Guardant360 testing and a diagnosis of HCC as documented by ordering providers on the test requisition form (TRF) was performed. Serial tests were defined as having Guardant360 analysis performed on more than one sample collected at more than one timepoint. Chi-squared analysis was completed to assess associations between maximum variant allele fraction (maxVAF) changes and identification of new genes altered on subsequent tests. Results: 106 patients were tested serially with Guardant360 with a total of 272 tests. The median age of patients tested was 65 years (range: 16-91); 75% were male. Approximately 73% of patients had 2 serial tests, 95% had 2-4 serial tests; 5% had 5 or more. 105/106 (99%) of patients had serial tests with genomic alterations detected across multiple tests, of which 68 (64.8%) had new pathogenic alterations compared to their previous test(s) (Table). Increases in maxVAF at the time of re-testing were associated with findings of new molecular alterations (p=0.03). Potentially actionable molecular alterations accounted for 19% (13/68) of new alterations and included mutations in KIT and BRAF and amplifications in MET, BRAF, RAF1, PDGFRA, KIT, and FGFR2. Conclusions: Serial ctDNA testing in patients with HCC identified numerous potentially actionable alterations in nearly 1 in 5 patients for which a clinical trial or matched treatment option may be available. Non-invasive longitudinal genomic assessment via ctDNA provides an opportunity to examine these trends in a larger cohorts and assess impact on clinical outcomes for patients with HCC who undergo serial testing.[Table: see text]
Emerging treatments for advanced cholangiocarcinoma: Addressing the knowledge gap.
Authors: Heller Elizabeth J , Smith Keira A , Wright Kristin L , Williams Sarah L
Published: January 2022

484

Background: The identification of actionable genetic mutations for patients with cholangiocarcinoma has enabled more effective treatments for this condition, but research indicates that clinicians face challenges in maintaining a working knowledge of evolving data. This study was conducted to determine if an online, case-based continuing medical education (CME)/nursing continuing professional development (NCPD)–approved activity could identify and address gaps in clinicians’ knowledge regarding the individualized treatment of patients with cholangiocarcinoma. Methods: The activity, Emerging Treatment Strategies for Advanced Cholangiocarcinoma, chaired by Lipika Goyal, MD, was made accessible starting on May 24, 2021. Learners participated in a 1-hour activity that highlighted emerging therapeutic targets in cholangiocarcinoma, with an emphasis on novel therapies for advanced disease and strategies to monitor and manage treatment-related adverse events. Learners completed a repeated-pairs pre- and post-activity assessment consisting of case-based questions that gauged their ability to apply emerging data to clinical decision making. Knowledge gaps and learning gains were calculated based on percentages of learners obtaining correct responses on the pre- and post-activity assessments. Significance was assessed using a chi-squared test. Results: As of September 27, 2021, 224 clinicians had completed the activity for credit. Baseline assessment data revealed gaps in knowledge regarding emerging actionable targets and management of treatment related-adverse events. The activity resulted in significant gains in knowledge and competence related to these topics, with P < 0.0001 for all learning gains. Conclusions: These data indicate that a substantial knowledge gap exists regarding the latest developments in cholangiocarcinoma treatment. They also demonstrate that online, case-based CME/NCPD-approved activities can result in statistically significant improvements in clinicians’ knowledge of therapeutic advances and management of treatment-related adverse events for patients with cholangiocarcinoma.[Table: see text]
Survey of challenges in access to diagnostics and treatment for neuroendocrine tumor patients (SCAN): The diagnostic process of GEP-NETs in Australia, Canada, China, France, Germany, the United Kingdom, and the United States of America.
Authors: McDonnell Mark , Bouvier Catherine , Pavel Marianne E. , Singh Harjit , Howe James R. , Singh Simron , Chen Jie , Van Genechten Dirk , Gellerman Elyse , Dureja Sugandha , Leyden Simone , Rodien-Louw Christine , Kolarova Teodora , O'Toole Dermot
Published: January 2022

502

Background: SCAN assessed the global delivery of NET diagnostics and treatment. This analysis focused on the diagnostic process in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients in countries with more robust respondent samples (at least 100 units of analysis): Australia (AU), Canada (CA), China (CH), France (FR), Germany (DE), United Kingdom (UK), and the United States (USA). Methods: During Sept-Nov 2019, 2359 NET patients & caregivers, and 436 healthcare professionals (HCPs) completed a self-reported online survey, available in 14 languages, disseminated via INCA and its partner networks. Results: 71% (1670/2359) were GEP-NET patients, 71% of which were from 7 countries (1188/1670), namely AU (7%, 120/1670), CA (9%, 154/1670), CH (7%, 114/1670), FR (8%, 137/1670), DE (9%, 149/1670), UK (11%, 191/1670) and USA (19%, 323/1670). Primary GEP-NETs were predominantly small intestinal (SI) with similar proportions in AU, CA, DE, FR,, UK and US and smaller in CH (*p < 0.001, Chi-squared). Second most common primary was pancreatic NET (similar across countries). Misdiagnosis was very frequent and occurred at least once but most commonly multiple times (table). The most frequent misdiagnoses were irritable bowel syndrome (AU 60%, CA 34%, CH 14%, FR 27%, DE 31%, UK 55%, USA 55%) and gastritis (AU 42%, CA 37%, CH 51%, FR 51%, DE 37%, UK 30%, USA 51%). Patients presented with stage IV disease in more than half of cases in 5 countries (table). On average three HCPs were involved in the diagnostic process in all above-mentioned countries. The HCPs who most often suggested the test that led to the correct diagnosis were gastroenterologists in CH 28%, FR 43%, DE 34%, USA 28%, and GPs in AU 28%, CA 27%, and UK 24% (45/191). In the majority of cases the diagnosis was received in a hospital without a NET specialist, except for CH (AU 38%; CA 42%; CH 25%; FR 36%, DE 51%, UK 44%, USA 45%). Conclusions: SCAN demonstrates some interesting geographical variations with respect to tumor demographics and stage at presentation. Nonetheless, delayed GEP-NET diagnosis remains a significant global challenge. Enhanced knowledge about GEP-NETs in hospitals without NET specialists, especially among gastroenterologists and family doctors (GPs), will drive improvements in global NET care.[Table: see text]
Real-world outcomes in patients with neuroendocrine tumor receiving peptide receptor radionucleotide therapy.
Authors: Hentzen Stijn , Mehta Kathan , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Baranda Joaquina Celebre , Williamson Stephen K. , Sun Weijing , Kasi Anup
Published: January 2022

504

Background: (177)Lu-Dotatate, a form of Peptide Receptor Radionuclide Therapy (PRRT), was approved by FDA for treatment of somatostatin-receptor-positive NETs in 2018. Clinical trials prior to the FDA approval of (177)Lu-Dotatate showed favorable outcomes but there is limited published real world outcomes data. Methods: After obtaining IRB approval we retrospectively evaluated the efficacy of (177)Lu-Dotatate PRRT for somatostatin receptor positive gastroenteropancreatic NET patients at University of Kansas Cancer Center between June 2018 and September 2021. Results: A total of 65 patients received PRRT of which 58 completed treatment and 7 are still undergoing therapy. The 58 patients who completed treatment had a median age of 61.5 years, included 24 females and 34 males, and were 86% Caucasian and 12% black. These patients had primarily NETs of small bowel (n=24) and pancreatic (n=14) origin. Pathology showed grades 1 (21), 2 (25), and 3 (4) with a majority of well-differentiated tumors (47). All 4 treatments of PRRT were completed by 43 patients. In the entire cohort, response assessment to PRRT revealed 14 (26.9%) partial response (PR), 31 (59.6%) with stable disease (SD) and 7 (13.5%) with progressive disease (PD). In subset analysis, we found that patients with nonfunctional disease (n=29) had a higher rate of PR 42.3% vs 11.5% (p=0.0147) and higher disease control rate 96% vs 78% (p=0.042) than functional disease (n=29). Patients with nonfunctional disease had a lower PD 3.85% vs 23% (p=0.0147) and 53% vs 65% stable disease than functional disease. The table below shows clinical characteristics of these patients. Conclusions: Our real world outcomes analysis of NET treated with PRRT shows improved PR when compared to the initial clinical trials which is promising for patients. In addition, we found that there was statistically significant improved response rate in patients with non functional tumors which has not been described in literature before. If our study findings are validated in a larger cohort then it may guide patient selection for PRRT therapy in the future.[Table: see text]
Genomic predictors of benefit from checkpoint inhibition in neuroendocrine carcinoma.
Authors: McGarrah Patrick Walsh , Gile Jennifer , Liu Alex John , Mansfield Aaron Scott , Leventakos Konstantinos , Desai Aakash , Tella Sri Harsha , Sonbol Bassam Bassam , Starr Jason S. , Hobday Timothy J. , Halfdanarson Thorvardur Ragnar
Published: January 2022

512

Background: The role of immune checkpoint inhibitors (ICIs) in the treatment of extrapulmonary neuroendocrine carcinoma (EP-NEC) has yet to be established. While objective responses have been observed, it is still unknown which patients are likely to derive benefit. We investigated the genomic profiles of patients who did and did not benefit from ICIs. Methods: Previously we reported the objective responses to ICI in a retrospective series of patients with EP-NEC. RECIST 1.1 criteria were used to categorize patients as achieving disease control (DC = CR, PR, or SD) vs progressive disease (PD). The EMR was reviewed to identify patients who had genomic panels performed, and results were extracted for analysis. Results: Of 31 patients eligible for RECIST assessment, 19 had genomic panels available (9 with DC: 4 SD, 5 PR vs 10 with PD). Of those with NEC histology specified, 9 were small cell, 1 combined large and small cell, 3 were large cell. All tumors were microsatellite-stable. All but one (with TMB = 25) of 16 tumors with TMB status available were < 10 m/MB. Of those with disease control, 67% had both TP53 and RB1 alterations, compared with only 10% in those with progressive disease; this was statistically significant ( p = 0.0198, Fisher exact). Of 7 tumors with TP53 + RB1 alterations, 4 were specified as small cell carcinoma. Half of those with PD showed alterations in β-catenin pathway genes CTNNB1 or APC, compared to only one of the DC group, but this did not reach significance ( p = 0.1409, Fisher exact). In an analysis of all Mayo patients (not just those treated with ICI) with NGS data available (Tempus and FoundationOne), concurrent TP53 + RB1 alteration was significantly more common in SCLC than in EP-NEC (Table). Conclusions: In this small series of patients with EP-NEC treated with ICIs, the SCLC-like genomic signature of concurrent TP53 + RB1 alterations was significantly more common in those with disease control than in those with progressive disease. An analysis of all patients with NGS data (not just on ICI) showed that the dual alteration was more common in SCLC, and SCLC also had more TMB-high tumors. This may explain why ICIs are more effective in SCLC than in EP-NEC. Further study is warranted to determine whether TP53 + RB1 mutations predict response to ICI in NEC.[Table: see text]
A multi-institutional study of the impact of the COVID-19 pandemic on pancreatic cancer diagnosis and management.
Authors: Rosso Claudia , Valerin Jennifer B. , Oviedo Parisa , Radgoudarzi Niloofar , Chen Wen-Pin , McLaren Christine E. , White Rebekah Ruth , Zell Jason
Published: January 2022

526

Background: The impact of COVID-19 on cancer patients may be attributed not only to its direct effects on the immune system but also to delays in diagnosis and treatment. Data on the effects of COVID-19 on pancreatic ductal adenocarcinoma (PDAC) patients are scarce. Therefore, we set out to determine the impact of the pandemic on diagnosis and treatment initiation. We hypothesized that time from diagnosis to treatment would be increased in the COVID era compared to the pre-COVID era. Methods: We conducted an IRB-approved retrospective chart review of 488 patients diagnosed with PDAC from March 2019 to September 2020 at two academic medical centers. Patients were divided into two groups, based on the date of initial pathologic diagnosis. We defined the pre-COVID era as March 2019 to March 2020, the 12-month time period before California’s statewide lockdown. The COVID era was defined as the 6 months following the lockdown, March 2020 to September 2020. Demographics, clinical stage, and treatment type were recorded. In addition, initial clinical encounter date, pathologic diagnosis date, and initial treatment date were also collected. All data were gathered at two large-scale academic institutions. Descriptive statistics were used in the analysis. Results: There were 333 patients diagnosed during the pre-COVID era and 155 patients during the COVID era. While race/ethnicity and age at diagnosis were statistically similar for both groups, females made up a significantly larger proportion of COVID era patients than pre-COVID era patients ( p= 0.02). There was no significant difference in clinical stage at diagnosis between the two groups ( p= 0.84). In the pre-COVID era, 19.5% of cases were resectable, 11.1% borderline resectable, 20.1% locally advanced, and 31.8% metastatic. In the COVID era, 17.4% of patients were resectable, 11% borderline resectable, 23.9% locally advanced, and 32.9% metastatic. Median time from pathologic diagnosis to initiation of treatment was 32 days for the pre-COVID era patients and 28 days for the COVID era patients ( p= 0.38). Initial treatment type was also similar between the two groups ( p= 0.29). Conclusions: Fortunately, our data indicate that the COVID-19 pandemic has not significantly prevented PDAC patients from seeking care. Additionally, it does not appear that COVID-19 has delayed treatment initiation or changed initial treatment type. We believe that the successful adoption of telemedicine and other safety protocols have allowed patients with PDAC to continue receiving appropriate care during the pandemic.[Table: see text]
Cancer Commons’ virtual tumor board program: A patient-centric advisory panel and real-world data registry.
Authors: Rahib Lola , Chang David Kuang-Fu , Sohal Davendra , Kinsey Conan Grant , Christensen Deborah , Shapiro Mark , Zelada-Arenas Fatima , Paulson Andrew Scott , Beg Muhammad Shaalan
Published: January 2022

527

Background: We initiated a nationwide Virtual Tumor Board (VTB) program for pancreatic cancer (PC) patients (pts). The VTB consists of oncology experts and serves as an advisory panel by providing information on treatment (Tx) options based on a comprehensive review of patients’ oncologic history. Personalized Tx options and their rationales are provided and outcomes tracked in a prospective registry (XCELSIOR). Methods: PC pts who participated in XCELSIOR shared access to their full medical records, which were collected, processed, and abstracted. The panel reviewed cases asynchronously through an interactive platform followed by a VTB which was held weekly through videoconferencing. Tx options were summarized into a written report and provided to patients and their physicians. Outcomes and quality of life are tracked longitudinally through an IRB-approved 21CFR11 compliant observational registry (XCELSIOR). Results: From 9/2020 to 8/2021, the VTB reviewed 79 unique cases; 56% were male; median age at diagnosis was 66 (50-87). At the time of VTB, 68 (87%) had metastatic disease and 8 (10%) had locally advanced disease. Median prior therapy lines was 2 (0-9), with 26 (35%), 24 (32%), 6 (8%), and 19 (25%) pts having received 1, 2, 3 and 4+ lines of therapy, respectively. Median time from diagnosis for pts presenting after 1, 2, and 3+ lines of prior Tx was 9.5, 11, and 17.5 months, respectively. First-line Tx was FOLFIRINOX in 40 (53%) pts and gemcitabine/nab-paclitaxel in 22 (29%) pts. At the time of VTB, 32 (37%) of patients had stable disease, 23 (26%) had disease progression, 18 (21%) had recently started a new Tx, 7 (8%) were responding to Tx, 3 (3%) had stable disease on imaging but rising CA 19-9, and 4 (4%) were others. Prior to VTB, 69 (87%) pts had molecular profiling results available. Collectively the VTB provided 375 Tx and diagnostic (NGS, imaging, etc.) options with a median of 4 (1-12) options per patient. As of 9/8/2021, 87 VTB reports were provided. Of 25 instances of ‘no Tx decision’, 10 (40%) are deceased, 10 (40%) are stable, and 5 (10%) had other reasons. Of the 25 people who started a subsequent Tx, 14 (56%) were identified by the VTB. These included 9 (64%) FDA-approved, 3 (21%) off-label, and 2 (14%) on-trial Tx. Tx not identified by the VTB included 3 (33%) FDA-approved, 2 (22%) off-label, 2 (22%) on-trial, and 2 (22%) local Tx. Conclusions: We present our experience of utilizing a platform for patients to receive a virtual tumor board review and utilize an IRB-approved registry as a learning system. Early data indicate successes in identifying treatment and clinical trial opportunities. Future steps include streamlining communication with primary oncologists and enhancing access to treatments. NCT03793088.
Optimal preoperative multidisciplinary treatment in borderline resectable pancreatic cancer: Results of a dual-center study.
Authors: Kimura Nana , Yamada Suguru , Takami Hideki , Murotani Kenta , Yoshioka Isaku , Shibuya Kazuto , Sonohara Fuminori , Hoshino Yui , Hirano Katsuhisa , Watanabe Toru , Baba Hayato , Mori Kosuke , Miwa Takeshi , Tanaka Haruyoshi , Kanda Mitsuro , Hayashi Masamichi , Matsui Koshi , Okumura Tomoyuki , Kodera Yasuhiro , Fujii Tsutomu
Published: January 2022

530

Background: For borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC), upfront surgery was standard in the past, and the usefulness of neoadjuvant treatment (NAT) has been reported in recent years. However, few studies have been conducted to date on whether there is a difference in optimal treatment between BR-PDAC invading the portal vein (BR-PV) or abutting major arteries (BR-A). The objective of this study was to investigate the optimal treatment for BR-PV and BR-A. Methods: We retrospectively analyzed 199 patients with BR-PDAC (88 BR-PV and 111 BR-A). For each BR-PV and BR-A, we analyzed the following points. 1) Comparison of prognosis of upfront surgery vs. NAT, 2) Comparison of regimens in patients who underwent NAT, 3) Prognostic factors in patients who underwent resection after NAT. Results: 1) In BR-PV patients who underwent upfront surgery (n = 46)/NAT (n = 42), survival was significantly better in the NAT group (3-year overall survival (OS): 5.8%/35.5%, p = 0.004). In BR-A patients who underwent upfront surgery (n = 48)/NAT (n = 63), survival was also significantly better in the NAT group (3-year OS:15.5%/41.7%, p < 0.001). 2) The prognosis tended to be better in patients who received newer chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine with nab-paclitaxel than older regimens such as gemcitabine and/or S-1, in each BR-PV and BR-A patients. The R0 rate was significantly higher (100%) when radiotherapy was used in combination with chemotherapy, regardless of the chemotherapeutic regimen. 3) In 36 BR-PV patients who underwent surgery after NAT, univariate analysis revealed that normalization of tumor marker levels ( p = 0.028) and preoperative high prognostic nutritional index (PNI) ( p = 0.022) were significantly associated with a favorable prognosis. In 39 BR-A patients who underwent surgery after NAT, multivariate analysis revealed that preoperative PNI > 42.5 was an independent prognostic factor (hazard ratio: 0.15, p = 0.014). The length of NAT was not a prognostic factor for either BR-PV or BR-A. Conclusions: NAT using newer chemotherapy is essential for improving the prognosis of BR pancreatic cancer. These findings suggest that prognosis may be improved by maintaining good nutritional status during preoperative treatment, not by the length of preoperative treatment. In addition, surgery after normalization of tumor markers levels by preoperative treatment contributes to the prolongation of survival.
Health outcomes of gBRCA testing strategies for metastatic pancreatic cancer patients.
Authors: Fan Lin , Agnihotri Neeharika , Ambavane Apoorva , Li Weiyan , Joo Seongjung , Yoo Hyun Kyoo , Muston Dominic
Published: January 2022

537

Background: About 4-8% metastatic pancreatic cancer (mPC) patients have germline BRCA mutation (gBRCAm). Identifying gBRCAm through early testing benefits mPC patients through: 1. better health outcomes when gBRCAm patients receive platinum (plat) based 1st line (1L) chemotherapy compared to non-plat 1L regimen; 2. additional benefit, if eligible, from olaparib (O) maintenance treatment (mTx), which was approved by the FDA for the gBRCAm mPC patients who have not progressed on at least 16 weeks of a 1L plat regimen. Objective: To evaluate the health outcomes of gBRCA testing and treatment strategies among mPC patients using simulation model. Methods: A 3-state partitioned survival model was developed to assess the lifetime (20 year) health outcomes among treatment naïve mPC patients for the following strategies: 1. No gBRCA testing, no O mTx; 2. gBRCA testing before 1L, no O mTx; 3. gBRCA testing before 1L, O mTx; 4. gBRCA testing after 1L, O mTx. Without gBRCAm information before 1L (i.e., strategy 1&4) or if gBRCA negative, 45% mPC patients with good performance status (PS) and 27% with poor PS received 1L plat. We assumed that for gBRCAm patients, if known, 90% with good PS and 50% with poor PS received 1st line plat (i.e., strategy 2&3) in the base case. We assumed gBRCA testing had 100% of sensitivity and specificity. OS and PFS survival curves were extrapolated from pivotal trials. The additional health outcome benefit from O mTx after 16 weeks were modeled using efficacy from POLO trial. Health outcomes were measured by life years (LY) and, after applying health utilities by health state, quality adjusted life years (QALY). Results: The proportion of gBRCAm mPC patients receiving O mTx were 58.7% (4.4% of mPC patients) for strategy 3 vs 30.0% (2.2% of mPC patients) for strategy 4. For gBRCAm mPC patients, no testing generated the least LY and QALY, while testing before 1st line with O mTx resulted in the most. This trend was also observed in the overall cohort of mPC patients with the best outcomes from testing before 1st line with O mTx and worse outcomes from no testing or testing after 1st line with O Mtx. These survival gains are primarily derived by higher proportion of patients on platinum with better survival along with O Mtx gains. Conclusions: mPC patients achieve the highest health benefits by gBRCA testing before 1L treatment followed by O mTx, even with less than 5% mPC patients becoming eligible for O mTx (strategy 3).[Table: see text]
A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer.
Authors: Ueno Makoto , Morizane Chigusa , Ikeda Masafumi , Sudo Kentaro , Hirashima Yoshinori , Kuroda Masataka , Fukuyama Yuki , Okusaka Takuji , Furuse Junji
Published: January 2022

553

Background: Although FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of unresectable pancreatic cancer patients, high unmet medical needs still exist for the treatment of this cancer. Nivolumab has shown efficacy for multiple cancer types in not only its monotherapy but also combinations with conventional chemotherapies. This study aimed to assess the efficacy and safety of nivolumab in combination with modified FOLFIRINOX, which is one of the first line chemotherapy for pancreatic cancer. Methods: Thirty-one treatment-naïve patients with metastatic, unresectable/recurrent pancreatic cancer patients received nivolumab (480 mg, every 4 weeks) plus modified FOLFIRINOX (oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2, every 2 weeks). The primary endpoint was objective response rate (ORR) (central assessment). Secondary endpoints were overall survival (OS), progression-free survival (PFS) (central assessment), safety etc. Results: The median duration of follow-up was 13.40 months. ORR was 32.3% (CR: 0.0%, PR: 32.3%) and the median duration of response was 7.36 (range 3.5-20.1+) months. Median OS and PFS were 13.40 (90% CI 10.87-15.24) months and 7.39 (90% CI 3.88-7.59) months, respectively. The 1-year survival rate was 54.8 (90% CI 39.1-68.1) %. The most frequently reported grade 3-4 drug-related adverse events were neutrophil count decreased (38.7%), decreased appetite (16.1%), hypokalemia (12.9%), febrile neutropenia (9.7%), nausea (9.7%) and white blood cell count decreased (9.7%). Adrenal insufficiency (3.2%) was observed as immune mediated adverse event. Conclusions: Nivolumab in combination with modified FOLFIRINOX had a manageable safety profile in patients with metastatic pancreatic cancer. Additional work is needed to determine the population who can benefit from the combination. Clinical trial information: JapicCTI-184230.
Preliminary results of a phase 1 study of sea-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Bajor David Lawrence , Gutierrez Martin , Vaccaro Gina M. , Masood Ashiq , Brown-Glaberman Ursa , Grilley-Olson Juneko E. , Kindler Hedy L. , Zalupski Mark , Heath Elisabeth I. , Piha-Paul Sarina Anne , Zhou Peigen , Lu Hailing , Ansari Sahar , Hayman Jonathan , Schmitt Michael W. , Coveler Andrew L.
Published: January 2022

559

Background: SEA-CD40 is an investigational nonfucosylated IgG1 monoclonal agonistic antibody targeted to CD40, expressed on antigen-presenting cells. SEA-CD40 binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. PDAC can be treated with gemcitabine + nab-paclitaxel (GnP), often with poor survival. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation to CD8+ T cells. In preclinical models, the combination of SEA-CD40 and chemotherapy resulted in significant antitumor activity which is further enhanced with anti-PD1 treatment. We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). Methods: Patients (pts) ≥18 years old with untreated metastatic PDAC and Eastern Cooperative Oncology Group performance scores of 0 or 1 were enrolled. GnP were administered on Days 1, 8, and 15 of each 28-day cycle with 10 or 30 μg/kg SEA-CD40 IV on Day 3. Pembro was administered every 42 days starting on Day 8. Results: As of July 9, 2021, 61 pts were treated: 40 and 21 pts at 10 and 30 μg/kg SEA-CD40, respectively. Minimum follow-up was 5 months. The most frequent treatment-emergent adverse events (TEAEs) are shown in Table. 5 (8%) pts experienced an AE leading to treatment (tx) discontinuation (3 and 2 in 10 and 30 μg/kg SEA-CD40 dose, respectively), 35 (57%) pts experienced a serious TEAE (22 and 13 pts in 10 and 30 μg/kg, respectively). Two tx-related deaths occurred: colitis attributed to pembro, and septic shock attributed to GnP. Pts had transient increases in circulating cytokines and chemokines associated with immune activation and trafficking as well as increases in markers of activation on peripheral NK cells and T cells. Conclusions: The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing. Clinical trial information: NCT02376699. [Table: see text]
A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.
Authors: Parikh Aparna Raj , Weekes Colin D. , Blaszkowsky Lawrence Scott , Franses Joseph Wang , Ting David Tsai , Mehta Arnav , Roeland Eric , Ryan David P. , Allen Jill N. , Clark Jeffrey William , Ly Leilana , Loosbrock Isabella , Jarnagin Joy X. , Bannon Allison , Caldwell Darcy K. , Yeap Beow Y. , Wo Jennifer Y. , Hong Theodore S.
Published: January 2022

564

Background: PARP inhibitors have activity as monotherapy in BRCA1/2 mutated metastatic pancreatic cancer; however, several other genes and associated proteins exist in the homologous recombination repair (HRR) pathway promoting resistance to chemotherapy and radiation-induced damage. Tumors with HRR deficiency have an impaired ability to repair themselves and are susceptible to PARP inhibition, but ionizing radiation can also induce DNA breaks. Ongoing research suggests that PARP inhibitors may cause radio-sensitization and may also enhance sensitivity to immunotherapy. We conducted a phase 2 study of niraparib and dostarlimab with radiation in a biomarker unselected PDAC population given PARP inhibitors' immunomodulatory and radiosensitizing effects. Methods: In this open-label, single-arm, phase-2 study, eligible patients had histologically confirmed MSS PDAC, ECOG PS 0-1, and progressed on at least one line of jm. Treatment consisted of niraparib 200 mg daily on a 21-day cycle, dostarlimab 500 mg every 3 weeks every 4 weeks for the first four doses, then 1000 mg every 6 weeks, and 3 fractions of 8 Gy at Cycle 2. Treatment continued until progressive disease, discontinuation, or withdrawal. The primary endpoint was DCR by RECIST 1.1 with radiological evaluations every 3 months. Secondary endpoints included DCR by irRECIST, PFS, OS, and safety. Responses were defined as disease control outside the radiation field. We obtained serial tumor biopsies, including pre-treatment. A two-stage design was used, requiring disease control in at least one of the first 15 patients before proceeding to the full accrual of 25 patients. Intention to treat analysis included all patients receiving at least one dose of any study agent. Results: We enrolled and treated 15 pts (median age 60 years [range 37-77], 53% male) from 08/2020 to 05/2021. Overall, DCR was 0/15 (95% CI: 0-22%), median PFS was 1.6 months (95% CI: 1.1-2.7), and median OS 3.1 months (95% CI: 1.5-7.7). Among 27 treatment-related serious adverse events, 15 (56%) were grade 3, including decreased CD4 lymphocytes, thrombocytopenia, anemia, and fatigue being the most common. Conclusions: The combination of niraparib and dostarlimab with radiation did not meet the pre-specified criteria for expansion to full accrual. Further analyses of dose intensity in this heavily pretreated and evaluation of in-field responses are underway. Further investigation of the combination with biomarker selection is warranted. Clinical trial information: NCT04409002.
Real-world clinical outcomes of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens: Impact of prior irinotecan (IRI) exposure.
Authors: Yu Kenneth H. , Cockrum Paul , Surinach Andy , Lamarre Neil , Wang Shu , O'Reilly Eileen Mary
Published: January 2022

580

Background: Subgroup analyses of the NAPOLI-1 study identified that among patients who were IRI naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm (overall survival (OS): 6.7 months vs 4.2 months). This treatment benefit was not observed among those previously exposed to IRI (OS: 4.6 months in study arm vs 4.8 months in control arm). This study sought to understand the impact of prior exposure to IRI on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan -based regimens between January 2016 and October 2020. Patient characteristics, OS and progression-free survival (PFS) were assessed. Prior IRI was defined as IRI given in a prior regimen in the metastatic setting. Cox proportional hazard (PH) methods were used to calculate hazard ratios (HRs). HRs were adjusted to account for demographics and relevant clinical covariates. Patients without prior exposure to IRI were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for unexposed patients relative to the exposed). Results: 675 patients with mPDAC treated with a liposomal irinotecan-based regimen were included. Median age at treatment initiation was 69 (IQR: 62 – 75) years and among patients with available ECOG performance status (PS), 77.4% had a PS of 0-1. 181 (27%) patients were previously exposed to IRI in the metastatic setting (Table). The unadjusted OS HR was 1.3 (95% CI: 1.1 – 1.6, p < 0.001) and the unadjusted PFS HR was 1.4 (95%CI: 1.2 – 1.7, p < 0.001). After adjustment for baseline characteristics the adjusted OS HR was 1.0 (95% CI: 0.8 – 1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95%: 0.8 – 1.4, p = 0.5626). Conclusions: The results of this study suggest prior exposure to IRI is not a predictor of worse clinical outcomes for patients treated with liposomal irinotecan-based treatment when accounting for key clinical characteristics in a multivariable model. The results from this real-world study can be used to support treatment sequencing decisions for patients with mPDAC following first line therapy. This is the largest real-world evidence study to date of patients with mPDAC treated with liposomal irinotecan.[Table: see text]
Promising survival and disease control in third-line or greater metastatic or locally advanced pancreatic cancer patients following chemo-radiation and novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy.
Authors: Seery Tara Elisabeth , Nangia Chaitali Singh , McKean Heidi Ann , Sender Leonard S. , Bhar Paul , Reddy Sandeep K. , Soon-Shiong Patrick
Published: January 2022

582

Background: Pancreatic cancer claimed an estimated 47,050 lives in the USA in 2020, with an expected median overall survival (OS) of 3 months in 3rd line. (Manax ASCO GI 2019), with no evidence of disease control in these late stage patients. We hypothesize that effective response against pancreatic cancer requires orchestration of both the innate and adaptive immune system to accomplish immunogenic cell death with survival benefit. Herein we report the first results of a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine superagonist), and allogeneic off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: We report data from a multi-center study, on 55 3rd line or greater, subjects treated with low dose, chemo radiation Nab-paclitaxel (100 mg/ m2 IV), Gemcitabine (600 mg/m2 IV); Cyclophosphamide (50 mg PO BID) and low dose SBRT. This induction immuno-modulation therapy to induce DAMPs was followed with investigational agents activating the innate and adaptive systems: Aldoxorubicin (150 mg/m2 IV), N-803, an IL-15 superagonist (15 μg/kg SC) and PD-L1 t-haNK (̃2 × 109cells/dose IV). Prophylactic G-CSF or EPO was not allowed. All treatments were administered on an outpatient basis. Results: As of submission, median follow-up is 3.9 months. Median age 62, M:F ratio 35:20. ECOG 0-1,92%. 41/55 (75%) subjects reported a grade ≥3 AE related to the chemo radiation, anemia 44%, neutropenia 24%, thrombocytopenia 11%, all others < 10%. SAEs attributed to investigational agents were reported in 5/55 (9%) patients. Of the 44 patients evaluable at 3 months to date, the OS is 81.8% (36/44), 95% CI: 67.3%, 91.8%. The disease control rate of 47 evaluable patients is 36.2% (17/47) 95% CI 22.7%,51.5%. No treatment related deaths have occurred. Treatment is ongoing for 16 subjects, with 14 months as the longest duration on therapy to date. Median OS not yet reached with 28/55 alive to date. Median PFS is 2.4 months (95% CI: 2.0, 3.7) and 36% of subjects not having progressed to date. Conclusions: Historical 3 month median OS in 3rd line metastatic pancreatic cancer patients has been exceeded. Early safety and promising efficacy is seen in QUILT 88 investigating a novel combination immunotherapy protocol of low-dose chemoradiation, N-803 and PDL1 t-haNK therapy. Updated data will be presented. Clinical trial information: NCT04390399.
Palliative radiosurgery for localized pancreatic cancer in the elderly.
Authors: Sckolnik Steven , Fishel Rotem , Borazanci Erkut Hasan , Amini Albert , Thosani Amar
Published: January 2022

583

Background: At least 15% of patients diagnosed with localized pancreatic cancer are medically unfit for surgical resection or systemic therapy. Traditionally, these patients are enrolled in palliative care with symptom management alone. With local progression of their disease, they may experience pain, obstruction, weight loss and nausea. Radiosurgery is a localized high dose conformal therapy allowing for noninvasive treatment of pancreatic cancer. This study retrospectively examines the role of palliative radiosurgery as monotherapy for elderly patients who are not candidates for standard of care therapy. Methods: From 2017-2021, 28 patients over the age of 80 with biopsy confirmed pancreatic adenocarcinoma and localized disease by imaging were retrospectively evaluated. All had been deemed not to be candidates for surgical resection or systemic chemotherapy. Outcomes were reviewed to evaluate patient characteristics, local control, quality of life, ECOG status and survival duration. Results: Median patient age was 84 years (range 80-99). All 28 patients received SBRT radiosurgery to the pancreas with 35-40Gy in 5 fractions with photon LINAC platform. Mean ECOG score was 1.2 at time of treatment. At 6 month follow up, 18 patients were alive with a mean ECOG of 1.4. Four patients reported grade 2 acute GI toxicity in the first three months with no late toxicity reported. Eight patients developed local progression while fourteen patients developed distant metastatic disease. Six patients at least one year out from treatment have no evidence of disease progression. Median overall survival is 10.8 months. Conclusions: Pancreatic radiosurgery is a safe and effective method of palliative therapy for elderly patients who are not candidates for surgical resection or systemic therapy. It can provide durable local control, relief of pain and obstructive symptoms, is well tolerated with minimal toxicity and provides favorable survival when compared to palliative care alone.
Circulating tumor DNA-based genomic landscape of early-onset pancreatic cancer.
Authors: Barnett Reagan , Dada Hiba I. , Drusbosky Leylah , Clemens Keelia , Hochster Howard S. , Gulhati Pat
Published: January 2022

588

Background: The incidence of gastrointestinal and obesity related cancers, including pancreatic cancer, is increasing in individuals <50 years old. Early-onset pancreatic cancer (EOPC; age<50 years old at diagnosis) is characterized by higher incidence in males, enrichment for KRAS wild-type tumors with targetable genomic alterations (GAs), and improved outcomes compared to average-onset pancreatic cancer (AOPC; age>50 years old at diagnosis). Little is known about the genomic correlates underlying these clinical differences. In this study, we sought to characterize the circulating tumor DNA (ctDNA) landscape in EOPC compared to AOPC. Methods: We analyzed ctDNA samples from a total of 8548 patients (EOPC n=488 [age<30yo n=13, 30-39yo n=87, 40-49yo n=388]; AOPC n=8060) collected prospectively between December 2017 to March 2021 using a 73 gene next generation sequencing panel (Guardant360). Statistical analyses were performed using Fisher’s exact test. Results: Of the 488 EOPC patients, 261 (53%) were male and 227 (47%) were female. Median age was 45yo in EOPC and 69yo in AOPC. Contrary to prior reports from tissue-based sequencing studies, EOPC patients were more likely to harbor KRAS alterations (p≤0.0001), specifically KRAS G12V (p≤0.0072) and KRAS amplifications (p≤0.0001). 1.24% of pancreatic cancer patients harbored KRAS G12C mutations; 0.05% were in EOPC patients. The most common currently-targetable GAs identified in EOPC were PIK3CA (10%), BRCA1/2 (10%), EGFR (9%), BRAF (7%), MET (7%), ATM (7%), FGFR1/2 (7%), CDK6 (5%), and ERBB2 (4%). EOPC patients had higher proportion of targetable GAs in BRCA2 (p≤0.041), MET (p≤0.005), and PIK3CA (p≤0.0023) compared to AOPC. Conversely, AOPC patients had higher proportion of GAs in TP53 (p≤0.0001) and ATM (p≤0.0001). MSI-high and TMB-high were detected in 0.07% and 0.06% of EOPC patients respectively, while 0.6% and 1.7% AOPC patients were MSI-high and TMB-high. Gene fusions were detected in 0.3% pancreatic cancer patients, predominantly in FGFR2 (0.2%) and FGFR3 (0.02%). Potential germline variants were detected in both EOPC and AOPC patients, most commonly in BRCA2 (54%). Females displayed higher proportion of TP53 (p<0.0001), EGFR (p<0.0029), CDKN2A (p<0.0001), BRCA2 (p<0.0336) and ATM (p<0.0001) mutations compared to males. Gender was predictive of the pattern of GAs in EOPC with MET (p≤0.0027) , ARID1A (p≤0.0376) , and BRAF (p≤0.0034) alterations enriched in males, and PIK3CA (p≤0.0017) alterations enriched in females. Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of EOPC. Based on this age and gender-stratified molecular characterization of pancreatic cancer, EOPC is a distinct molecular entity compared to AOPC. Identification of multiple targetable GAs may improve patient outcomes in EOPC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.