bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.
Authors: Park Robin , Lopes da Silva Laércio , Nissaisorakarn Voravech , Riano Ivy , Saeed Anwaar
Published: January 2021

293

Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.
Association of early recurrence within one year of liver transplant for hepatocellular carcinoma with poor survival.
Authors: Li Bryan Cho Wing , Chiu Joanne Wing Yan , Yau Thomas , Leung Roland Ching-Yu , Tang Vikki , Shing Kit Bong , Kwok Gin Wai , Cheung Tan To , She Wong Hoi , Ma Ka Wing
Published: January 2021

296

Background: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant is challenging. All the clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. Here we review outcome, and the safety and efficacy of the application of systemic medical therapies in this clinical setting. Methods: This is a retrospective cross-sectional study of consecutive adult patients with recurrence of HCC following liver transplant for the indication of treatment of HCC in Queen Mary Hospital from January 2005 to January 2018. Results: Forty-three consecutive patients with a recurrence of HCC following liver transplant were identified from 2005 to 2018. Median survival from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p< 0.001) after adjustment with peritumoural vascular invasion, first line therapy with sorafenib, any second line therapy and use of mTOR inhibitors as immunosuppressants, with a hazard ratio of 0.104 (log-rank test, p<0.001). 41 patients who received medical systemic therapies, 34 (79.1% ) received sorafenib as the first line systemic therapy. 47.1% (N= 16) received subsequent lines of systemic therapies (ranging from 1 to 4 lines). Hand-foot syndrome was most common among the adverse events and it was observed in 34.7% patients treated with sorafenib. It led to dose interruptions in 8.8 % of patients who were given sorafenib. 26.7% had grade 1 diarrhoea. 14.3% had grade 1 transaminase rise. Conclusions: Early recurrence within one year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.
Advances in the treatment of cholangiocarcinoma: Effect of online education on clinician knowledge and confidence.
Authors: Fisher Geoff Roy , Koekkoek Sanneke , Scot-Smith Camille , Malka David
Published: January 2021

302

Background: This study determined whether online continuing medical education could improve the knowledge and confidence of clinicianson the latest developments in the treatment of cholangiocarcinoma (CCA). Methods: A 30-minute online video panel discussion was launched for countries outside the USA in March 2020. Data was collected to June 2020. Educational effect assessed with repeated-pairs pre-/post-activity, where individual participants served as their own control. Three multiple-choice, knowledge questions and one self-efficacy, five-point Likert scale confidence question were analyzed. Chi-squared test assessed pre- to post-activity change (5% significance level, P <.05). Magnitude of change in total number of correct responses overall, and for each question, were determined with Cramer’s V (<.06=Modest, 0.06-0.15=Noticeable, .16-.26=Considerable, >.26=Extensive). Results: 85 oncologists (oncs) and 44 gastroenterologists (gastros) completed pre- and post-activity questions. A considerable educational effect was observed for both oncs (V=.174, P<.0001) and gastros (V=.246, p<.0001) with average % of correct responses increasing from 62 to78% and 47 to 71%, respectively. Clinicians with 3/3 answers correct increased post-activity (11 to 48% for oncs, 28 to 51%, for gastros). Improvements in % of correct responses post-activity were seen for questions on the molecular target for pemigatinib, the subtype of CCA where IDH mutations are detectable, and the need for comprehensive molecular testing at diagnosis of metastatic CCA (relative improvements: 31%, 38%, and 11% for oncs; 155%, 50% and 14%, for gastros). 78% of oncologists’ and 72% of gastros’ responses were improved or reinforced post-activity. 21% of all participants stated they would modify treatment plans. Confidence in incorporating routine broad molecular testing in the treatment of CCA improved post-activity with a total average confidence shift of 25% for oncs and 32% for gastros. Conclusions: This on-demand, online video panel discussion resulted in a considerable education effect. Online medical education is valuable in improving knowledge and confidence, as well as identifying areas of continued educational need.
Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC): Planned interim efficacy and safety analysis.
Authors: Arora Sukeshi Patel , Moseley Jennifer L. , Tenner Laura LaNiel , Arellano Luisa , Salazar Mary , Liu Qianqian , Michalek Joel , Mahalingam Devalingam
Published: January 2021

305

Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437.
Penpulimab (Anti-PD-1) combined with anlotinib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Updated results from a phase Ib/II study.
Authors: Jiao Shun Chang , BAI LI , Dong Jiahong , Bai Chunmei , Hu Chunhong , Shen Liangfang , Qin Qun , Bai Yuxian , Fan Jia , Zang Aimin , Zhu Yanyun , Han Chun , Li Juan , Zhang Pengfei , Ye Sisi , Kang Xindan , Qiao Qian , Wang Zhongmin Maxwell , Li Baiyong , Xia Yu
Published: January 2021

306

Background: Combined therapy of an immune checkpoint inhibitor with a targeted antiangiogenic agent had been proved to be effective for the treatment of uHCC. Penpulimab was engineered to eliminate FcγR binding and ADCC/ADCP completely, where ADCC/ADCP effects could induce T-cell apoptosis and clearance and then compromise anti-tumor activity. Penpulimab demonstrated a slower PD-1 antigen binding off-rate, which resulted in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and might contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Methods: In this open-label, multicenter phase Ib/II study, patients (pts) without prior systemic treatment, and classified as BCLC stage B (not amenable for locoregional therapy) or C, Child-Pugh ≤7, and ECOG PS ≤ 1 received Penpulimab (200mg IV Q3W) and Anotinib (8 mg PO 2weeks on/1 week off). Primary endpoint was ORR (RECIST v1.1); secondary endpoints were safety, DCR, DoR, TTP, PFS and OS. Results: 31 pts (median age 56 years [23–74], ECOG 0/1 [64%/36%], BCLC B/C [23%/77%], HBV/HCV [61%/7%]) received combined therapy. As of August 31, 2020, median follow-up time was 11.9 mons (range 3.7-17.7). Median PFS was 7.6 mons with 6-mons PFS rate was 57.6% while median TTP was 8.5 mons with 6-mons TTP rate was 62.7%. Median overall survival had not been met and 6-mons OS rate was 93.2%. The ORR was 31.0% (9/29) and DCR was 82.8% (24/29). At data cutoff, 77.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 90.3% of pts (≥G3 in 16.1% [5/31], no G5, treatment discontinuation in 9.7% [3/31]). Most common TRAEs (≥15%) were increased AST (38.7%) and ALT (35.5%), increased blood bilirubin (22.6%),asthenia (22.6%),decreased platelet count (19.4%) and rash (16.1%). Conclusions: Penpulimab plus Anlotinib showed favorable antitumor efficacy and an acceptable safety profile in pts with uHCC. The further randomized, phase 3 study of Penpulimab in combination with Anlotinib at a higher dose (10 mg PO 2 weeks on/1 week off) in this setting is ongoing (NCT04344158).
Phase I study of the novel pro-drug MIV-818 in patients with hepatocellular carcinoma, intra-hepatic cholangiocarcinoma or liver metastases.
Authors: Evans T.R. Jeffry , Van Cutsem Eric , Prenen Hans , Middleton Mark R. , Sarker Debashis , Tunblad Karin , Oberg Fredrik , Morris Tom , Basse Linda , Plummer Elizabeth Ruth
Published: January 2021

309

Background: MIV-818 is an orally administered troxacitabine (TRX)-based nucleotide prodrug. It is highly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs. The tri-phosphate is incorporated into DNA during replication, which leads to DNA double strand breaks, DNA damage responses, and cytotoxicity. Methods: Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with treatment-refractory hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM) from solid tumors were enrolled. In phase Ia, MIV-818 monotherapy was administered in an intra-patient dose-escalation design with doses of 3-70mg for 3-5 days in cycles of 21 days. Phase Ib is an inter-patient dose escalation in a 3+3 cohort design and is currently ongoing. Treatment is given until disease progression or unacceptable toxicity. The primary objective is to assess safety and tolerability and, for phase Ia, also to establish the starting dose for phase Ib. Key secondary objective was to evaluate the overall response rate based on RECIST v1.1. The pharmacokinetics of MIV-818 and its metabolites were evaluated, and on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818. Results: Nine patients (7M; 2F), ECOG performance status 0 (n=3) or 1 (n=6), median age = 57 years (range: 50-84) with HCC (2 pts), iCCA (1) or LM (6) from solid tumors (mainly GI tract), previously treated with median 2 (1-5) lines of therapy, were included in phase Ia. Patients were dosed up to 60 mg 5 days/week. The most common treatment related AEs were those in the hematological system: neutropenia grade (gr) 1-4, neutropenic sepsis gr 4; thrombocytopenia gr 1-2, anemia gr 1-2. Elevated bilirubin gr 1-3 and liver enzymes gr 3 were also reported. Most of the AEs were reversible. Five pts discontinued due to AE and 4 pts discontinued due to progressive disease outside the liver after 2-4 cycles. Starting dose of phase Ib was determined to be 40mg 5 days/week. Tumor biopsies showed evidence of selective DNA damage in tumor tissue, including in hypoxic regions, with minimal or no impact of MIV-818 observed in healthy liver tissue. Conclusions: MIV-818 had an acceptable safety and tolerability profile. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. Updated safety and efficacy data from phase Ib will be presented at the meeting. (NCT03781934). Clinical trial information: 2018-000995-14.
A phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers.
Authors: Javle Milind M. , Bridgewater John A. , Gbolahan Olumide B. , Jungels Christiane , Cho May Thet , Papadopoulos Kyriakos P. , Thistlethwaite Fiona C. , Canon Jean-Luc Re , Cheng Lulu , Ioannidis Sonia , Gogov Sven , Naing Aung
Published: January 2021

311

Background: Arginase, secreted in the tumor microenvironment by myeloid suppressor cells, is a major regulator of arginine-mediated immune response. Arginase inhibition by INCB001158 increases arginine, which reverses the immunosuppressive effects of neutrophils and myeloid-derived suppressor cells on T cells. The current standard first-line (1L) treatment for advanced biliary tract cancers (BTC) is gemcitabine/cisplatin chemotherapy. The combination of INCB001158 immunotherapy and standard 1L treatment may provide additional clinical benefit in pts with advanced or metastatic BTC. Methods: This open-label phase 1/2 study evaluated the safety, tolerability, and antitumor activity of INCB001158 in pts with advanced or metastatic solid tumors. In phase I, dose escalation of INCB001158 (50, 75, and 100 mg twice daily [BID]) was used to determine the recommended phase II dose (RP2D) of INCB001158 + gemcitabine/cisplatin. Phase II used a Simon 2-stage design and evaluated objective response rate (ORR; RECIST v1.1), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) of INCB001158 RP2D + gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2 Days 1 and 8 of 21-day cycle). Here we report preliminary safety and activity from the cohort of pts with BTC. Results: The phase I dose-escalation group identified a RP2D for INCB001158 of 100 mg BID. At a data cutoff of July 1, 2020, 33 pts with BTC in phase II treated with INCB001158 100 mg BID + gemcitabine/cisplatin were evaluable. Adverse events (AEs) related to INCB001158 and/or chemotherapy occurred in 88% of pts and 73% of pts had AEs related specifically to INCB001158 (Table). Treatment was interrupted due to INCB001158-related TEAEs in 30% of pts (n=10); discontinuation related to INCB001158 occurred in 3% (n=1). Treatment did not result in immune-related or significant additive chemotherapy-associated toxicity. ORR was 24% (8/33; 95% CI, 11.1–42.3) based on confirmed response per investigator’s assessment; stable disease occurred in 42% of pts. Median DOR (95% CI) was 5.8 (4.1–not reached) mo, and the DCR was 67%. Median PFS (95% CI) was 8.5 (5.7–10.1) mo. Conclusions: Preliminary data suggest the combination of INCB001158 100 mg BID + gemcitabine/cisplatin was tolerable and did not result in significant added toxicity. Response rates and PFS suggest that some pts with BTC may benefit from this combination. Clinical trial information: NCT03314935. [Table: see text]
Safety profile of immune checkpoint inhibitors versus sorafenib as first-line treatment in advanced hepatocellular carcinoma: A meta-analysis of randomized controlled trials.
Authors: Rizzo Alessandro , Frega Giorgio , Ricci Angela Dalia , Palloni Andrea , Tavolari Simona , Brandi Giovanni
Published: January 2021

315

Background: Systemic treatment with tyrosine kinase inhibitors such as sorafenib represents the mainstay of advanced-stage hepatocellular carcinoma (HCC). However, survival outcomes remain disappointing, mostly because of the onset of acquired resistance and a suboptimal safety profile, which frequently requires treatment modifications and early discontinuation of treatment – thus, interfering with compliance and long-term outcomes of patients. With immune checkpoint inhibitors (ICIs) quickly expanding as a novel therapeutic option in advanced HCC, the toxicity profiles of these agents should be kept in mind. We performed a meta-analysis with the aim to compare all-grade (G) adverse drug events (ADEs) of ICIs (alone or in combination with other anticancer agents) versus sorafenib monotherapy across randomized controlled trials (RCTs) of first-line treatment for advanced HCC. Methods: Eligible studies included RCTs comparing ICIs versus sorafenib as first-line treatment in HCC. Safety profile from each selected study was investigated for all-G most common ADEs. Outcomes of interest were as follows: pruritus, diarrhea, hand-foot skin reaction (HFSR), fatigue, aspartate aminotransferase (AST) increase, rash, hypertension and decreased appetite. Results were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method. All statistical analyses were performed using R studio software. Results: Two RCTs (CheckMate 459, IMbrave 150) involving 1,228 patients were included in the analysis. Patients treated with ICIs showed higher risk of pruritus (OR 1.99, 95% CI = 1.22-3.24) while sorafenib treatment was associated with higher risk of diarrhea (OR 0.26, 95% CI = 0.18-0.37) and HFSR (OR 0.01, 95% CI = 0-0.04). Conversely, no statistically significant differences were observed in terms of fatigue (OR 0.84, 95% CI = 0.45-1.58), AST increase (OR 1.21, 95% CI = 0.78-1.88), rash (OR 0.71, 95% CI = 0.46-1.11), hypertension (OR 0.28, 95% CI = 0.01-9.76) and decreased appetite (OR 0.41, 95% CI = 0.14-1.21) between the two groups. Conclusions: Although the substantial heterogeneities affecting our analyses, ICIs appear feasible in advanced HCC, being endowed with an acceptable safety profile. Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in advanced HCC.
Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post-hoc analysis of the randomized, phase III KEYNOTE-240 study.
Authors: Edeline Julien , Cattan Stéphane , Merle Philippe , Daniele Bruno , Chan Stephen Lam , Yau Thomas , Bouattour Mohamed , Lim Ho Yeong , Chao Yee , Knox Jennifer J. , Ogasawara Sadahisa , Garrido Marcelo , Cheng Ann-Lii , Zhu Andrew X. , Finn Richard S. , Siegel Abby B. , Rahman Ahmadur , Liu Chih-Chin , Kudo Masatoshi
Published: January 2021

318

Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE (KN)-224 (NCT02702414) evaluated pembrolizumab (pembro; anti-PD-1) in sorafenib (sora)-treated pts with aHCC and demonstrated an OR rate of 17% that was durable in responders receiving pembro, ultimately leading to its FDA approval. In KN-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KN-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KN-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KN-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to examine the association between survival after the landmark with response achieved prior to the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HRs and 95% CIs for survival after the landmark were calculated from the Cox proportional model with Efron’s method of tie handling with responder status as a single covariate. Analyses were performed in the ITT population. Results: As of Jan 2, 2019, the median time from randomization to data cutoff was 21.2 months (range 13.4-30.4) for pembro. There were 51 pts (18.3%) with a BOR of CR or PR in the pembro arm and 6 pts (4.4%) with a BOR of PR (no CR) in the pbo arm (excluded from landmark analyses). OS after landmark time was longer for responders compared with nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders versus nonresponders were 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis demonstrates that pts with sora-treated aHCC who achieve OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KN-224. Clinical trial information: NCT02702401. [Table: see text]
Changes in treatment and outcomes of stage II/III rectal cancer patients treated with trimodality therapy (TT) between 2006-2016: An NCDB analysis.
Authors: Kennecke Hagen F. , Bahnson Henry T. , Lin Bruce , Kaplan Jennifer , Pham Huong , Suen Andrew , Simianu Val
Published: January 2021

32

Background: Trimodality therapy (TT) remains standard for stage 2/3 rectal cancer and emerging evidence supports better outcomes with total neoadjuvant therapy (TNT) than similar therapy given post-operatively (Post-op). Real-world practice patterns and sequence of TT have significant implications on rectal cancer quality of care, outcomes and clinical trial design, and are not well described. Methods: The National Cancer Database was used to identify patients with clinical (c) stage 2/3 rectal adenocarcinoma diagnosed between 2006-2016, while pathologic (p) stage 2/3 was used when c stage was missing. Patients were included if they received Chemo/Radiation (C/RT), single or multiagent (SA or MA) chemotherapy (CT) and surgery. TNT was defined as receipt of pre-op C/RT and MA CT and no post-op therapy. Survival analyses were performed using Kaplan-Meier (KM) estimates and Cox univariate and multivariate hazard ratios (HRs) adjusted for TNT group, sex, race, year of diagnosis, stage, facility type, and age of diagnosis. Five-year KM survival proportions were limited to years 2006-2012, while Cox HRs were estimated from 2006 to 2015. Results: Of 32,467 patients who received TT, 8883 (27%) received TNT and 23,584 were classified no-TNT. TNT and no-TNT cohorts were numerically similar in age, race and gender. A significantly higher proportion of pStages 0-2 patients were observed in the TNT vs the no-TNT cohorts (61% vs. 48%, p < .001). In analysis of annual treatment patterns of the whole cohort, a gradual reduction in Post-op C/RT was observed between 2006 (28%) and 2016 (8%, p < .001), while use of TNT and MA CT did not increase. A migration to lower pStages 0/1/2/3 was seen between 2006 (1/10/31/57%, respectively) and 2016 (3/22/29/45%) (2016) (p < .001). Five-year OS analysis showed superior OS for Pre-op vs Post-op C/RT (74 vs 69%, HR = .81, p < .001), and MA CT vs. SA CT (76 vs 71%, HR = 0.79, p < .001) but inferior 5-y OS for the TNT vs. no-TNT cohorts (74 vs 78%, HR = 1.17, p < .001). Conclusions: Between 2006-16, a minority of patients treated with TT for stage 2/3 rectal cancer received TNT which did not increase over time. Significant annual shifts from Post-op C/RT to Pre-op C/RT, and migration to lower pStages were seen during this time period. Pre-op C/RT and MA CT were associated with improved OS, while TNT patients experienced inferior OS vs. the no-TNT cohort, possibly related to confounding factors in this observational cohort; multivariate sub-group analysis to be presented. Emerging evidence in support of TNT may further change treatment patterns and outcomes. [Table: see text]
Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors.
Authors: Wong Jeffrey Sum Lung , Kwok Gin Wai , Tang Vikki , Li Bryan , Leung Roland Ching-Yu , Chiu Joanne Wing Yan , Ma Ka Wing , She Wong-Hoi , Tsang Wing Yan Josephine , Cheung Tan To , Yau Thomas
Published: January 2021

330

Background: Programmed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICI) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in advanced HCC patients with progression on prior ICIs. Methods: Advanced HCC patients with documented tumour progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analysed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Twenty-five patients were included. The median age was 62 (range 51-83). 68% were of Child-Pugh (CP) grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range 2.76-30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% C.I. 1.61-4.31). Median OS was 10.9 months (95% C.I. 3.99-17.8) and the 1-year, 2-year and 3-year survival rates were 42.4%, 32.3% and 21.6% respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) grade 1 or 2. CP and ALBI grades were significantly associated with OS (p=0.006 and p<0.001 respectively). Overall, 52% of patients experienced TRAEs and 12% experienced grade 3 or above TRAEs. Conclusions: Ipilimumab and nivolumab/pembrolizumab can achieve durable antitumour activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.
In search of novel synthetic lethality anti-cancer drug targets in intrahepatic cholangiocarcinoma: MTAP genomic loss.
Authors: Ross Jeffrey S. , Schrock Alexa Betzig , Madison Russell , Danziger Natalie , Pavlick Dean , Sokol Ethan , Hemmerich Amanda , Huang Richard , Ramkissoon Shakti H. , Israel Mason A. , Gjoerup Ole , Venstrom Jeffrey Michael , McGregor Kimberly
Published: January 2021

337

Background: The association of BRCA tumor suppressor gene (TSG) inactivation and PARP inhibitor efficacy through a mechanism of synthetic lethality (SL) is now well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (S-methyl-5'-thioadenosine phosphorylase) genomic alterations (GA) has been proposed as a new SL based anti-tumor strategy and under consideration for development for intrahepatic cholangiocarcinoma (IC). Methods: 2,170 cases of clinically advanced IC were submitted for comprehensive genomic profiling (CGP) to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI) using a hybrid capture based assay (F1CDx). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: 328 (15%) ICs featured MTAP inactivation (MTAP-IC). 48% of MTAP-IC cases were female and 52% were male with a median age of 66 years (range 26-93 years). MTAP-IC featured 6.3 GA per sample. The median TMB was 2.5 mut/Mb with only 2% of cases with TMB ≥10 mut/Mb. No (0%) MTAP-IC cases were MSI-high. Of 112 MTAP-IC IHC stained for PD-L1, 4% were PD-L1 high (> 50%), 14% were PD-L1 low (1-49%) and 82% were PD-L1 negative. 99% of MTAP inactivation was by copy number (CN) loss and 1% was due to non-CN mutation. In MTAP-IC, 99% featured CDKN2A loss and 95% featured CDKN2B loss (9p21 co-deletion). TP53 was mutated in 31% and KRAS in 24% (3% G12C). Other currently non-targetable GA included ARID1A (19%), BAP1 (16%) and SMAD4 (13%). Among potentially targetable GA, the MTAP-IC featured 12% FGFR2 GA (8% rearrangements), 10% BRAF (8% V600E), 7% IDH1, 7% PIK3CA, 4% BRCA2, 4% ERBB2 (2% amplification) and 3% MET. Conclusions: Comprehensive genomic profiling elucidated that MTAP GA are frequent in IC and features relatively high GA/tumor, including 9p21 co-deletion, but relatively low TMB and PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. In addition to the potential targeting of PRMT5 in MTAP-IC tumors, co-altered genes known to be targets in IC such as FGFR2, IDH1 and BRAF are still prevalent in MTAP-IC, indicating potential for combining targeted therapies in some MTAP-IC patients.
Health-related quality of life and time from diagnosis among young adult colorectal cancer survivors.
Authors: Miller Kimberly Ann , Stal Julia , Gallagher Phuong , Kaslander Jonathan N , Freyer David R. , Marin Priscilla , Lenz Heinz-Josef , Milam Joel , Barzi Afsaneh
Published: January 2021

34

Background: Incidence of colorectal cancer (CRC) in patients under 50 years of age is rising. Quality of life in survivorship is not well-described in this population. We compared health-related quality of life (HRQoL) in CRC survivors ≤ 50 years old who were 6-18 months or 19-36 months from initial diagnosis or relapse. Methods: A cross-sectional online survey was administered in collaboration with a national organization for young CRC survivors. The Functional Assessment of Cancer Therapy (FACT-C) was used to measure HRQoL, which assesses HRQoL globally, including a CRC specific scale, and emotional, physical, social, and functional well-being domains. T-tests were conducted to compare HRQoL between survivors who were 6-18 months versus 19-36 months from diagnosis/relapse. Results: This sample (n=308) had a mean age of 33.76 SD±6.68; 201 (65.3%) were male; tumor location was colon or rectal in 41.7% and 58.3%, respectively. The majority (55.23%) were diagnosed with stage 2 disease; 98.0% were non-metastatic. 42.2% experienced relapse; 25% had an ostomy. Most survivors were 6-18 months (N=189; 61.4%) from diagnosis/relapse, and key demographics and disease characteristics did not significantly differ between those who were shorter versus longer time from diagnosis/relapse. The mean global HRQoL score was 67.3 out of a possible score of 136. Across domains, scores were low, with social well-being the highest (15.15/28) and emotional well-being the lowest (11.44/24). Social well-being was significantly higher among survivors who were 6-18 months from diagnosis/relapse compared to those 19-36 months (15.98 for 6-18 months vs. 13.83 for 19-36; p<0.01), as was functional well-being (13.20 for 6-18 months vs. 11.12 for 19-36; p<0.01). Emotional well-being and physical well-being did not significantly differ between groups. Conclusions: Overall HRQoL scores were low among younger CRC survivors, and social and functional well-being were significantly worse for those longer from diagnosis. Appropriate counseling and other targeted interventions are necessary to maintain HRQoL over time in this at-risk population. [Table: see text]
Clinical correlation of cadherin-17 (CA17 aka CDH17) marker with advanced tumor stages and poor prognosis of cholangiocarcinoma in a retrospective cohort of 180 patients.
Authors: Zheng Bohao , Shen Sheng , Wong Tony K , Gong Zi-Jun , Sun Wentao , Ni Xiaojian , Wang Jiwen , Hu Mei-yu , Liu Han , Ni Xiaoling , Liu Houbao , Luk Moon Ching , Suo Tao
Published: January 2021

344

Background: Aberrant expression of cadherin-17 (CA17, aka CDH17) cancer marker is often observed in major gastrointestinal (GI) cancers. In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). Methods: A total of 180 patients with detailed demographic and clinical data were enrolled in this study and randomly divided into a training cohort (N = 120) and a validation cohort (N = 60). Biopsy samples (tumor and adjacent normal tissue) collected for tissue microarray were examined by immunohistochemistry using a mouse anti-CA17 monoclonal antibody (Clone 7C5). Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. Results: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts (P < 0.001), and positively correlated with aggressive tumor phenotypes, like larger tumor size (P = 0.004), lymph node metastasis (P < 0.001), and advanced TNM stage (P < 0.001). Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS)(P = 0.002) and recurrence-free survival (P = 0.03). Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients (Training cohort: HR:1.716, 95% CI:1.116-2.638; P = 0.014; Validation cohort: HR: 1.811, 95%CI:1.028-3.892; P = 0.035), which indicated that the CA17 is much more efficient than serum CA19-9 (Training cohort: HR: 1.000, 95%CI: 1.000-1.001; P = 0.006; Validation cohort: HR: 1.000,95%CI:1.000-1.001; P = 0.013) in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had a better prognostic performance as compared with current TNM staging systems. Conclusions: CA17 cancer biomarker was aberrantly expressed in CCA tumor tissues, and its high expression level positively correlated with aggressive tumor phenotypes. Furthermore, CA17 was an independent adverse prognostic factor for CCA patients’ survival, which may serve as a potential drug target for CCA patients.
Targeted therapies in cholangiocarcinoma: Assessment of US oncologist practice patterns.
Authors: Parikh Kinjal , Cameron Davecia Ragoonath , Abair Tristin , Kugel Patrick , Vogel Arndt
Published: January 2021

347

Background: Chemotherapy is a mainstay treatment modality for patients with advanced cholangiocarcinoma (CCA). Recent developments and new approvals have led to changing paradigms, incorporating the use of targeted therapies for patients with progressive disease. Given the need for a greater understanding of the molecular alterations, varying targets, and available and emerging therapies, education is needed to assess knowledge regarding these recent advances in unresectable CCA. The goal of this activity was to increase the knowledge of self-assess the learning needs of oncologists in treating patients with unresectable CCA. Methods: The education included 25 multiple choice questions in a continuing medical education (CME)-certified clinical practice assessment to assess practice gaps. The questions were designed to measure knowledge, competence, confidence, and attitudes of oncologists regarding clinical evidence, role of molecular testing, and place in the treatment paradigm for targeted therapies in unresectable CCA. The self-assessment was made available online to physicians as a learning tool to gain foundational knowledge, as well as receive feedback about their performance as compared to other test-takers, to improve self-awareness of their own personal educational gaps. The activity launched 6/24/20, and data are reported through 8/31/20. Results: A total of 1,009 learners, including 758 physicians, participated in the activity. Of the 104 oncologists that participated, a majority practiced in the community setting, saw patients with a range of cancers, and were not confident about using targeted therapies or recognizing targets for biomarker testing. Oncologists demonstrated the following gaps related to: NGS sequencing and biomarkers: 21% do not use; 32% use upon progressive disease; 35% did not realize that not all panels detect FGFR2 fusions; 20% do not test for biomarkers; 29% and 56% test for IDH or FGFR, respectively; 60% recognize the incidence of IDH1 mutations; Clinical trial (FIGHT202 and ClarIDHy): 45% were able to identify biomarker eligibility for pemigatinib; 9% were able to identify pemigatinib OS outcomes; 30% were able to recognize most common grade 3 AE of pemigatinib; 51% recognized the PFS endpoint with ivosidenib; 34% were able to identify eligibility for ivosidenib; 55% recognized most common AEs of ivosidenib. Conclusions: This CME-certified clinical practice assessment identified gaps in knowledge, competence, and confidence regarding testing and use of targeted therapies and emerging data in patients with unresectable CCA. As new data emerges and the number of targets and targeted therapies expand, continued education remains important to continue to optimize patient care.
Tumor burden in serotonin secreting pancreatic neuroendocrine tumors after initiating telotristat ethyl.
Authors: Giacalone Susan , Di Gialleonardo Valentina , Murali Kris , Joish Vijay N.
Published: January 2021

367

Background: Pancreatic neuroendocrine tumors (pNETs) characterized by high serotonin levels and carcinoid syndrome (CS) are rare. We evaluated tumor burden in a subgroup of patients with pNETS from the real-world TELEACE study before and after initiating telotristat ethyl (TE) in US clinical practice. Methods: Detailed methods of the TELEACE study have been reported previously. This was a retrospective, single arm, pre-post physician panel-based chart review of patients who received TE for at least 6 months. Descriptive statistics analyzed demographic, clinical, laboratory and radiological data extracted from medical charts of TELEACE patients with pNETS. Results: Fifty-two patients with pNETS initiating TE were eligible for this analysis. The average age at the time of TE initiation was 60+10.4 years; 64% were males. The majority of patients had well-differentiated (60%) tumors and low-grade (54%) tumor status. Patients received TE for an average of 11.5+7.84 months, and 21% were still receiving TE at the time of data extraction. Diarrhea and flushing were the most common CS symptoms recorded at the time of TE initiation. Urinary 5-HIAA levels were reported for 9 patients before and for 2 patients after TE initiation. Mean (median) 5-HIAA levels before and after TE initiation were 693 (211) and 22 (22) µmol/24h, respectively. Significant mean reduction in tumor size of 0.67 cm after TE initiation (P = 0.017) was observed. Conclusions: This subgroup analysis of the TELEACE study population showed that the addition of TE to somatostatin analog treatment may positively impact tumor burden for patients with functional pNETs.
Copy number alterations in plasma cell-free DNA from metastatic gastroenteropancreatic neuroendocrine neoplasms.
Authors: Boons Gitta , Vandamme Timon , Lybaert Willem , Roeyen Geert , Rondou Tim , Papadimitriou Konstantinos , Janssens Katrien , Demey Wim , Dero Isabel , Van Camp Guy , Peeters Marc , Op de Beeck Ken
Published: January 2021

372

Background: Recent studies, including our proof-of-concept study, demonstrated the possibility to detect tumor-derived molecular alterations in cell-free DNA (cfDNA) from plasma of patients with a gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). More in-depth evaluation of the biomarker potential of cfDNA in GEP-NENs is warranted, since highly sensitive and specific blood-based biomarkers are an important unmet need for this tumor type. The aim of our study was to detect tumor-associated copy number alterations (CNAs) in cfDNA from GEP-NEN patients to molecularly characterize the tumor and to estimate tumor fraction, as a measure of tumor burden, and to evaluate changes in these parameters over time. Methods: Metastatic GEP-NEN patients were included within NETwerk, a multi-institutional network of nine hospitals in Belgium. Clinicopathological data were collected to correlate experimental and clinical findings. Plasma samples were collected from all patients and cfDNA was extracted and subjected to shallow whole-genome sequencing (WGS). Detection of CNAs and estimation of tumor fraction, based on the sequencing data, were performed using the R-based tool ichorCNA. Results: In total, 80 samples of 29 metastatic GEP-NEN patients were analyzed using shallow WGS. All patients had a well-differentiated GEP-NEN of Grade 1/2 and primary sites were pancreas (N = 15), small intestine (N = 9), colon (N = 1), caecum (N = 1), ileocaecal valve (N = 1), pylorus (N = 1) and unknown (N = 1). Median number of samples per patient was two, with a median time between first and last sampling of six months. In 25 cfDNA samples from nine patients (31%), CNAs with tumor fractions higher than 3% could be detected. The primary tumor site of all CNA-positive patients was pancreas, corresponding to 60% of included pancreatic NEN (PNEN) patients. Six of the CNA-positive patients were included at initiation of everolimus treatment. The detected CNA patterns were similar to the copy number profiles of PNENs described in literature, e.g. whole-chromosome gains of chromosomes 5, 7, 9, 12, 13, 14, 19 and 20. CNA profiles were relatively stable over time, although in two patients new alterations did arise. Tumor fractions changed over time, which could be linked to changes in tumor burden, tumor progression and treatment response according to RECIST1.1 criteria and will be further examined, including in additional samples that are being collected. Conclusions: Cell-free DNA of metastatic GEP-NEN patients contains CNAs that correspond to CNA profiles seen in tumor tissue samples. CNAs can be used to quantify the tumor fraction in cfDNA over time, which will be linked to tumor progression in our ongoing study, particularly in the promising subgroup of PNEN patients.
Characterization of undiagnosed pancreatic ductal adenocarcinoma on CT scans.
Authors: Chang John , Bartels Madelyn , Beyer Kelsey , Maitland Ashley , Peterson Richard Taft , Goldinger Stephen , Papesh Megan , Kundranda Maddapa , Koo Phillip , Dragovich Tomislav , Choti Michael A.
Published: January 2021

380

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths. At present, the best 5-year survival is 25% for resectable PDAC. For small (1 cm) stage 1 PDAC, resection has resulted in much better survival. The goal of this study was to evaluate the appearance and location of early undiagnosed PDAC on computed tomography scans (CT) prior to diagnosis with the goal of minimizing missing early PDAC. We also categorize the errors as either perceptive or cognitive. Methods: PDAC cases were retrospectively reviewed from 1/1/2012 through 12/31/2018 from our tumor registry, identifying 81 cases with paired CT scans both at the time of and prior to diagnosis. Among these, 31 contained imaging features considered diagnostic or suspicious for early PDAC(38%). These “errors” were classified by radiologic features and as well as by location. In addition, errors were classified into “perceptive errors" when the first study was read as normal, and as “cognitive errors” when the report noted an abnormality but failed to note suspicion for malignancy. Results: Among the 31 undiagnosed PDAC, 18 had features of an identifiable mass (58%), 9 had pancreatic ductal dilatation (29%), and 4 had evidence of perivascular soft tissue (13%). 44% of undiagnosed tumors were located in the head-neck, 39% in the body, and 17% in the tail. Perceptive errors were found in 58% and 42% were cognitive. No significant differences were seen between perceptive and cognitive errors based on suspicious features. Conclusions: Radiologic findings of early PDAC was retrospectively evident in more than one third of cases in which prior imaging was performed. These findings are most often masses or ductal dilatation. Location of these undiagnosed tumors were distributed throughout the gland. This study identifies the radiologic features of undiagnosed PDAC which may provide an opportunity for future prospective studies and improved technology which may improve early detection of pancreatic cancer.