bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of adjuvant S-1 chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.
Authors: Kobayashi Shogo , Nakachi Kohei , Ikeda Masafumi , Konishi Masaru , Ogawa Gakuto , Uesaka Katsuhiko , Yanagimoto Hiroaki , Morinaga Soichiro , Wada Hiroshi , Shimada Kazuaki , Takahashi Yu , Nakagohri Toshio , Gotoh Kunihito , Kamata Ken , Shimizu Yasuhiro , Ajiki Tetsuo , Kawamoto Yasuyuki , Ueno Makoto , Okusaka Takuji , Furuse Junji ,   Hepatobiliary and Pancreatic Oncology Study Group of Japan Clinical Oncology Group (JCOG)
Published: January 2022

408

Background: JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients (pts) with biliary tract cancers (BTCs) that showed the superiority of adjuvant S-1, in terms of the overall survival (OS). Previous reports have suggested that major hepatectomy (MH) may affect the dose intensity as well as frequency of adverse events (AEs) and reduce the treatment efficacy of chemotherapy, due to impaired liver function and drug metabolism. Therefore, we investigated whether MH might affect the feasibility of adjuvant S-1 chemotherapy. Methods: Among the 440 pts enrolled in the JCOG1202 study, 207 pts who received adjuvant S-1 were included in this analysis. We compared the rate of treatment completion, the frequency of AEs, and the dose intensity of adjuvant S-1 after MH versus non-major hepatectomy (NMH). MH was defined as right hemi-hepatectomy, right trisectionectomy, left trisectionectomy, and central bi-sectionectomy, with or without pancreatoduodenectomy. Results: Of the 207 pts, 42 pts had undergone MH and 165 pts had undergone NMH. The primary cancers in the MH group were mainly intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. The pretreatment characteristics of the pts were as follows: performance status 0 (MH vs. NMH: 81.0% vs. 89.1%), biliary reconstruction (performed: 81.0% vs. 82.4%), time from hepatectomy to initiation of adjuvant S-1 therapy (median: 60 vs. 57 days), platelet count (17.7 vs. 23.4 x 104/μL), and serum albumin (3.5 vs. 3.8 g/dL). The treatment completion proportion was lower in the MH group as compared to the NMH group (59.5% vs. 75.8%; treatment completion ratio, 0.786 (95% CI, 0.603-1.023), p = 0.0733), and the median dose intensity was lower in the MH group than in the NMH group (90% vs. 100%, p = 0.0358). The proportion of pts who discontinued adjuvant S-1 due to occurrence of AEs in the MH group vs. the NMH group was 23.8% vs. 10.3%. The major reasons for treatment discontinuation were biliary infection, nausea/vomiting, and diarrhea; these AEs were mainly observed in the first cycle; the frequency of grade 3-4 biliary infection during adjuvant S-1 therapy was 19.0% in the MH group versus 4.2% in the NMH group. Conclusions: In regard to adjuvant S-1 therapy for pts with resected BTC, the treatment completion proportion and dose intensity were lower in the MH group as compared to the NMH group. Caution should be exercised against the development of biliary infections during postoperative adjuvant S-1 therapy after MH in BTC pts.
Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation: A retrospective analysis.
Authors: Bang Kyunghye , Yoo Changhoon , Ryu Min-Hee , Park Sook Ryun , Kim Hyung-Don , Ryoo Baek-Yeol
Published: January 2022

410

Background: Lenvatinib is approved for use in patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, its clinical outcomes in patients experiencing HCC recurrence after liver transplantation (LT), remain unclear. Further, despite of immunotherapeutic advances (atezolizumab plus bevacizumab, pembrolizumab, and nivolumab) in the management of advanced HCC, patients with prior LT are not benefited because of the risk of allograft rejection, and they are also excluded in the most prospective clinical trials for novel agents. Thus, we investigated the efficacy and safety of lenvatinib treatment in patients with recurrent HCC after LT. Methods: This single center, retrospective study included 22 patients with recurrent HCC after LT who received lenvatinib at the Asan Medical Center, South Korea, between November 2019 and March 2021. Lenvatinib was given 12mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight < 60 kg. Response and adverse events (AEs) were graded according to RECIST v1.1 and NCI CTCAE v5.0. Results: The median age was 58 years (range, 20-69) and 95.5% (n = 21) were male. Most common etiology of HCC was hepatitis B (n = 18, 81.8%). The median time to recurrence after LT was 6.6 months (95% CI, 4.2-9.1 months). Prior to systemic therapy, transarterial embolization (TACE) (n = 12, 54.5%) was the most commonly used therapy for recurred HCC after LT. At the time of lenvatinib initiation, 95.5% (n = 21) of the patients were Child-Pugh A with 15 (68.2%) and 7 (31.8%) patients classified as ALBI grades 1 and 2, respectively. All patients were at BCLC stage C and lenvatinib was administered as first-line (n = 19) and second-line (n = 3) therapy. The objective response rate (ORR) was 13.6%. With a median follow-up duration of 5.2 months (range, 1.7-14.5 months), the median progression-free survival (PFS) was 6.6 months (95% CI: 3.6-9.5 months) and overall survival (OS) was 14.5 months (95% CI: not assessable). The 6-month PFS and OS rates were 59.8% and 88.8%, respectively. Patients with ALBI grade 2 showed significantly poorer OS [11.1 months (95% CI: not assessable)] compared to patients with ALBI grade 1 [14.5 months (95% CI: not assessable)] ( p= 0.011). AEs were hypertension (n = 8, 36.4%), thrombocytopenia (n = 7, 31.8%), and fatigue (n = 6, 27.3%). Conclusions: Lenvatinib was effective and showed manageable toxicities in patients with recurrent HCC after LT. These outcomes are comparable to those from the pivotal REFLECT trial where patients with LT were excluded. Better baseline liver function (ALBI grade 1) at lenvatinib initiation correlated with better survival outcomes.
Liver-directed concurrent chemoradiotherapy versus sorafenib in hepatocellular carcinoma with portal vein tumor thrombus.
Authors: Kim Jina , Byun Hwa Kyung , Kim Tae Hyung , Kim Sun Il , Kim Beom Kyung , Kim Do Young , Seong Jinsil
Published: January 2022

424

Background: This study aimed to investigate the efficacy of liver-directed concurrent chemoradiotherapy (LD-CCRT) compared with sorafenib in patients with liver-confined locally advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods: Patients treated with sorafenib and LD-CCRT between 2005 and 2016 were reviewed. Patients with extrahepatic disease and those without PVTT were excluded, leaving 28 and 448 patients in the sorafenib and LD-CCRT groups, respectively. Propensity score matching was performed to balance the differences in clinical features between the two groups. Results: At baseline, the sorafenib group presented higher incidences of unfavorable clinical features, including type 3-4 PVTT (53.6% vs. 30.6%) and bilateral disease extent (64.3% vs. 31.5%), than the LD-CCRT group. A total of 27 patients from the sorafenib group and 52 patients from the LD-CCRT group were matched. At a median follow-up duration of 73 months (range, 11-110 months), the median overall survival (OS) was 4.0 and 8.7 months in the sorafenib and LD-CCRT groups, respectively (p = 0.001). The Cox proportional hazard model showed that LD-CCRT was a significant prognostic factor for OS. One patient from the sorafenib group and seven patients from the LD-CCRT group underwent surgical treatment (liver transplantation or liver resection). Patients who underwent surgical treatment had significantly longer OS than those who did not undergo surgery. Conclusions: LD-CCRT showed superior survival outcomes to sorafenib in HCC patients with PVTT. LD-CCRT could be an efficient means of local tumor control that can enable surgical treatment with a curative intent in selected patients.
Updated analysis with longer follow up of a phase 2a study evaluating erdafitinib in Asian patients (pts) with advanced cholangiocarcinoma (CCA) and fibroblast growth factor receptor (FGFR) alterations.
Authors: Feng Yin-Hsun , Su Wu-Chou , Oh Do-Youn , Shen Lin , Kim Kyu-Pyo , Liu Xiufeng , Liao Huimin , Qing Min , Qian Jiaqi , Triantos Spyros , Sweiti Hussein , Park Joon Oh
Published: January 2022

430

Background: Pts with CCA progressing after first-line therapy have limited treatment options. We report an updated analysis of the ongoing LUC2001 open-label, multicenter, phase 2a study (NCT02699606) investigating the efficacy and safety of erdafitinib in Asian pts with advanced CCA and FGFR alterations who progressed after ≥1 prior systemic treatment. Methods: Eligible adults (aged ≥18 years) received erdafitinib 8 mg once daily (QD) with pharmacodynamically guided up-titration to 9 mg QD. The primary endpoint was objective response rate (ORR; RECIST 1.1); secondary endpoints included best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Survival estimates were determined by the Kaplan–Meier method. Results: Of 232 patients with CCA who underwent molecular screening, 39 (16.8%) had FGFR alterations (21 [9.1%] fusions and 19 [8.2%] mutations). Overall, 22 (9.5%) eligible pts (median age, 52 [range, 29–69] years) were enrolled and received treatment. Median follow-up was 22.4 (range, 2.3–47.0) months; median treatment duration was 6.2 (range, 1.5–35.6) months. All 22 pts received ≥1 line of prior systemic therapy and 12 (55.0%) pts had ≥2 prior lines of therapy. The ORR was 40.9% (95% CI, 20.7%–63.6%) and median time to response was 1.8 (range, 1.5–5.6) months. Median DOR was 7.3 (95% CI, 3.7–17.5) months, median PFS was 5.6 (95% CI, 3.6–12.7) months, and median OS was 40.2 (95% CI: 9.9–not estimable) months (Table). Responses were observed in 8/14 pts with FGFR fusions and 1/8 pts with FGFR mutations and in pts who received 1 or ≥2 prior lines of therapy. All 22 pts had ≥1 treatment-emergent adverse event (TEAE), the most common being dry mouth (15/22 [68.2%]) and stomatitis (14/22 [63.6%]). Grade ≥3 TEAEs occurred in 15/22 (68.2%) pts (11/22 [50.0%] were treatment related), of which the most common were stomatitis (3/22 [13.6%]) and alanine aminotransferase (ALT) increased (3/22 [13.6%]); 11/22 (50.0%) pts had ≥1 serious TEAE (1/22 [4.5%] pts had a serious treatment-related TEAE). A TEAE leading to death occurred in 1 patient (sepsis; not treatment-related). Conclusions: Asian pts with advanced CCA and FGFR alterations treated with erdafitinib had durable efficacy and a manageable safety profile, supporting the earlier findings of erdafitinib benefit in this population. Clinical trial information: NCT02699606. [Table: see text]
Varlitinib in combination with gemcitabine and cisplatin for treatment-naïve advanced biliary tract cancer.
Authors: Oh Do-Youn , Yong Wei-Peng , Chen Li-Tzong , Kim Ji-Won , Park Jin Hyun , Hsu Kenneth , Lindmark Bertil , McIntyre Nicola , Collins Barbara , Firth Carl
Published: January 2022

439

Background: Standard first-line treatment for advanced biliary tract cancer (BTC) with gemcitabine plus cisplatin confers only modest benefits (objective response rate [ORR], 26%; Valle et al. N Engl J Med 2010;362:1273-1281) and patient prognosis is poor. Therefore, new first-line strategies are urgently required. Human epidermal growth factor receptor (HER) tyrosine kinases are commonly overexpressed in BTC. Varlitinib is a reversible small molecule pan-HER inhibitor. Methods: This was a multicentre, phase 1B/2 study in patients with advanced BTC who had not received prior systemic therapy. Using a modified 3+3+3 escalation design in phase 1B, patients received oral varlitinib twice daily (BID) every day (starting dose 200 mg BID) plus gemcitabine/cisplatin on Days 1 and 8 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and safety profile of varlitinib in combination with gemcitabine plus cisplatin. Patients were evaluable for MTD if they had varlitinib treatment compliance of ≥80% and received 2 doses of chemotherapy in Cycle 1, or if they experienced a dose-limiting toxicity (DLT) in Cycle 1. Preliminary efficacy was a secondary objective. Results: Overall, 23 patients were enrolled in Korea (3 sites), Singapore (1 site), and Taiwan (1 site). Patient characteristics at baseline: male, 52%; median (range) age, 66 (47-82) years; ECOG PS, 0 (43%)/ 1 (57%); primary tumor site, intrahepatic bile duct (43%)/ extrahepatic bile duct (22%)/ gallbladder (22%)/ ampulla of Vater (13%). In total, 11 and 12 patients were included in the varlitinib 200 mg and 300 mg cohorts, of whom 9 and 7 were evaluable for MTD, respectively. DLTs were observed in 2 patients in the 200 mg cohort. Prior to study termination, the 300 mg dose was being assessed with 1 patient experiencing a DLT. In the overall population (n = 23), 36% of patients in the 200 mg cohort and 67% in the 300 mg cohort had at least one grade ≥3 treatment-related adverse event. Grade ≥3 treatment-related investigations abnormalities and blood and lymphatic system disorders were reported in 27% and 18% of patients in the 200 mg cohort, and 25% and 25% of those in the 300 mg cohort, respectively. Among all 23 patients, 8 had a partial response and 12 had stable disease for ≥12 weeks, giving an ORR of 35% and a disease control rate of 87%. The median (Q1-Q3) duration of objective response was 4.0 (2.8-11.0) months. At the time of analysis, 17 patients had progression events and 6 were censored. The median (Q1-Q3) progression-free survival was 6.8 (5.1-10.7) months. Conclusions: Varlitinib combined with gemcitabine plus cisplatin was well tolerated and associated with preliminary anti-tumor activity in patients with treatment-naïve advanced BTC. Clinical trial information: NCT02992340.
Updated results of the phase II ALTER-H004: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of recurrence after surgery.
Authors: Wu Zheng , Wang Zheng , Zhang Lei , Song Xiaojing , Du Xilin , Tan Kai
Published: January 2022

445

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and a leading cause of tumor related death. Hepatectomy is considered to be the main radical treatment for HCC. However, the high recurrence rate remains a major challenge. Adjuvant therapy to effectively reduce recurrence is particularly important for patients (pts) with high recurrence factors. Transarterial chemoembolization (TACE) as adjuvant therapy for pts with high recurrence risk factors after hepatectomy is recommended in several guidelines, but the effect is still unsatisfactory. Here, we updated the results of ALTER-H004 which aimed to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Methods: Pts with histologically confirmed HCC and undertook hepatectomy within 1-2 months will be recruited in this study. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5 cm and < 10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II). Eligible pts received conventional TACE treatment with pirarubicin and platinum within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week of) was given until disease recurrence or unacceptable toxicity. The calculated sample size was 48. The primary endpoint was disease free survival (DFS). Secondary endpoints were 1-year DFS rate, time to recurrence and safety. Results: As of September 14, 2021, 24 pts were enrolled and 23 pts received at least once tumor assessment. According to RECIST 1.1, 17 of 24 did not progress were still on treatment and 5 relapsed. One withdrew the consent and 1 discontinued because of intolerable adverse events. The longest duration of treatment is 15.24 months. The DFS were not mature and the 6-month DFS rates were 75.11% (95% CI: 46.28̃89.91). 12 of 24 pts (50.0%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 4 pts (16.7%) included hypertension (29.2%), hyperbilirubinemia and hematologic toxicities. No grade 4 or 5 TRAEs occurred. Conclusions: Preliminary results suggested that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and manageable adverse events, which should be validated in more pts consecutively. Clinical trial information: NCT04213118.
Tremelimumab (day 1 only) and durvalumab in combination with transarterial chemoemobilization (TACE) in patients with hepatocellular carcinoma (HCC).
Authors: Buchalter Jemma , Browne Iseult , Mac Eochagain Colm , Flynn Calvin , Carroll Hailey Kathryn , Galligan Marie , Bourke Michele , Lester-Grant Amy , Desmond Fiona , Hoey Katherine , Ryan Ronan , Cantwell Colin P , McCann Jeffrey , McDermott Ray , MacNicholas Ross , Duffy Austin G
Published: January 2022

451

Background: TACE induces a peripheral anti-tumor immune response, which may be amplified by immune checkpoint inhibitors (ICI). Combining TACE with dual ICI therapy has been shown to be safe and feasible. Recent data has suggested that Day 1-only anti-CTLA4 dosing could potentially lead to a stronger immune response with a tolerable safety profile though this novel schedule has not previously been combined with TACE. Methods: Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at 2 dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumor biopsies were obtained at time of TACE. Results: 13 patients enrolled on study; N = 3 at DL1 and N = 10 at DL2. M:F 10:3. Median age 70 (65-74). BCLC B/C 4/9. Extrahepatic disease 6/7. Aetiology: NASH (N = 3), alcohol-related disease (N = 1), HCV (N = 2), hemochromatosis (N = 1), unknown (N = 6). 1 patient discontinued due to G3 colitis. All patients evaluable for response with 2/10 patients on DL2 experiencing PR (at 8 weeks) and overall 8/13 SD and 3/13 PD as best response. Updated PFS and OS data to be presented. Conclusions: Tremelimumab (Day 1 only) and Durvalumab in combination with TACE is safe and feasible in patients with HCC. Follow-up is ongoing and full safety and efficacy data will be presented. Clinical trial information: 2019-002767-98.
Efficacy and safety of anlotinib combined with TACE among patients with intermediate and advanced-stage hepatocellular carcinoma (HCC).
Authors: Zheng Lin , Li Hailiang , Guo Chenyang , Hu Hongtao , Li Fangkun
Published: January 2022

454

Background: Given that the onset of hepatocellular carcinoma (HCC) remained insidious, HCC was usually diagnosed of intermediate and advaned stage and surgical resection was not available. Currently, TACE was considered as the standard of care for patients with intermediate and advaned stage HCC, which yielded a complete tumor necrosis rate of 10%̃20% and a median overall survival of 16-20 months. Interestingly, studies had demonstrated that TACE could result in up-regulation of VEGF expression and tumor angiogenesis, thus contributing to tumor recurrence or distant metastasis to some extent. As a novel oral multi-target antiangiogenic TKI, anlotinib could inhibit both tumor angiogenesis and tumor cell proliferation simultaneously. Therefore, anlotinib combined with TACE might play a synergistic action for patients with HCC. Consequently,this retrospective study aimed to investigate the efficacy and safety of anlotinib combined with TACE for patients with intermediate and advaned stage HCC. Methods: This single-center retrospective study involved 75 HCC patients with intermediate and advaned stage BCLC staging B or C and ECOG PS ≤ 2. Enrolled pts was treated with TACE plus anlotinib (12 mg, qd, 2 weeks on 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS), while the secondary outcomes included safety, objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) and safety. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: By the cutoff date of August, 2021, the median PFS of the 75 pts was 8.0 months (95%CI, 6.3-9.7). The median OS was not yet reached and the 6-month OS rate was 97.3%. In best overall response assessment, there were 13.3% CR (10/75), 45.3% PR (34/75), 34.7% SD (26/75) and 6.7% PD (5/75). Confirmed ORR and DCR was 58.7% (95% CI: 46.7%-69.9%) and 93.3% (95% CI: 85.1%-97.8%) respectively according to mRECIST. Only 5.3% (4/75) of pts had grade 3 treatment-related adverse events (TRAEs). No grade ≥ 4 TRAEs were observed. And the most common TRAEs were hypertension (20%), hand-foot skin reaction (8%), anorexia (6.7%) and diarrhea (6.6%). Conclusions: It was indicated that anlotinib combined with TACE for patients with intermediate and advaned stage HCC demonstrated promising anti-tumor efficacy and a favorable safety profile. The conclusion should be validated in prospective clinical trials subsequently.
Phase 1b/2 study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive): Efficacy results in previously untreated patients.
Authors: Iyer Renuka V. , Li Daneng , Dayyani Farshid , Rowe Julie Haewon , Beg Muhammad Shaalan , Kasturi Vijay , Abrams Thomas Adam
Published: January 2022

462

Background: The combination of a checkpoint inhibitor, atezolizumab, and angiogenesis inhibitor, bevacizumab, has improved the standard of care in advanced hepatocellular cancer with a median PFS of 6.8 months and 1-year overall survival of 67.2%. Tivozanib (a selective VEGFR 1,2 &3 TKI) has been combined with durvalumab in the phase I portion of the Deductive study (N=7) and the combination was well tolerated with the most common AEs being anorexia, cough, diarrhea, dysphonia, fatigue, hypertension and palmar-plantar erythrodysesthesia. (Ref: Iyer et al, JCO 39(3):294). Two of seven patients achieved a confirmed partial response. Here we report the preliminary efficacy data (PFS and OS) after 1 year of follow up of these patients. Methods: Major eligibility criteria included patients with age ≥18 yrs with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria included co-infection with HBV and HCV and significant organ dysfunction. The primary objective was to establish the RP2D and to determine the safety and tolerability for this combination in patients with advanced HCC. Secondary objectives included assessment of the ORR, PFS, and OS in this population. Results: Seven patients were enrolled in phase I part of the study. Two of seven patients achieved a confirmed partial response. Median PFS in this patient group was 7 months and 1-year survival was 80%. Kaplan-Meier plots of PFS and OS will be shown for patients with previously untreated advanced HCC. Conclusions: The combination of tivozanib and durvalumab in patients with untreated advanced HCC was considered tolerable and resulted in a median PFS of 7 months and 1-year overall survival of 80%. This is comparable to the outcomes seen with atezolizumab and bevacizumab. Enrollment is nearly complete with 19 of 20 patients in the front-line cohort enrolled; a second cohort of 20 patients who have progressed on prior bevacizumab and atezolizumab has been opened and is also enrolling. Data for the first line cohort will be presented at the meeting. Clinical trial information: NCT03970616.
Preclinical evaluation of LCK as a novel therapeutic target in YAP-activated and FGFR2-altered cholangiocarcinoma.
Authors: Conboy Caitlin , Yonkus Jennifer , Buckarma EeeLN , Mun Dong-Gi , Werneburg Nathan , Watkins Ryan , Guo Yi , Wang Juan , O'Brien Daniel , Buijsman Rogier , Vu Diep , De Man Jos , Ilyas Sumera , Truty Mark J. , Borad Mitesh J. , Pandey Akhilesh , Gores Gregory J. , Smoot Rory L.
Published: January 2022

463

Background: Molecularly targeted therapy is gaining traction in cholangiocarcinoma with the first FDA approval of a targeted agent in 2020, the FGFR inhibitor pemigatinib. Yet response rates and efficacy are modest, and most cholangiocarcinoma patients still lack targeted therapy options. The hippo pathway effector, YAP, is an oncogene that is activated in the majority of cholangiocarcinoma, yet attempts to develop YAP inhibitors have not yet been clinically successful. Recently, we described a novel mechanism of YAP regulation, via tyrosine phosphorylation by the Src-family kinase LCK. Therefore we hypothesized that LCK inhibition by may be therapeutic in cholangiocarcinoma through suppression of YAP activity. Methods: NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. In vitro pharmacodynamics were defined. In cholangiocarcinoma cells, specificity for LCK inhibition was determined by mass spectrometry-based unbiased analysis of the tyrosine phosphoproteome following treatment with NTRC 0652-0 or genetic deletion of LCK. YAP phosphorylation and cotranscriptional activity, cell viability, and apoptosis were assessed. A panel of eight cholangiocarcinoma patient derived organoids (PDO) were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft (PDX) models bearing FGFR2-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. Results: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to YAP inhibition and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression. PDOs demonstrated variable sensitivity to NTRC 0652-0, correlated with basal YAP tyrosine phosphorylation and drug-induced suppression of YAP co-transcriptional activity. FGFR2-altered cholangiocarcinoma was also identified as a subset with enrichment of YAP target genes. Cells from an FGFR2-altered PDX were sensitive to NTRC 0652-0 despite being primarily resistant to pemigatinib. In two PDX models of FGFR2-altered cholangiocarcinoma, daily oral treatment with NTRC 0652-0 inhibited YAP tyrosine phosphorylation, and resulted in stable plasma and tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Conclusions: A novel LCK inhibitor, NTRC 0652-0, reduced YAP signaling and demonstrated preclinical efficacy in multiple patient-derived models of cholangiocarcinoma. LCK is a novel therapeutic target in cholangiocarcinoma, and YAP activation or FGFR2-alteration are potential biomarkers for response.
Clinicopathologic correlates and prognostic relevance of the immune checkpoint CD73 (NT5E) in resected biliary cancers (BC).
Authors: Salati Massimiliano , Caputo Francesco , Spallanzani Andrea , Gelsomino Fabio , Ricco' Beatrice , Luppi Gabriele , Reggiani Bonetti Luca , Barbato Anna , Ferrante Luigi , Biondi Roberta , Iuliano Antonella , Gambardella Gennaro , Salatiello Maria , Iaccarino Antonino , Pisapia Pasquale , Troncone Giancarlo , Dominici Massimo , Franco Brunella , Carotenuto Pietro
Published: January 2022

473

Background: CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. The expression of CD73 has been linked to poorer patients (pts) outcome across several cancer types and the targeted inhibition of this immunoinhibitory protein has been recently advanced to clinical development. However, the clinicopathologic role of CD73 as well as its potential implications are largely unexplored in BC. Methods: The expression of CD73 was assessed by immunohistochemistry on both tumour (tCD73) and stromal tissue (sCD73) of a clinically-annotated cohort of radically-resected BC and scored for staining intensity as follows: +1, +2 and +3. RNAseq was performed on RNA isolated from surgical specimens. Differences between groups were evaluated using the Chi-square test. Survival functions were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. The Cox proportional hazards model was used to assess the impact of covariates on survival outcomes. Results: CD73 immunohistochimichal expression was evaluated on resected specimens of 70 BC pts. 43 pts (61%) were tCD73-positive, while 44 pts (62%) were sCD73-positive. Among the former group, the intensity score was 1+ in 19 pts (44%), 2+ in 16 pts (37%), 3+ in 10 pts (23%), while in the latter group was 1+ in 22 pts (50%), 2+ in 10 pts (22%) and 3+ in 12 pts (27%). CD73 positivity was associated with older age (> 70 years, p = 0.01), gallbladder subsite (p = 0.03), and nodal involvement (p = 0.04). Patients with tCD73-positive BC experienced a significantly shorter relapse-free survival (8,4 vs 39,4 months; p = 0.016) and overall survival (60,7 vs 13,7 months; p = 0.017). Notably, high tCD73 expressors (score 3+) displayed the poorest prognosis (12,03 months; p = 0.023). When evaluated on univariate and multivariate analysis, tCD73 positivity was an independent prognostic factor for both relapse-free survival (p = 0.038) and overall survival (p = 0.023), together with ECOG PS and pTNM stage. Whole-transcriptome sequencing is ongoing to correlate CD73 expression with cancer-related pathways. Conclusions: In this study, we provided a clinicopathologic characterization of CD73 expression in resected BC, demonstrating that tCD73 is an independent negative prognostic biomarker in this disease. Although these findings are in need of a validation in larger dataset, they foster novel combination of anti-CD73 agents with conventional therapy in the poorer-prognosis subset of CD73-positive BC.
Patient-reported outcomes (PROs) in pancreatic cancer clinical trials (CTs).
Authors: Grewal Udhayvir Singh , Ahmed Danya , Dhaliwal Lovekirat Singh , Laheru Daniel A. , Lou Emil , Beg Muhammad Shaalan , Nipp Ryan David , Gupta Arjun
Published: January 2022

534

Background: Incorporating PROs into CTs is critical for patients with pancreatic cancer, as these individuals often experience a high symptom burden and prioritize maximizing quality of life (QOL). Methods: We reviewed protocols of completed U.S. CTs listed on ClinicalTrials.gov that investigated curative/palliative interventions in pancreatic cancer from 1995-2020. We assessed up to August 2021 if CT publications reported PRO results through linked publications and an independent search through PubMed/MEDLINE. We extracted CT details (funding, eligibility, etc), and if PROs (outcome directly reported by patients) were listed as an endpoint (primary/secondary/exploratory). We classified interventions as cancer-directed (e.g. chemotherapy), supportive care (e.g. neurolysis), or other (e.g. curcumin). Results: We reviewed 619 protocols and included 379 in the analysis. Most CTs investigated cancer-directed interventions (317, 83.6%). Only 43 (11.4%) included PROs as endpoints (Table). In these, most of the PROs assessed QOL (34, 79.1%) and pain (15, 34.9%). For the 33/43 (76.7%) protocols that listed a specific PRO instrument, EORTC-QLQ C30 (11/33, 33.3%) was the most common. Only 6 (18.2%) protocols included pancreatic cancer-specific PROs, such as QLQ-PAN26. Supportive care CTs were more likely to assess PROs than cancer-directed CTs (odds ratio, OR= 62.6, 95% CI 16.7-234.3, p<0.0001). Protocols listed PROs as a primary, secondary, and exploratory endpoint in 15 (34.9%), 25 (58.1%), and 3 (6.9%) CTs respectively. Most CTs (13/15, 86.7%) with PROs as a primary endpoint evaluated supportive care interventions. Of 15 CTs with PROs as a primary endpoint, 10 (66.7%) had results published. Of 28 CTs assessing PROs as a secondary/exploratory outcome, 20 (71.4%) had published results and 12 (42.9%) included PRO data. Conclusions: From 1995-2020, only 11.4% of pancreatic cancer CTs incorporated PROs as endpoints. Supportive care CTs were more likely to include PROs than cancer-directed CTs. Our findings underscore the need to improve efforts to incorporate PROs into CTs for patients with pancreatic cancer. Data as number (%).[Table: see text]
Cost-effectiveness of universal screening for germline BRCA mutations in metastatic pancreatic cancer.
Authors: Ingram Myles , Pumpalova Yoanna S , Park Jiheum , Lim Francesca , Ferris Jennifer S. , Bates Susan Elaine , Manji Gulam Abbas , Kong Chung Yin , Hur Chin
Published: January 2022

536

Background: Germline BRCA1/2 mutations (gBRCAm) increase the risk of pancreatic ductal adenocarcinoma (PDAC). The NCCN 2020 guidelines recommend testing for gBRCAm in metastatic PDAC patients if the patients have a personal history and/or familial history of PDAC (current standard-of-care). However, given the advances made in genetic testing, universal gBRCAm testing for metastatic PDAC patients can be considered. The cost-effectiveness of universal gBRCAm screening has yet to be compared to the current standard-of-care. The purpose of our study was to explore the cost-effectiveness, treatment outcomes, costs, and quality-of-life impact of universal gBRCAm screening. Methods: We developed a decision-analytic mathematical model comparing the cost and health outcomes of universal gBRCAm screening against the current standard-of-care. Inputs for the model were estimated using clinical trial data and published literature. No intervention was used as a comparator. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100,000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall survival (OS), progression-free survival (PFS), life-years (LYs) and total cost of care (USD). Results: Universal gBRCAm screening was the cost-effective strategy, totaling incremental QALYs of 1.61 at a cost of $73,682 per QALY when compared to no intervention. A one-way sensitivity analysis found that the standard-of-care becomes the cost-effective strategy when the prevalence of gBRCAm is lowered to 2% of the base case. Conclusions: Our model found that universal gBRCAm screening is cost-effective and even cost-savings for patients with metastatic PDAC. Additional clinical trial data with sufficient follow-up are needed to confirm our findings.[Table: see text]
Differences in pretreatment frailty across gastrointestinal (GI) cancers in older adults: Results from the Cancer and Aging Resilience Evaluation (CARE) registry.
Authors: Arora Sankalp , Fowler Mackenzie , Harmon Christian , Al-Obaidi Mustafa , Outlaw Darryl Alan , Hollis Robert , Gbolahan Olumide B. , Khushman Moh'd M. , Giri Smith , Williams Grant Richard
Published: January 2022

542

Background: Frailty is an independent predictor of mortality in older adults and has been used to predict surgical complications and chemotherapy toxicities in GI cancers. How frailty differs between GI cancer types is unknown and could explain disparities in cancer outcomes. Our goal was to examine differences in pre-treatment frailty and geriatric assessment (GA) domain impairments between pancreatic, hepatobiliary, and colorectal cancers (CRC). We hypothesized that patients with more aggressive cancers (such as pancreatic cancer) would have increased frailty and more GA impairments, even prior to initiation of treatment. Methods: Our study included older adults age ≥60 years with cancer enrolled in the CARE Registry at the University of Alabama at Birmingham (UAB) who underwent a patient-reported GA during their initial visit with a GI medical oncologist. The GA was performed prior to any cancer-directed therapy. Frailty was defined using the 44-item CARE frailty index constructed based on principles of deficit accumulation described by Rockwood et al. We evaluated differences in frailty and GA domains between patients with CRC, pancreatic, and hepatobiliary cancers. Lastly, using a multivariable model we examined the adjusted odds ratio (aOR) of frailty by GI cancer type (reference CRC), adjusted for age, sex, race, cancer stage, and comorbidities. Results: Our study included 505 patients; 211 (41.8%) with CRC, 178 (35.2%) with pancreatic, and 116 (23.0%) with hepatobiliary cancers. Mean age of 70 years (standard deviation of 7) and 59% male. Cancer types did not differ by age, race, or sex. Patients with pancreatic and hepatobiliary cancers had more advanced cancer stage at time of assessment (stage IV 36.2% for CRC, 44.9% for pancreatic, and 45.2 for hepatobiliary; p=0.007). Older adults with pancreatic cancer had the highest prevalence of frailty (23.3% for CRC, 40.6% for pancreatic, and 34.3% for hepatobiliary; p=0.001), instrumental activities of daily living limitations (50.2% for CRC, 64.3% for pancreatic, and 52.7% for hepatobiliary; p=0.018), and malnutrition (40.8% for CRC, 70.3% for pancreatic, and 45.4% for hepatobiliary; p< 0.001). In multivariable analyses, older patients with pancreatic cancer had a 2.0 times higher odds of frailty in comparison to patients with CRC (aOR 2.0 95% CI 1.2-3.3, p=0.007). Conclusions: Older adults with pancreatic cancer had a higher prevalence of pre-treatment frailty, malnutrition, and functional impairments compared to CRC and hepatobiliary cancers. A focus on early intervention in these patients with optimization of nutrition and targeted physical/occupational therapy prior to and during treatment may help mitigate these factors and potentially improve outcomes.
Potential serum protein biomarkers of cancer cachexia, muscle atrophy, and survival in pancreatic ductal adenocarcinoma.
Authors: Cameron Miles , Judge Sarah , Judge Andrew
Published: January 2022

545

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of death in the United States. Treatment is difficult and often complicated by the presence of cachexia, a systemic wasting condition affecting most PDAC patients at diagnosis. Skeletal muscle atrophy is a hallmark of cachexia and predicts outcomes after surgery and chemotherapy. In this study, we sought to identify possible serum biomarkers of cachexia, which correlates with changes to lean body mass and survival, using an aptamer-based platform in patients with PDAC. We hypothesize that unique proteins associate with cachexia and survival measures. Methods: Using SomaScan we measured the serum levels of 4,006 proteins in 21 patients with PDAC undergoing curative surgery. Clinical data and anthropometric measurements derived from pre-operative CT imaging were compared to protein levels with Spearman correlational analyses and logistic regression. We then queried DAVID Bioinformatics database to identify enriched functional protein categories. Results: Mean age was 66.9 ± 8.91 years, and mean body-weight loss in the six months preceding diagnosis was 12.6 ± 8.80%. Using consensus guidelines considering percent weight loss and skeletal muscle mass and radiation attenuation, 10 subjects (46.7%) were defined as “cachectic.” We found 241 proteins significantly correlated to Cancer Weight Loss Grade (a composite measure of percent body weight loss and body mass index). High IDUA, CTLA4 and USE1, in particular, predicted the worst weight loss grade with 75% sensitivity and 92% specificity (AUC = 0.8894, odds ratio: 36, p = 0.0068). Four additional proteins significantly correlated with skeletal muscle index (CK-MM, CK-MB, PCOC2 and ADH4) while 13 proteins significantly correlated with muscle radiation attenuation. Lastly, we identified 18 proteins that significantly correlated with survival quartile. Of these, we found that elevated HS6ST2 and DEPP significantly predicted early recurrence and death compared to those with lower levels (medial survival: 177 days v. 850 days, p = 0.0049). Of the correlative proteins, enriched gene ontology terms included signal peptide (28.2), cytokine (6.86), negative regulation of endopeptidase activity (3.39), and immunoglobulin domain (3.24). Conclusions: Cancer cachexia in PDAC and various gastrointestinal malignancies remains a key clinical issue. While there are no definitive biomarkers currently in use to diagnose and manage cachexia preemptively, we present several potential candidates in a small cohort of patients. Ultimately, such assays may better elucidate common cachexia-inducing pathways, a shared spectrum of biomarkers and allow for the development of more specific therapies targeting cachexia.
Adjuvant gemcitabine (GEM) versus gemcitabine plus capecitabine (GEMCAP) in resected pancreatic adenocarcinoma: A retrospective analysis.
Authors: Kang Sora , Yoo Changhoon , Lee So Heun , Chang Heung-Moon , Jeong Jae Ho , Kim Kyu-Pyo , Ryoo Baek-Yeol
Published: January 2022

547

Background: For patients who underwent curative-intent upfront surgery, adjuvant chemotherapy is the current standard of care. The previous, randomized phase 3 ESPAC-4 study showed significantly improved overall survival (OS) with GEMCAP compared to GEM. However, this study was conducted in European countries and its implication in Asian patients has not been explored yet. We conducted a retrospective analysis to evaluate the efficacy and safety of GEMCAP compared to GEM regimen. Methods: Between January 2017 and December 2020, a total of 292 patients who received adjuvant GEM or GEMCAP after curative-intent surgery in Asan Medical Center, Seoul, Korea, were included in this retrospective analysis. Results: Adjuvant GEM and GEMCAP were administered in 161 patients (55.1%) and 131 patients (44.8 %), respectively. Compared the GEMCAP group, age of patients were significantly older in the GEM group (median 66 vs 63 yo, p = 0.025); otherwise, there was no significant difference in baseline characteristics between two groups. With the median follow-up duration of 39.4 months (95% CI 36.9 - 45.0 months) in GEM group and 39.4 months (95% CI 34.7-41.6 months) in GEMCAP group, the median OS was 36.8 months (95% CI 29.7-43.5 months) and 46.1 months (95% CI 31.5 months – not reached) in the GEM group and GEMCAP group, respectively (unadjusted HR 0.72, 95% CI 0.51-1.02, p = 0.065). The median recurrence-free survival was 14.3 months (95% CI, 12.9-17.7 months) and 17.0 months (95% CI, 13.3-28.8 months) in the GEM group and GEMCAP group, respectively (p = 0.52). In the GEMCAP group, hand-foot skin reaction (any grade, 15.27 % vs 0.62 %, p < 0.001), neutropenia (78.6% vs 67.7%, p=0.037) and thrombocytopenia (30.53% vs 20.5%, p=0.035) were more common in the GEMCAP group compared to the GEM group. In multivariate analysis, adjuvant GEMCAP was significantly associated with better OS compared to adjuvant GEM (adjusted HR 0.64, 95% CI, 0.44-0.91, p = 0.014). Otherwise, moderate or poor histologic grade, lymph node positive, positive resection margin, and elevated CA 19-9 levels (> median) were significantly associated with poorer OS. Conclusions: In this retrospective analysis for Korean patients, adjuvant GEMCAP showed consistent clinical outcomes shown in the ESPAC-4 trial. As mFOLFIRINOX is the new standard of care for medically fit patients with resected pancreatic adenocarcinoma, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.
Nal-IRI+5-FU/LV vs 5-FU/LV in metastatic pancreatic cancer: Additional safety report of randomized Japanese phase 2 trial.
Authors: Okusaka Takuji , Ikeda Masafumi , Ioka Tatsuya , Ueno Makoto , Teng Zhaoyang , Furuya Momoko , Furuse Junji
Published: January 2022

549

Background: Based on a phase II study conducted in Japanese metastatic pancreatic cancer (NCT02697058) and a global phase III study, nal-IRI obtained market authorization in March 2020 in Japan for "Unresectable pancreatic cancer after disease progression following cancer chemotherapy". After one year of practice, physicians have a sense that some of the safety profile of nal-IRI to be slightly different from conventional irinotecan. The purpose of this report is to explore additional points of the nal-IRI safety in the Japanese study. Methods: This analysis with the safety population of nal-IRI+5-FU/ l-LV group was done for the incidence, time to first onset (TTO), and time to resolution (TTR) for the events associated with 12 identified risks in the Risk Management Plan (RMP)(Table) and other selected GI toxicities. Prophylaxis used were also analyzed. Results: Myelosuppression (82.6%), diarrhoea (58.7%) and hepatic dysfunction (41.3%) were commonly reported of the 12 identified risks. The median (m) TTO of these TEAEs was 16 days (range: 6, 73), 9 days (1, 61), and 22days (2,325) respectively. As for the mTTR, it was 8.0 days (95% CI: 8.00, 9.00), 4.0 days (4.00, 8.00), and 40.0 days (9.00, -) respectively. For the myelosuppression, there were 4 patients who received G-CSF for the treatment of ≥ grade 3 myelosuppression. The 8 patients who experienced diarrhoea leading to dose reduction had no recurrence of ≥grade3 diarrhoea after intervention. For other GI toxicities, anorexia occurred in 28/46 patients (60.9%) with mTTO 4.0 days (range: 2, 132) and mTTR 12.0 days (95% CI: 6.00, 26.00). Summary of TTO for the events associated with identified risks in the RMP. * Intestinal obstruction, enteritis, disseminated intravascular coagulation, interstitial lung disease, ventricular extrasystoles are also included in the RMP but not observed. Discussion: This is the first report of nal-IRI safety profile details such as timing in Japanese patients. It is interesting to note that some TEAEs appear different in practice regarding TTR in comparison with conventional irinotecan. This difference can be due to the unique PK profile of nal-IRI as a result of utilizing liposomal technology but needs to be further elucidated. Conclusions: Although the TEAEs occurred with nal-IRI+5-FU/ l-LV were controllable with proper management in Japanese patients, some with prolonged toxicities should be carefully managed. Clinical trial information: NCT02697058. [Table: see text]