bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.