Recurrent Biliary Tract Cancer Research Articles

Combination anlotinib and toripalimab for an advanced biliary tract cancer patient with high Eastern Cooperative Oncology Group performance status: a case report.

Up to 80% of biliary tract cancer (BTC) patients relapse within 3 years after surgery and the efficacy of second-line treatment remains dismal for patients who progressed on gemcitabine and cisplatin chemotherapy. Median overall survival of patients with palliative chemotherapy is less than 1 year. The feasibility and safety of targeted therapies plus immunotherapies remain scanty currently, and patients with recurrent or advanced BTCs often experience a rapid decline in Eastern Cooperative Oncology Group (ECOG) performance status. This case report is the first report suggesting a 17-month progression-free survival (PFS), partial response, and another 11-month PFS after progressive disease of anlotinib plus toripalimab in advanced BTC with high ECOG performance status. We report a 67-year-old Chinese male with BTC. He was observed with progressive disease after surgical resection, adjuvant chemotherapy, palliative chemotherapy, and diagnosed with American Joint Committee on Cancer clinical stage IV (cT3N0M1) extrahepatic BTC. The patient experienced a rapid decline in performance status, and he received oral anlotinib and toripalimab with informed consent. MRI scans showed partial response on 22 June 2022. PET-CT showed that tumor activity has been inhibited on 8 March 2023. He achieved 17 months of PFS. Although the patient developed solitary lung metastasis, he had a continuous survival benefit from treatment of anlotinib plus toripalimab after lung radiotherapy. Until the writing of the case draft, he had achieved another 11 months of PFS. The present case suggests that anlotinib plus toripalimab might be a potential effective treatment for advanced BTCs patients with high ECOG performance status.

Abstract CT133: A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in >5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT133.

Prognostic Significance of Sarcopenia and Eicosapentaenoic Acid (EPA) Levels in Patients With Unresectable Pancreatic or Biliary Tract Cancer.

This study aimed to investigate the relationship between prechemotherapy blood eicosapentaenoic acid (EPA) levels, sarcopenia, and overall survival in patients with pancreatic and biliary tract cancer undergoing chemotherapy. Forty-five patients with recurrent, non-resected pancreatic or biliary tract cancer undergoing chemotherapy were retrospectively analyzed. The skeletal muscle mass was measured at the third lumbar vertebra. Sarcopenia cut-off values were based on the Japanese Society of Hepatology sarcopenia assessment criteria. Two months after starting chemotherapy, the patients received enteral nutrition containing omega-3 fatty acids. Patients with pancreatic and biliary tract cancers with low pre-treatment blood EPA levels had significantly more intense sarcopenia than those with high EPA levels (p=0.023). Patients with sarcopenia before chemotherapy had significantly lower overall survival than those without sarcopenia. Multivariate analysis revealed blood EPA concentration as an independent prognostic factor (p<0.01). Lumbar muscle volume, a marker of sarcopenia, showed a clear positive correlation with prechemotherapy EPA concentration (p=0.008). In patients administered with enteral nutrition containing omega-3 fatty acids, both EPA concentration and lumbar muscle volume were significantly higher than those prior to intervention, indicating sarcopenia improvement due to the intervention. In patients with recurrent non-resected pancreatic and biliary tract cancer, low blood EPA levels before chemotherapy are associated with sarcopenia and poor prognosis.

Skeletal muscle status and survival among patients with advanced biliary tract cancer

BackgroundStudies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes.MethodsWe identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change.ResultsCompared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15–2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07–2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD.ConclusionsSkeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.

Treatment patterns of gemcitabine-based chemotherapy in patients with de novo and recurrent advanced biliary tract cancer.

454 Background: Biliary tract cancers (BTC) are often diagnosed at advanced stages (aBTC) when prognosis is poor. In the Phase 3 TOPAZ-1 study (NCT03875235), durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival versus placebo plus GemCis. To better understand the context of the TOPAZ-1 trial results in the US, we looked at first-line (1L) treatment patterns in participants with aBTC treated with GemCis and other gemcitabine (Gem)-based chemotherapy (CT) regimens. Methods: This retrospective observational cohort study used linked electronic health records and medical and pharmacy claims data from the Optum Market Clarity Database. Adults diagnosed with de novo or recurrent aBTC, who initiated 1L Gem-based CT between January 2016 and March 2022, were identified and followed from the index date (defined as the first administration of Gem-based CT on or after initial BTC diagnosis date) until death, end of continuous enrollment, or end of study period, whichever occurred first. Variables including patient demographics, clinical characteristics, and treatment patterns were described. Results: A total of 580 patients were included in the analysis with either de novo aBTC (n=481, 82.9%) or recurrent aBTC (n=99, 17.1%) with median follow-up time of 10.4 (interquartile range: 6.4, 17.5) and 12.0 (interquartile range: 6.3, 21.9) months, respectively. Mean (SD) age was 64.6 (11.2) and 66.8 (10.4) years, with 45.7% and 54.5% male in the de novo and recurrent aBTC groups, respectively. Most patients were white (77.6%). The most frequent site of primary tumor diagnosis was single-site intrahepatic (overall 62.8%, de novo 66.7%, recurrent 43.4%). In the 12 months prior to index date, 38.5% of patients had biliary obstruction, 30.2% had biliary stents, 29.3% had jaundice, and 17.1% had nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Common comorbidities included cardiovascular disease (50.9%), obesity (46.8%), and diabetes (35.2%). The most common 1L CT was GemCis followed by Gem for both the de novo (n=355, 73.8% and n=36, 7.5%) and recurrent groups (n=58, 58.6% and n=26, 26.3%), respectively. Approximately half of participants (50.9%) switched to a new line of treatment, 33.3% discontinued 1L CT, and 15.9% remained on 1L CT at last follow-up. Most frequent 2L treatments included fluorouracil/oxaliplatin (36.9%) and capecitabine (14.2%). Further analysis will characterize outcomes and regimen duration. Conclusions: Findings from this retrospective study showed that the most common 1L therapies were GemCis and Gem among both de novo and recurrent patients with aBTC. These results provide insight into aBTC treatment practices and may help inform treatment decisions.

MO7-3 Network meta-analysis of first-line therapy for unresectable, advanced or recurrent biliary tract cancer

MO7-3 Network meta-analysis of first-line therapy for unresectable, advanced or recurrent biliary tract cancer

The impact of osteosarcopenia in patients with unresectable or recurrent biliary tract cancer receiving palliative chemotherapy.

Osteosarcopenia is a newly described syndrome that has been reported to be associated with worse outcomes in various types of cancer. However, its impact on survival in biliary tract cancer remains unclear. This study evaluated the impact of osteosarcopenia on survival in patients with unresectable or recurrent biliary tract cancer. A total of 306 patients with unresectable or recurrent biliary tract cancer who initiated chemotherapy at our institution between 2015 and 2021 were retrospectively investigated. Skeletal muscle index and bone mineral density were measured using pretreatment cross-sectional computed tomography images. Baseline characteristics and survival outcomes were compared between patients with osteosarcopenia and those without. The Cox proportional hazards regression model was used to identify factors associated with survival. Osteosarcopenia was present in 66 patients (22%) and was associated with older age (74 vs. 69years, P<0.001) and female sex (58 vs. 37%, P=0.003). Patients with osteosarcopenia tended to have worse performance status (P=0.098), higher modified Glasgow prognostic score (P=0.082), higher neutrophil to lymphocyte ratio (P=0.058) and were significantly less likely to receive combination chemotherapy (68 vs. 80%, P=0.044) than those without. Osteosarcopenia was associated with reduced survival (8.9 vs. 14.0months, P<0.001) and was identified as an independent factor predicting shorter survival in multivariate analysis. Osteosarcopenia was associated with poor survival in unresectable or recurrent biliary tract cancer treated with chemotherapy. This study highlights the potential importance of screening for osteosarcopenia in patients with biliary tract cancer.

Safety and Effectiveness of Chemotherapy in Elderly Biliary Tract Cancer Patients.

The safety and effectiveness of chemotherapy in elderly patients with biliary tract cancer (BTC) remain unclear. Therefore, we retrospectively reviewed patients who underwent chemotherapy for locally advanced, metastatic, or recurrent BTC at our institution from January 2016 to December 2021. Of the 283 included patients, 91 (32.5%) were aged 75 years or older when initiating chemotherapy. Elderly patients were more likely than non-elderly patients to receive monotherapy with gemcitabine or S-1 (58.7% vs. 9.4%, p < 0.001) and were less likely to experience grade 3-4 toxicities (55.4% vs. 70.2%, p = 0.015). The rates of termination due to intolerance (6.5% vs. 5.8%, p = 0.800) and transition to second-line chemotherapy (39.1% vs. 40.3%, p = 0.849) were similar between groups. In the overall cohort, age was not an independent predictor of overall survival (OS). Within the elderly cohort, there were no differences in severe adverse events between patients receiving monotherapy and combination therapy (50.0% vs. 63.2%, p = 0.211). Median OS was longer in the combination therapy group (10.4 vs. 14.1 months; p = 0.010); however, choice of monotherapy was not an independent predictor of overall survival. Monotherapy appears to be a viable alternative in selected elderly BTC patients.

Impact of conversion surgery after chemotherapy in patients with initially unresectable and recurrent biliary tract cancer.

Gemcitabine, cisplatin, and S-1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression-free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401-3C). A total of 246 patients were enrolled in KHBO1401. We compared progression-free and overall survivals between the conversion surgery and non-conversion surgery groups. Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S-1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S-1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19-9 (CA19-9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1-year progression-free survival rates in the conversion surgery and non-conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286-0.843, p = 0.0092). One-year overall survival rates in the conversion surgery and non-conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226-0.877, p = 0.0197). Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19-9 level.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan

AimsIn Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026.Materials and methodsWe constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts’ opinions.ResultsIn 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively.LimitationsOnly those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered.ConclusionsThe present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

CTX-009 (ABL001), a bispecific antibody targeting DLL4 and VEGF A, in combination with paclitaxel in patients with advanced biliary tract cancer (BTC): A phase 2 study.

540 Background: CTX-009 is a novel bispecific antibody that simultaneously inhibits Delta-like ligand 4/Notch-1 (DLL4) and VEGF A, two signaling molecules which play an important role in angiogenesis in the tumor microenvironment. DLL4 is induced by VEGF and acts to the downstream of VEGF, and synergistic effect for dual blockade of both DLL4 and VEGF was evaluated in preclinical models. A phase 1b study assessed the safety, tolerability, pharmacokinetics and efficacy of CTX-009 in combination with paclitaxel or irinotecan in patients (pts) with advanced solid tumors. Encouraging results in the Phase 1b in BTC pts, including two durable Partial Responses (PRs) out of 3 pts, prompted the expansion of the study to include a Phase 2 cohort in which BTC pts are treated in 2L or 3L setting. We present preliminary results from this Phase 2 study. Methods: This open-label, multi-center, single-arm Phase 2 study investigated pts with unresectable advanced, metastatic or recurrent BTC in advanced 2L or 3L setting. Eligible pts were treated with CTX-009 (10 mg/kg IV biweekly) in combination with paclitaxel (80 mg/m2 IV on Day 1, 8, 15 q4-weekly). The primary objective was to assess the objective response rate (ORR) based on RECIST v1.1. Secondary endpoints included time to treatment failure (TTF), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Overall, 24 pts have been enrolled (IHCC: 9, EHCC: 3, GB: 7, AoV: 5) and as of the data cut-off date (August 12, 2022), the median follow-up duration was 11.8 months (m) (range: 1.6-16.4) and 3 pts remained on treatment. 11 pts were treated in 2L and 13 pts treated in 3L. There were 9 confirmed PRs by investigator’s assessment and ORR was 37.5% (95% CI: 18.8-59.4; 2L: 63.6%, 3L: 15.4%). Median DOR and PFS were 9.4 m (95% CI: 3.5–NE) and 9.4 m (95% CI: 5.4-11.1), respectively. Median TTF was 5.9 m (95% CI: 3.9-9.8) and median OS has not been reached (95% CI: 11.0–NE); the OS rate at 12 m was 53.0% (95% CI: 29.8–71.7). Treatment-related adverse events (TRAEs) of any grade were reported in 100% of pts and TRAEs of ≥ grade 3 were reported in 75% of pts (including one grade 5 pneumonia). The most frequent TRAEs of ≥ grade 3 were neutropenia (50.0%), hypertension (16.7%), anemia (12.5%), and thrombocytopenia (8.3%). Six pts (25.0%) experienced treatment-emergent AEs (confusional state, pulmonary embolism, blood creatinine increased, pneumonia, biliary fistula, and large intestine perforation) that led to discontinuation of the study treatment. Conclusions: This Phase 2 study has shown promising efficacy in BTC pts treated in 2L or 3L setting. TRAE rate based on mode of action was high, but DLL4/VEGF targeting in BTC has a potential of development. Further investigation of safety and efficacy of this regimen is warranted. Clinical trial information: NCT04492033 .

A multicenter, single-arm, phase II study of nivolumab in patients with biliary tract cancer with a PD-L1 combined positive score ≥ 1.

533 Background: Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and high unmet medical needs still exist for the treatment of this disease. Nivolumab has shown its effectiveness against multiple cancer types, especially those with PD-L1 expression. This study assessed the efficacy and safety of nivolumab in BTC patients with a combined positive score (CPS) ≥ 1 who were refractory or intolerant to the standard of care (SOC): gemcitabine, cisplatin and tegafur/gimeracil/oteracil (S-1). Methods: This was a single-arm, multicenter, open-label, prospective phase II study. Key eligibility criteria were as follows: having unresectable or recurrent BTC (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer); being refractory or intolerant to SOC; having adequate hepatic, renal and hematological function; and having a CPS ≥ 1 in central assessment. Patients received nivolumab (480 mg, every 4 weeks) until disease progression, clinical deterioration, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the central review according to RECIST 1.1. The secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled between Mar 11, 2020 and Mar 15, 2021, of them 12 received one regimen and 72 received two or more regimens. The median follow-up period was 6.90 months. ORR per central assessment was 10.7% (CR: 3.6%, PR: 7.1%), and ORR per investigator assessment was 15.5% (CR: 2.4%, PR: 13.1%). The median PFS per central and investigator assessment was 1.02 (95% CI 0.95–1.77) months and 2.48 (95% CI 1.87–2.83) months, respectively. The median OS was 6.90 (95% CI 5.26–9.20) months. The median duration of response per central and investigator assessment was not reached (range 2.8–13.0+) and 10.15 (range 2.0–12.8+) months, respectively. The 1-year survival rate was 25.3% (95% CI 15.4–36.4). The most frequent treatment-related adverse events were pyrexia (19.0%), pruritus (16.7%), and decreased appetite (13.1%). Conclusions: Nivolumab may have some activity with a durable response and a manageable safety profile in heavily treated BTC patients with CPS ≥ 1. Clinical trial information: JapicCTI-205097 .

Characterization of long-term survivors in the TOPAZ-1 study of durvalumab or placebo plus gemcitabine and cisplatin in advanced biliary tract cancer.

531 Background: At the primary analysis of TOPAZ-1 (NCT03875235; data cut-off [DCO] Aug 11, 2021), durvalumab (D) + gemcitabine and cisplatin (GC) significantly improved overall survival (OS) vs placebo (PBO) + GC in participants (pts) with advanced biliary tract cancer (BTC), with OS curves that separated over time (Oh et al. NEJM Evid 2022), that persisted with further follow-up (DCO Feb 25, 2022; HR, 0.76 [95% CI, 0.64–0.91]; 18-month OS, 34.8% [D + GC] vs 24.1% [PBO + GC]; Oh et al. Ann Oncol 2022 Abs 56P). We characterized long-term survivors (LTS) in TOPAZ-1. Methods: Pts untreated for unresectable locally advanced, recurrent or metastatic BTC received D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on days 1 and 8 Q3W, up to 8 cycles, followed by D (1500 mg Q4W) or PBO. Characteristics and outcomes of LTS (pts who survived ≥18 months after randomization; DCO Feb 25, 2022) were assessed. Results: There were more LTS with D + GC vs PBO + GC (Table). Characteristics of LTS were consistent with the full analysis set (FAS, all randomized pts) including age, sex, region, primary tumor location, disease classification (metastatic vs locally advanced) and PD-L1 expression. Recurrent disease was more common than initially unresectable disease in LTS vs FAS. Median exposure to study treatment was 11.3 months (mo; D), 9.7 mo (PBO) and 5.5 mo (GC, both arms) in LTS and 7.3 mo (D), 5.8 mo (PBO) and 5.1 mo (GC, both arms) in FAS. The objective response rate in LTS was greater with D + GC vs PBO + GC (44.3%, D + GC; 33.8%, PBO + GC), and greater for both groups vs FAS (26.7%, D + GC; 18.7%, PBO + GC). A higher proportion of LTS in the PBO + GC group received subsequent anticancer therapy, including immunotherapy, than LTS in the D + GC group. The frequency of treatment-related adverse events leading to discontinuation in LTS was consistent with FAS. Conclusions: In TOPAZ-1, characteristics of LTS were generally consistent with the FAS. Overall, LTS were more common with D + GC; LTS in the PBO + GC group appear to be associated with higher frequency of subsequent treatments, including immunotherapy. Clinical trial information: NCT03875235 . [Table: see text]

A prospective multicenter phase II study of FOLFIRINOX as a first-line treatment for patients with advanced and recurrent biliary tract cancer

SummaryGiven the promising activity and tolerability of FOLFIRINOX as a second-line treatment for advanced biliary tract cancer (BTC), it can be an attractive first-line treatment option as well.This is a single-arm, open-label, multicenter phase II study to evaluate the safety and efficacy of FOLFIRINOX as a first-line treatment for patients with advanced BTC. Primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), tumor response and safety. This study defined primary endpoint might be met when the lower limit value of 80% confidence interval [CI] of the median PFS ≥ 6.0 months.Between June 2016 and March 2020, 35 BTC patients (21 intrahepatic, 10 extrahepatic, 2 gallbladder, 2 ampulla) including 26 unresectable and 9 recurrent disease were enrolled. After a median follow-up of 13.9 months, the median PFS and OS were 7.4 (80% CI, 5.5–7.5) and 14.7 (80% CI, 11.8–15.7) months, respectively. Complete response was achieved in 1 (2.9%) and partial response in 10 (28.6%), giving an objective response rate of 31.4% and disease control rate of 74.3%. Major grade 3–4 adverse events included neutropenia (54.3%), leukopenia (34.4%), febrile neutropenia (17.1%), thrombocytopenia (8.6%), cholangitis (8.6%), anemia, nausea, diarrhea, and peripheral sensory neuropathy (2.9% each).FOLFIRINOX was well tolerable in patients with advanced BTC, however, this study did not meet the primary endpoint to conduct a phase III trial. Thus, further explorations are required to find a subset of patients and/or certain clinical scenario which might be beneficial from FOLFIRINOX.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): An investigator-initiated multicenter phase 2 study (HERB trial).

4006 Background: BTCs have an aggressive tumor biology with limited treatment options. With a HER2-positivity rate of 5–20% in BTCs, case series and small clinical trials have shown signs of activity for HER2 blockade in these pts. T-DXd is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. The HERB trial is an investigator-initiated, multicenter, single-arm phase 2 trial of T-DXd in pts with HER2-expressing BTCs. Methods: Centrally confirmed HER2-expressing (HER2-positive: IHC3+ or IHC2+/ISH+, and HER2-low-expressing [HER2-low]: IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-) pts with BTCs who were refractory or intolerant to gemcitabine containing regimen received 5.4 mg/kg of T-DXd every 3 weeks. The primary endpoint was the confirmed objective response rate (ORR) in HER2-positive pts by independent central review. The sample size of 22 had 80% power with one-sided alpha error of 5%; threshold ORR, 15%; and expected ORR, 40%. The ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) in HER2-positive/-low pts, and incidence of treatment-emergent adverse events (TEAEs) were assessed as secondary endpoints. Results: A total of 32 pts, 24 with HER2-positive and 8 with HER2-low BTCs, received T-DXd. Twenty-two pts with HER2-positive, excluding 2 ineligible pts, were identified for primary efficacy analysis. Among the 22 pts, IHC3+ and IHC2+/ISH+ were 45.5% and 54.5%, primary sites: gallbladder/extrahepatic/intrahepatic/Vater were 11/6/3/2, median number of prior regimens was 2 (range, 1–4). The confirmed ORR in HER2-positive pts was 36.4% (8/22; 2 CR and 6 PR; 90% CI, 19.6–56.1), indicating statistically significant improvement in ORR (P = 0.01). The DCR, median (m) PFS, mOS were 81.8% (95% CI, 59.7–94.8), 4.4 months (mo) (95% CI, 2.8–8.3), 7.1 mo (95% CI, 4.7–14.6), respectively. In addition, encouraging efficacy were seen even in HER2-low pts; ORR, DCR, mPFS, and mOS were 12.5% (1/8; 1 PR; 95% CI, 0.3–52.7), 75.0% (95% CI, 34.9–96.8), 4.2 mo (95% CI, 1.3–6.2), and 8.9 mo (95% CI, 3.0–12.8), respectively. In the safety analysis set (n = 32), TEAEs of &gt; = grade (G) 3 occurred in 81.3% (26/32); the common TEAEs were anemia (53.1%), neutropenia (31.3%), and leukopenia (31.3%). TEAEs leading to drug discontinuation occurred in 8 pts (25.0%). Eight pts (25.0%) had interstitial lung disease (ILD; G1/G2/G3/G5 were 3/1/2/2) not adjudicated by an independent committee. Conclusions: T-DXd showed promising activity in pts with HER2-expressing BTCs. Although the safety profile was generally consistent with other T-DXd studies, ILD, an important identified risk of T-DXd, requires more careful monitoring and intervention. These results support further exploration of T-DXd in this patient population. Clinical trial information: JMA-IIA00423.

Health-related quality of life in patients treated with gemcitabine/cisplatin and durvalumab ± tremelimumab in chemotherapy-naïve advanced biliary tract cancer.

4117 Background: In the phase 2 (NCT03046862), gemcitabine/cisplatin (GemCis) and durvalumab (D) ± tremelimumab (T) in chemotherapy-naïve advanced biliary tract cancer (BTC) showed a high objective response rate and durable clinical benefit. Based on this study, phase 3 trial (TOPAZ-1, NCT03875235) has been conducted and the positive result for adding D to GemCis has been reported. Health-related quality of life (HRQoL) for adding immunotherapy to cytotoxic chemotherapy in BTC has not been reported yet. We present HRQoL results from the phase 2 study. Methods: In this study, treatment-naïve patients with unresectable or recurrent BTC were enrolled into three cohorts. Patients received one cycle of GemCis followed by GemCis plus D and T (cohort 1) or, starting with the first cycle, received GemCis plus D (cohort 2) or GemCis plus D and T (cohort 3). The EORTC Quality of Life Questionnaire (QLQ)-C30 and BIL21 were administered at baseline and every cycle throughout treatment. Change from baseline to post-2 cycles and deterioration of HRQoL (≥10 points change) were analysed. Results: At data cut-off (March 22, 2021), 126 patients (32 in cohort 1, 47 in cohort 2, 47 in cohort 3) were included for this analysis. Compliance for QLQ was very high ( &gt; 90 %) at all time points. C30 global health status (GHS) scores remained stable at all time points and from baseline to post 2 cycles (mean [95% CI] change, 2.66 [-1.10‒6.42]), with greater improvements observed in patients with responder (a best response of complete response (CR) or partial response (PR)) (3.60 [-1.27 to 8.47]) compared to non-responder (stable disease (SD) or progressive disease (PD) (0.66 [-5.19 to 6.51]). For the overall cohort, functioning scales also remained stable from baseline to post 2 cycles. Nausea/vomiting (8.4 [4.45 to 12.36]), dyspnea (7.28 [2.17 to 12.4]), constipation (9.24 [3.35 to 15.13]), financial difficulties (5.53 [1.65 to 9.41]) in C30 and eating (5.53 [1.65 to 9.41]), tiredness (5.42 [1.23 to 9.6]), treatment side effects (7.98 [1.15 to 14.81] in BIL21 were worse at post 2 cycles. However, pain (-7.14 [-12.24 to -2.04]), diarrhea (-4.48 [-8.86 to -0.1]) in C30 and jaundice (-5.51 [-9.26 to -1.76]), pain (-6.02 [-9.7 to -2.34] in BIL21 were improved and more improvement was shown in responder compared to non-responder. Regarding deterioration of C30 GHS, median deterioration-free survival (months [95% CI]) was 4.14 (2.66-6.47) in all cohorts and there was no difference between responder (3.68 [2.27-7.92]) and non-responder (5.59 [2.73-9.46], Hazard ratio = 1.00 [95% CI, 0.62-1.61], p = 0.997). There was no difference among 3 cohorts. Conclusions: GemCis plus D ± T in chemotherapy-naïve advanced BTC generally preserved HRQoL and improved some symptom scales such as jaundice and pain although chemotherapy related symptom scales were worse.

A phase 2, randomized, open-label, multicenter study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.

4100 Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy (GemCis) is rather limited. TOPAZ-1 study suggested immunotherapy + GemCis as first line in advanced BTC significantly improved OS and PFS vs placebo + GemCis with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate first-line immunotherapy + antiangiogenic targeted drug + GemCis in advanced BTC. Methods: In this randomized controlled study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity. The primary objective was to assess the 1-year overall survival (OS). Secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 November, 2021), 48 pts were randomized to sintilimab + anlotinib + GemCis (n=26) or GemCis (n=22). The primary objective was not meet: the 1-year OS was 52.5% with sintilimab + anlotinib + GemCis and 36.3% with GemCis (p=0.437), but there was a trend of nominal OS benefit in patients treated with sintilimab + anlotinib + GemCis. PFS was significantly improved with sintilimab + anlotinib + GemCis vs GemCis (6.4m vs 5m; p=0.014). ORR was 37.5% with sintilimab + anlotinib + GemCis and 26.7% with GemCis. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 69.2% of pts receiving sintilimab + anlotinib + GemCis and38.7% of pts receiving GemCis. TRAEs led to discontinuation of any study medication in 7.7% of pts receiving sintilimab + anlotinib + GemCis and 9.1% of pts receiving GemCis. Conclusions: In pts with advanced BTC, sintilimab + anlotinib + GemCis could improve OS and PFS vs GemCis with manageable safety, indicating sintilimab + anlotinib + GemCis may be a new first-line standard of care regimen. Research Sponsor: Innoventbio Biologics, Inc, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT04300959.

Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial.

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable tetrapeptide-based linker and a potent topoisomerase I inhibitor. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. The rate of HER2 positivity in biliary tract cancer (BTC) has been reported to be 5-20%, and case reports and clinical trials have suggested that HER2 inhibitors might be active in HER2-positive BTC. Here we describe the rationale and design of the phase II HERB trial that will evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing unresectable or recurrent BTC. The primary end point will be the centrally assessed objective response rate in HER2-positive patients.

Effects of an enteral nutrient-rich therapy with omega-3 fatty acids in patients with unresectable or recurrent biliary tract cancer or pancreatic cancer during chemotherapy: a case–control study

To evaluate omega-3 fatty acid-rich enteral nutrient effects in patients with unresectable or recurrent biliary tract or pancreatic cancers during chemotherapy. Enteric nutritional supplements containing omega-3 fatty acids (Racol®) was administered to aforementioned patients with cancers during chemotherapy. The skeletal muscle mass and blood test data were obtained pre-administration and 28 and 56 days after. Patients with pancreatic cancer were administered the digestive enzyme supplement pancrelipase (LipaCreon®) 28 days after the start of Racol® administration. The number of chemotherapies skipped due to neutropenia was recorded for 2 months before and after enteral nutrient initiation. In all 39 patients, the skeletal muscle mass increased on day 56 versus baseline (median 17.3 kg vs. 14.8 kg, p < 0.01), number of chemotherapies skipped decreased (mean: 0.65 times/month vs. 1.3 times/month, p = 0.03), and retinol-binding protein (mean: 2.56 mg/dL vs. 2.42 mg/dL, p = 0.05) increased. Patients with pancreatic cancer showed increased blood eicosapentaenoic acid concentration on day 56 versus baseline (median: 48.1 μg/mL vs. 37.0 μg/mL, p = 0.04) and increased skeletal muscle mass (median 16.8 kg vs. 14.4 kg, p = 0.006). Baseline median neutrophil count increased significantly from 2200/μL at baseline to 2500/μL (p = 0.04). Patients with biliary tract cancer during chemotherapy also exhibited increased skeletal muscle mass following omega-3 supplementation (median 17.3 kg vs. 15.8 kg, p = 0.01). In patients undergoing chemotherapy for unresectable or post-recurrence pancreatic and biliary tract cancers, high-omega-3 fatty acid nutrition therapy use improved skeletal muscle maintenance and chemotherapy dosing intensity.

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study

Immunotherapies have shown clinical activity in patients with advanced biliary tract cancer, for which outcomes remain poor despite standard of care treatment with gemcitabine and cisplatin. We aimed to evaluate gemcitabine and cisplatin plus durvalumab with or without tremelimumab as first-line treatment in patients with advanced biliary tract cancer. This open-label, single-centre, phase 2 study was conducted at Seoul National University Hospital. Eligible patients were treatment-naïve adults aged 18 years or older with histologically proven unresectable or recurrent biliary tract cancer, at least one measurable lesion based on the Response Evaluation Criteria in Solid Tumors (version 1.1), an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 12 weeks or longer, and adequate healthy organ and bone marrow function. Initially, all patients received one 3-week cycle of gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on day 1 and 8 followed by gemcitabine and cisplatin plus durvalumab (1120 mg) and tremelimumab (75 mg) on day 1 of each cycle, starting with the second cycle (chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group). Following protocol amendment, patients were recruited to receive gemcitabine and cisplatin plus durvalumab, starting on day 1 of the first cycle (chemotherapy plus durvalumab group) or gemcitabine and cisplatin plus durvalumab and tremelimumab also from day 1 of the first cycle (chemotherapy plus durvalumab and tremelimumab group) in parallel and allocated using a random block method. Assessors and patients were not masked to the treatment group. The primary endpoint was objective response rate, assessed in the efficacy population (ie, patients who were treated at least until the first tumour response assessment). This study is registered with ClinicalTrials.gov, NCT03046862 (active). Between March 2, 2017, and Feb 13, 2020, 128 patients were enrolled (32 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 49 in the chemotherapy plus durvalumab group, and 47 in the chemotherapy plus durvalumab and tremelimumab group). Four patients (two in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group and two in the chemotherapy plus durvalumab group) were excluded and 124 were evaluable for tumour response. The median duration of follow-up was 48·2 months (IQR 41·5-49·4) for the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 26·6 months (19·0-27·9) for the chemotherapy plus durvalumab group, and 24·2 months (20·7-31·7) for the chemotherapy plus durvalumab and tremelimumab group. 82 (66%) of 124 patients achieved an objective response (15 [50%] of 30 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 34 [72%] of 47 in the chemotherapy plus durvalumab group, and 33 [70%] of 47 in the chemotherapy plus durvalumab and tremelimumab group). The most common grade 3 and 4 adverse events were decreased neutrophil count (67 [53%] of 126), anaemia (50 [40%]), and decreased platelet count (24 [19%]), with no unexpected safety events. No adverse events leading to discontinuation or death occurred. Gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety in patients with biliary tract cancer. Gemcitabine and cisplatin plus durvalumab are being evaluated in the phase 3, TOPAZ-1 study (NCT03875235) as first-line treatment in patients with advanced biliary tract cancer. AstraZeneca; National Research Foundation of Korea (Grant No. 2021R1A2C2007430).