bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.
Authors: Edeline Julien , Merle Philippe , Fang Weijia , Assenat Eric , Pan Hongming , Rimassa Lorenza , Li Zhiwei , Blanc Jean-Frédéric , Yen Chia-Jui , Ross Paul J. , Hu Sheng , Zhang Tao , Tran Albert , Shao Guoliang , Bouattour Mohamed , Chen Yajin , Wu John , Li Vincent , Chica-Duque Sandra , Ren Zhenggang 
Published: June 2022

4072 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]
Immunogenomic characterization of biliary tract cancers: Biomarker enrichment for benefit to immune checkpoint blockade.
Authors: Park Wungki , Keane Fergus , Bandlamudi Chaitanya , Donoghue Mark , Tallón de Lara Paulino , Harding James J. , Khalil Danny , McKinnell Zoe , Sterpi Michelle , Cao Will , El Dika Imane H. , Balachandran Vinod P. , Soares Kevin , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Iacobuzio-Donahue Christine A , Abou-Alfa Ghassan K. , Solit David B. , O'Reilly Eileen Mary 
Published: June 2022

4083 Background: Several immunomodulatory molecules (PD-L1, B7H4, and CD276) have been associated with biliary tract cancer (BTC) subgroups, suggesting potential value to immune checkpoint blockade (ICB) in this lethal disease. Phase II monotherapy (pembrolizumab or nivolumab), and combination (atezolizumab and cobimetinib) ICB trials reported low response rates in unselected advanced BTC with a wide range of responses. A recent randomized phase III trial (TOPAZ-1) reported an overall survival (OS) benefit among patients (pts) with advanced BTC treated with chemotherapy and anti-PD-L1 ICB. However, no correlation between PD-L1 expression and OS was noted and biomarker enrichment strategy in BTC for immunotherapy remains a key to optimize OS. Methods: From our comprehensive clinico-genomic database for BTC at Memorial Sloan Kettering (MSK), a retrospective genomic landscape and neoantigen analysis was performed using MSK-IMPACT. Potential immunogenic subgroups were evaluated: homologous recombination deficiency (HRD) defined by pathogenic alterations in BRCA1/2, PALB2, and BAP1, microsatellite stability high (MSI-H) defined by MSIsensor score ≥10, and tumor mutation burden (TMB)>10. Clinical outcomes with anti-PD-1 ICB were evaluated. Results: Among N=1,190 pts with BTC, N=1,346 samples were sequenced between 03/2014 and 01/2022. Key actionable alterations included (%): IDH1, 2 (13, 3), FGFR2 fusions (9), ERBB2 amplification (5), BRAF V600E (2), RNF43 (2), POLE (2), NTRK1 fusion (<1). There were N=230 (17%) patients with putatively more immunogenic BTC (iBTC) identified by HRD [ BRCA1/2 (1, 2.4), PALB2 (1), BAP1 (9)], TMB>10, and MSI-H. Frequency, location (intrahepatic, ICC; extrahepatic, ECC; gallbladder, GBC), TMB, and genomic instability score (GIS) are summarized (Table). Among iBTC subgroup, N=32 pts received ICB. Their median follow up was 29.1 months. Median lines of prior therapy was 3. Median PFS was 5.6 M (95%CI: 1.2-10.1) and OS was 33.4 M (23.1-43.6). Conclusion: A subgroup of BTC pts (iBTC) benefit from ICB. Apart from MSI-H and TMB>10, other genomically-defined subgroups such as HRD may benefit from ICB. Prospective studies are needed to evaluate a better biomarker enrichment strategy beyond PD-L1 and TMB, that can represent other immunogenic aspects of tumor neoantigen and microenvironment. [Table: see text]
Health care resource utilization (HCRU) and costs in patients with biliary tract cancer (BTC) treated with systemic therapy in the United States (US).
Authors: Wang Liya , Singhal Mukul , Eluri Madhulika , Valderrama Adriana , Nepal Bal , Kamble Shital , Grabner Michael , Malhotra Usha , Siegel Abby B. , Swami Shilpi , Javle Milind M. 
Published: June 2022

4090 Background: BTC is associated with poor prognosis and limited treatment choices. There is limited evidence on HCRU and costs among BTC patients receiving systemic treatments (ST). This study examined HCRU and total direct cost of care among BTC patients treated with ST to understand the disease burden in management of BTC. Methods: A retrospective cohort study of BTC patients who received first line (1L) ST was conducted, using US private payer Cancer Care Quality Program data and administrative claims from the HealthCore Integrated Research Database between 07/01/2014 - 03/31/2021. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTC diagnosis were excluded. Per patient per month (PPPM) costs in 2020 USD were calculated during 1L, 2L, and 3L treatments associated with HCRU from inpatient, emergency room, and outpatient visits as well as outpatient pharmacy dispensing. Results: Among 298 BTC patients (biliary tract, n=203; gallbladder, n=65; bile duct, n=30; stage IV, n=231; stage III, n=28; stage I/II, n=39) who received ST, mean (SD) age was 61.7 (9) years at 1L treatment initiation, and the majority were female (58%). Following 1L treatment, 44% received 2L treatment, and 16% received 3L treatment. Median follow-up was 7.6 months. Among 201 (67%) patients who had hospitalization in the follow-up period, mean (SD) number of hospitalizations was 2.5 (2), and the average length of stay was 7.0 (5) days. Total PPPM all-cause costs were the lowest during 1L treatment (mean [SD]: $19,589 [$22,603]), and increased as the treatment advanced (2L: $22,617[$19,302]; 3L: $33,534[$40,588]). Similar trend was observed in BTC-related total costs with $16,237 ($22,452) in 1L, $19,083 ($18,670) in 2L and $27,609 ($39,949) in 3L. The table summarizes BTC-related HCRU and PPPM cost during each line of therapy. Conclusions: Study findings suggest significant resource use burden and high total direct medical costs for BTC patients receiving ST. Hospitalizations and outpatient visits represent important HCRU and cost for BTC. These data indicate a need for future newer innovative therapies in the management of BTC.[Table: see text]
Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab for hepatocellular carcinoma (HCC) in BCLC stage c: A prospective, single-arm, phase II trial (TRIPLET study).
Authors: Gu Yang-Kui , Zhang Tian-Qi , Zuo Meng-Xuan , Geng Zhi-Jun , Li Ji-Bin , Huang Zi-Lin , Wu Pei-Hong 
Published: June 2022

4106 Background: The combination of anti-angiogenesis and immune checkpoint blockade has been proven to improve clinical outcomes of advanced HCC. We assessed the efficacy and safety of HAIC combined with apatinib and camrelizumab for BCLC stage C HCC. Methods: Consecutive treatment-naive patients with BCLC stage C HCC were enrolled in this phase II trial (NCT04191889). Eligible patients were administrated with HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 2500 mg/m2; q3w), combined with apatinib (250 mg qd) and camrelizumab (200 mg q3w) for 6 cycles, followed by maintenance therapy with apatinib and camrelizumab until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Following an optimal Simon 2-stage design, 26 eligible patients needed to be included in the first stage, of whom at least 11 patients had to achieve objective responses to warrant further investigation in the second stage. Results: In the first stage, confirmed ORR was achieved in 16 and 20 patients per RECIST v1.1 and mRECIST, respectively, therefore enrollment of the second stage continued. From 4/13/2020 to 1/31/2022, 31 eligible patients were enrolled and 29 evaluable for efficacy analyses. The 31 patients were characterized with median age 45 years (range 30-67), men 96.77%, Child-Pugh A 100%, portal vein tumor thrombus Vp 1-2/Vp 3-4 25.81%/45.16%, and extrahepatic metastasis 12.90%. As of 1/31/2022, with a median follow-up of 18.07 months (95% CI 14.10 to 22.04), the confirmed ORR was 70.96% (95% CI, 53.41%-83.91%) with 22 partial responses (PR) per RECIST v1.1,while 87.10% (95% CI, 71.15%-94.87%) with 3 (9.68%) complete responses (CR) and 24 (77.42%) PR per mRECIST. The disease control rate (DCR) was 87.10% (95% CI, 71.15%-94.87%) whether per RECIST v1.1 or mRECIST. The median time to response (TTR) was 2.67 months (interquartile range (IQR), 1.43-2.96) per RECIST v1.1 and 2.03 months (IQR, 1.37-2.80) per mRECIST. The median progression-free survival (PFS) time was 9.37 months (95% CI 7.00 to 11.73) per RECIST v1.1 and 9.63 months (95% CI 5.82 to 13.44) per mRECIST, in particular, the liver-specific median PFS time was 10.80 months (95% CI 5.88 to 15.72) per mRECIST. The 6-month, 12-month, and 18-month overall survival rate were 93.1%, 85.8%, and 65.8%, respectively. Grade ≥3 adverse events (AEs) occurred in 74.19% of the patients, of which the most common AEs were decreased neutrophils (52.17%), decreased lymphocytes (43.38%), and increased ALT and AST (30.43% and 43.48% for each). Conclusions: The triplet treatment of HAIC, apatinib and camrelizumab showed promising clinical benefits and acceptable safety for BCLC Stage C HCC. Further confirmatory randomized controlled trial is about to get underway. Clinical trial information: NCT04191889.
A phase II study combining KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) and lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): Updated efficacy and safety results.
Authors: Xing Baocai , Da Xu , Zhang Yanqiao , Ma Yue 
Published: June 2022

4115 Background: PD-1 inhibitor with Lenvatinib were reported to improve ORR in patients with metastatic HCC. KN046 was a bispecific antibody that target both PD-1/PD-L1 and CTLA-4/B7 immune checkpoints pathway. Preliminary report already showed good efficacy and tolerable safety of the KN046+Lenvatinib regimen. Here we updated the efficacy and safety results with more enrolled patients and longer follow-up duration. Methods: This is an open-label, single-arm, multicenter, phase II trial in pts with unresectable or metastatic HCC. Enrolled patients (pts) with Barcelona Clinic Liver Cancer (BCLC) stage B or C who were not suitable for curative surgery or local therapy had received Lenvatinib 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW<60 kg) orally and KN046 5 mg IV on Day 1 of a 21-day cycle until disease progression or intolerable toxicity or 2-year treatment. Primary endpoints were safety and ORR by RECISTv1.1 per investigators. Results: As data cutoff (January 7, 2022) date, 55 enrolled pts received combination treatment with median duration of 25 weeks. For 52 evaluable pts, ORR was 51.9% (95% CI 37.6-66.0) (RECIST v1.1) and DCR was 86.5% (95% CI 74.2-94.4) (RECIST v1.1). Median PFS was 9.3 months (95% CI 7.0–not estimable [NE]), The median OS and DOR of pts were not reached. The overall incidence of KN046 related treatment-emergent adverse events(TRAEs) was 98.2%, with 27.3% Gr3. The most common Grade ≥ 3 TRAEs included platelet count decreased (7.3% of pts) and aspartate aminotransferase increased (3.6% of pts). The immune related adverse events (irAE) occurred in 14.5% of pts (grade ≥3 5.5%). 3 pts discontinued KN046 treatment due to ≥3 Gr TRAE, which was infusion related reaction, platelet count decreased and interstitial lung disease. 4 (7.2%) pts died from KN046 TRAEs (Hyponatremia, n=1; Interstitial lung disease, n=2; Cause of death unknown, n=1). Conclusions: KN046+Lenvatinib demonstrated a promising efficacy in ORR and PFS and the manageable safety profile in the first-line advanced unresectable or metastatic HCC treatment. These result support the KN046 plus Lenvatinib as a potential new treatment option for this population. Clinical trial information: NCT04542837.
IMMUTACE: A biomarker-orientated phase II, single-arm, open-label AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate-stage hepatocellular carcinoma (HCC; AIO-HEP-0217)—Updated efficacy results.
Authors: Saborowski Anna , Waldschmidt Dirk , Hinrichs Jan , Ettrich Thomas Jens , Martens Uwe Marc , Mekolli Ardian , De Toni Enrico N , Berg Thomas , Geißler Michael , Hausner Guido , Maenz Martin , Ehmer Ursula , Kirstein Marta , Vogel Arndt 
Published: June 2022

4116 Background: Immunotherapy based combinations recently revolutionized the treatment of patients (pts) with advanced HCC, but its significance in earlier stages remains to be determined. TACE is commonly used as first line treatment in intermediate HCC, but outcome of patients treated with TACE in real-life cohorts is still poor with a median overall survival (OS) below 20 months. The aim of this study was to determine the safety and efficacy of TACE combined with nivolumab. Methods: This is a phase II trial, that recruited 59 patients at 10 sites in Germany between 06/2018 and 06/2020. Pts received up to two TACE treatments followed by nivolumab (240 mg/ Q2W), initiated on day 2-3 after the first TACE session and continued until progression for a maximum treatment duration of two years. Primary endpoint was ORR (mRECIST; with ORR exceeding 55% (power = 80%; actual beta 0.17) as promising for further investigations). Secondary endpoints include mPFS, mTTFS (median time to failure of strategy), mOS, QoL, and safety/tolerability. Tumor tissue was obtained at baseline and blood samples were collected longitudinally for translational research. Results: 49 pts (14.3% HCV and 8.2% HBV) were enrolled and received at least one dose of nivolumab, median tumor size was 4.5 cm (0.9 – 15 cm) and median number 3 (1 – 12). ORR by mRECIST was 71.4% (CR: 16.3%, PR: 55.1%, SD 4.1%, PD: 14.3%). At a median follow-up of 20 months, mPFS was 7.2 mo (95% CI; 5.3 – 11.2; 40 events), mTTFS was 11.2 mo (95% CI; 7.2, 13.5; 42 events) and mTTSST (median time to subsequent systemic therapy) was 24.9 mo (95% CI; 12.2, - ; 21 events). Median duration of Nivolumab was 8.3 months and mOS was 28.3 mo (95% CI; 20 – not estimable; 23 events). Grade ≥3 treatment-related adverse events occurred in 34.7% of patients. Correlative analysis of efficacy with genetic alterations, gene expression signatures and changes of immune cell populations will be reported soon. Conclusions: The study met its primary endpoint and provides evidence for the efficacy of TACE in combination with nivolumab without new safety signals in pts with intermediate HCC and no prior systemic therapy. Our findings support further evaluation of nivolumab-based combinations for the treatment of intermediate HCC. Disclaimer: This study was supported with drug and funding by Bristol-Myers-Squibb. Clinical trial information: NCT03572582.
Impact of metformin on clinical outcomes in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.
Authors: Khalil Lana , Kang Sandra , McCook-Veal Ashley , Draper Amber , Diab Maria , Shaib Walid Labib , Alese Olatunji B. , El-Rayes Bassel F. , Akce Mehmet 
Published: June 2022

4118 Background: Non-alcoholic steatohepatitis (NASH) is an emerging etiology for hepatocellular carcinoma (HCC) and contributes to the increasing incidence of HCC worldwide. Patients with NASH often have risk factors of metabolic syndrome including hypertension, obesity, and type 2 diabetes (T2DM). NASH induced HCC has been shown to be associated with less response to immune check point inhibitors (ICIs) in HCC. Anti-diabetic agent metformin has been shown to be associated with improved outcomes in patients treated with ICIs in melanoma and non-small cell lung cancer. However, the impact of metformin on the efficacy of ICIs is not well defined in HCC. The main purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods: We performed a retrospective analysis of patients with advanced HCC treated with ICIs in first and later-line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were stratified based on their usage of metformin. OS and PFS were analyzed using Cox proportional hazard models and Kaplan-Meier analysis with log-rank test. Results: A total of 111 patients met inclusion criteria, 18 patients in the metformin group and 93 patients in the non-metformin group. Most common cause of HCC was viral hepatitis (52%), followed by NASH (29%), alcohol (8%) and other (11%). Baseline characteristics between the two groups were similar except all patients in the metformin group had a diagnosis of T2DM. ORR was 5.6%. (1 partial response) in the metformin group vs 22.6% (5 complete responses, 16 partial responses) in the non-metformin group. Median OS was 45.9 months in the non-metformin group vs 10.8 months in metformin group (HR 1.99, 95% CI 0.95-4.21, p = 0.064). Median PFS of 6.6 months vs 2.5 months (HR 1.75, 95% CI 0.93-3.29, p = 0.077). Moreover, metformin usage was associated with shorter median OS of 10.8 months (HR 1.96, 95% CI 0.75-5.09, p = 0.16) vs 20.9 months among patients with T2DM. OS was significantly worse in patients with poor ECOG performance status 2-3, MELD score 10-23, higher grade tumor histology, AFP > = 400, and use of IO in later lines of therapy. Conclusions: In this retrospective study metformin use was associated with worse clinical outcomes in advanced HCC patients treated with ICIs.
Efficacy of nivolumab and temozolomide in advanced neuroendocrine neoplasms (NENs) in a phase 2 clinical trial.
Authors: Owen Dwight Hall , Benner Brooke , Wei Lai , Sukrithan Vineeth , Goyal Ashima , Zhou Ye , Suffren Sheryl-Ann , Pilcher Carly , Christenson Gwen , Curtis Nancy , Savardekar Himanshu , Norman Ruthann , Ferguson Sarah , Kleiber Barbara , Wesolowski Robert , Carson William Edgar , Otterson Gregory Alan , Verschraegen Claire F. , Shah Manisha H. , Konda Bhavana 
Published: June 2022

4121 Background: Treatment options are limited in patients with metastatic NEN. Temozolomide (TEM) alone and in combination with capecitabine is active in NEN and has been shown to have immunomodulatory impact. Here we present the final results for the NEN cohort of a phase 2 trial of combination nivolumab and TEM in patients with advanced NEN along with observed peripheral immune changes. Methods: NCT03728361 is a non-randomized, two-cohort, open-label phase 2 trial of nivolumab and TEM in patients with metastatic NEN and small cell lung cancer. The NEN cohort enrolled patients with tumors of any WHO grade, location, and line of therapy; all patients had evidence of progression prior to study. Prior immunotherapy was not allowed. Treatment consisted of nivolumab 480 mg IV on day 1 and TEM 150 mg/m2 on days 1-5 of a 28-day cycle. The primary objective was efficacy measured as response rate (RR) by RECIST v1.1. Secondary objectives were progression free survival (PFS) and overall survival (OS), by the method of Kaplan–Meier. The translational objective was to analyze peripheral blood mononuclear cells (PBMCs) collected at screening (baseline) and on cycle 1, day 15 (C1D15) via mass cytometry. Results: The RR was 36% (n=10/28, 95% CI: 18.6%-55.9%), including 10 patients (36%) with PR, 16 (57%) with SD, and 2 (7%) with PD (Table). The disease control rate was 93%. Responses occurred across all WHO grades; 44% of patients with tumors with Ki-67 >20% had PR. There was a significant difference in ORR by primary tumor location (bronchial vs pancreas vs other, p=0.004). There was no significant difference in response by Ki-67% (p=0.872), or in patients treated as first line (31%) or beyond (40%, p=0.706). The median PFS was 8.9 months (95% CI: 3.9 – 11.1 months), and median OS was not reached (95% CI: 20.7 – NR months). Two immune related SAE’s occurred: myocarditis and diarrhea in one patient each; gr4 toxicities included neutropenia (10%) and thrombocytopenia (7%). Profiling of PBMCs revealed no correlation of baseline MDSC levels with clinical benefit, however significant changes within the T cell landscape, including a decrease in CD4+ T cells (59.6% ±13.08 vs. 56.5% ±13.01, p=0.001) and increase in CD8+ T cells (27.9% ±13.36 vs. 31.7% ±14.57, p=0.03) were observed. Conclusions: Combination nivolumab and TEM demonstrated promising efficacy in patients with NENs; median OS has not been reached. Clinical trial information: NCT03728361. [Table: see text]