bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib in PTEN-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective, phase II trial.
Authors: Yuan Zhen-gang
Published: June 2022

4092

Background: Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy after hepatocellular carcinoma. Prognosis of cholangiocarcinoma is poor and therapy options are limited. Bortezomib in unselected patients with BTC has been failed in previous clinical trial. Our previous research dedicates that PTEN-deficient facilitates sensitivity to proteasome inhibition in intrahepatic cholangiocarcinoma. In this open-label，prospective，phase II trial, we explore the efficacy and safety of bortezomib in PTEN-deficient advanced intrahepatic cholangiocarcinoma patients who have progressed during Gemcitabine based treatment. Methods: Between August 1, 2017, and July 31, 2021, A total of 130 patients were under went PTEN immunohistochemical staining for screening and 15 patients enrolled. Patients with PTEN-deficient advanced intrahepatic cholangiocarcinoma who had progressed after GC/Gemox therapies received bortezomib 1.3 mg/m2 days 1, 4, 8, and 11 of a 21-day cycle. The primary endpoint was objective response rate according to Response Evaluation Criteria in Solid Tumors v1.1. Results: The overall response rate was 23.1% (3/13) and disease control rate was 53.8% (7/13). The Median time of follow up was 4.2 months (95% CI: 0.7̃17.2 months). median progression-free survival was 2.3 months and the median overall survival was 9.6 months. Adverse events of any grade were reported in 14 patients. Thrombopenia was the most common toxicity. Conclusions: Bortezomib provided an encouraging objective response and disease control as second-line therapy for PTEN-deficient Patients with advanced intrahepatic cholangiocarcinoma, and improving the overall survival to 9.6 months. Bortezomib would be a promising treatment option in PTEN-deficient selected patients.
A prospective, multicenter, phase II trial of albumin-paclitaxel plus cisplatin versus gemcitabine plus cisplatin in first-line treatment of advanced biliary tract tumors.
Authors: Yang Xiao , Zhuang Liang , Dai Yuhong , Qiu Hong , Yuan Xianglin
Published: June 2022

4099

Background: The prognosis of biliary system tumors is poor, Gemcitabine combined with cisplatin has been the standard first-line treatment for advanced biliary system tumors, but its efficacy and adverse effects are unsatisfactory. Albumin-paclitaxel is a novel paclitaxel with a broad-spectrum anti-tumor effect, which has been widely used in the treatment of digestive system malignant tumors. Therefore, we designed this study to investigate the efficacy and safety of the combination of albumin-paclitaxel and cisplatin compared with gemcitabine combined with cisplatin in patients with previously untreated advanced biliary tract tumors. Methods: This is a multicenter, randomized, controlled, investigator-initiated Phase II trial designed to enroll patients with unresectable, recurrent, or metastatic cholangiocarcinoma (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma). After enrollment, patients were randomly assigned to the experimental TP group (albumin paclitaxel 125mg/m2 iv, D1, 8 cisplatin 75mg/m2 IV, D1 Q21 ) or the control GP group (gemcitabine 1000mg/m2 IV, D1, 8 cisplatin 75mg/m2 iv, D1 Q21) and received six cycles of chemotherapy. The primary endpoint was PFS, and the secondary endpoint was OS, ORR, and safety. Results: Up to January 2022, 67 patients were enrolled, the 41male and 26 female patients had a median age of 55(range 32-74) years. Of the 67 enrolled patients, 33 were randomly assigned to the TP group and 34 to the GP group. Among the these patients, 47 were diagnosed with intrahepatic cholangiocarcinoma, 7 with extrahepatic cholangiocarcinoma, and 13 with gallbladder cancer. 48 patients had completed at least 2 cycles of chemotherapy and were available for evaluation, mPFS in the TP and the GP groups was 7.7 and 7.5 months, respectively (HR 1.33, CI 0.61 - 2.91,P = 0.469), mOS in TP and GP groups was 12.1 months and 12.9 months, respectively (HR 1.62, 95% CI 0.67-4.17,P = 0.271). After the first assessment, the ORR was 39.4% and 35.3% in the TP group and the GP group, respectively. In terms of side effects, bone marrow suppression (61% vs 76%) was the most predominant adverse events in both groups, abnormal liver and kidney function (56% vs 67%), gastrointestinal reactions (including nausea, vomiting, diarrhea, constipation, etc.) (46% vs 43%), rash or allergy (44% vs 37%), and other side effects such as fever and influenza symptoms (21% vs 24%) were also observed in the TP group and the GP group. Conclusions: The result of this study showed that the regimen of albumin paclitaxel combined with cisplatin was non-inferior to gemcitabine combined with cisplatin in terms of PFS, OS and ORR, and the safety advantages of the combination of albumin paclitaxel and cisplatin make it a potential regiment for first-line treatment of advanced biliary tract tumors. Clinical trial information: ChiECRCT-20180167.
Quantitative analysis of spatial distribution of lymphocytes in hepatocellular carcinoma: A biomarker correlated with survival and gene expression in cancer immune system.
Authors: Lee Hong-Seok , Kim Kyungdoc , Kang Guhyun , Jung Kyu-Hwan , Kaseb Ahmed Omar , Lee Sunyoung S.
Published: June 2022

4119

Background: Tumor microenvironment (TME) is known to impact prognosis in hepatocellular carcinoma (HCC). Although digital pathology and artificial intelligence have been adopted in modern medicine and oncology, few quantitative biomarkers have been identified to predict the prognosis and guide treatment for HCC via an automated analysis of TME at the cellular level. Methods: Histopathological images and clinical data of 365 cases with HCC were obtained from TCGA (The Cancer Genome Atlas), and 60 of HCC pathology images and cancer lesion annotations were collected from PAIP2019 [1]. DenseNet-based HCC segmentation model (F1-score, 0.904) and Hover-Net-based cell detection model (F1-score, 0.914) were developed using PAIP2019 and MoNuSac datasets, respectively [2,3,4]. Each histopathology image of TME was segmented via the segmentation model into two areas: 1) non-tumoral regions that include the stroma; 2) tumoral regions where HCC cells are concentrated. The cell detection model recognized individual cells on images, specified lymphocytes, and calculated ratios of lymphocyte to total cell count (RLTCC) in segmented regions. RLTCC was then correlated with clinical survival outcomes, HCC primary risk factors, and RNA expression profiles. Results: RLTCC in tumoral regions was not significantly associated with prognosis. Patient groups with higher RLTCC in non-tumoral regions (RLTCC in NT) showed better overall survival (OS) than those with lower RLTCC in NT regardless of HCC risk factors (median OS 45.7 vs 18.6 months; log hazard ratio of -1.6 ± 1.1, p=0.006). These patients had significantly enriched expression of genes (p<0.05) related to cancer antigen presentation (higher gene expression by +33.7%), recognition of cancer cells by T-cell (+32.0%), T-cell priming and activation (+32.2%), immune cell localization to tumors (+31.9%), and killing of cancer cells (+24.7%). Those with HCC etiology of hepatitis B and C had more patients in the higher RLTCC in NT (17/21 patients, 81.0%; 23/29, 79.3%, respectively). In comparison, those with alcohol consumption showed equal distribution (26/53, 49.1%). The RLTCC in NT in hepatitis B/C groups was statistically higher than alcohol consumption group (p<0.05). Conclusions: A digital prognostic biomarker, RLTCC in NT of TME was identified as a significant prognostic indicator, and it was shown to correlate with RNA gene expression related to T-cell mediated cancer immunity. A retrospective analysis of clinical response from systemic therapy in relation to digital biomarkers is underway and will be reported. References: [1] Kim et al. Med. Image Anal. 67 (2021). [2] Riasatian, Abtin, et al. Med. Image Anal. 70 (2021). [3] Graham, Simon, et al. Med. Image Anal. 58 (2019). [4] Verma, Ruchika, et al. IEEE Trans Med Imaging 39.1380-1391 (2020).
Comparative genomic analysis and its prognostic impact on survival between viral hepatitis-related and non-viral hepatitis intrahepatic cholangiocarcinoma.
Authors: Chiang Nai-Jung , Tan Kien Thiam , Huang Chung-Yu , Chen Ming-Huang , Chiu Tai-Jan , Shan Yan-Shen , Li Chien-Feng , Chen Li-Tzong
Published: June 2022

4120

Background: Intrahepatic cholangiocarcinoma (IHCC) is hard-to-treat cancer with a high mortality rate worldwide. Hepatitis B virus (HBV) or hepatitis C virus (HCV) is involved in the development of IHCC, especially in Asian countries. Despite rapidly growing genomic profiling studies of IHCC in Western and Eastern populations in recent years, less on genomic heterogeneity of viral hepatitis-related and non-viral hepatitis IHCC been reported. This study aims to provide a comprehensive genomic analysis of IHCC and its prognostic value in IHCC populations with or without viral hepatitis infection. Methods: FFPE tissues from 157 patients with IHCC were subject to next-generation sequencing using the FoundationOne CDx (n = 52) or ACTOnco + comprehensive genomic profiling panels (n = 105). Genomic alterations and features, including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy-number variations (CNVs), fusion genes (only FoundationOne CDx), tumor mutations burden (TMB), and microsatellite instability (MSI) status, were analyzed. The prevalence of genetic mutations and their prognostic values were compared between patients with a history of hepatitis B/C infection (BC; n = 71, 45.2%) and those without hepatitis B/C infection (NBNC; n = 79, 50.3%). Seven patients had no medical record of HBV or HCV infection. Results: The most frequently mutated genes in BC- and NBNC-related IHCC populations were TP53, KRAS, and IDH1. The genetic alternations related to PI3K/AKT/mTOR signaling pathway and copy number gain of receptor tyrosine kinase were relatively dominant in BC-related IHCC. In contrast, the Ras/Raf/MAPK pathway alterations were frequently common in NBNC-related IHCC. In addition, we investigated the correlation between commonly altered genes or pathways and overall survival (OS). Interestingly, the prognostic biomarkers in BC- and NBNC-related IHCC were significantly different. The results showed that TP53 DNA-binding domain (DBD) and TET2 mutations were associated with poor prognosis in BC-related IHCC. On the contrary, CDKN2A deletion and Ras/Raf/MAPK pathway alteration were associated with inferior prognosis in NBNC-related IHCC. However, neither the PI3K/AKT/mTOR signaling alteration nor IDH1/2 mutation affected the OS in BC- or NBNC-related IHCC. Notably, we found that SWI/ SNF complex involved in ARID1A, ARID1B, ARID2, PBRM1, and SMARCA4 alterations exhibited a beneficial prognosis in BC-related IHCC patients, which has not been discussed in previous studies. Conclusions: This study provides comparative genomic profiling between BC- and NBNC-related IHCC and shows genomic heterogeneity and different dominant prognostic biomarkers and activated signaling pathways. Different treatment strategies should be considered in these two subpopulations based on these results.
Association of LAG-3 expression in circulating T cells and response to combination temozolomide (TMZ) and nivolumab (NIVO) in advanced neuroendocrine neoplasms (NENs): Results from an investigator-initiated phase 2 trial.
Authors: Sukrithan Vineeth , Benner Brooke , Wei Lai , Goyal Ashima , Zhou Ye , Suffren Sheryl-Ann , Pilcher Carly , Christenson Gwen , Curtis Nancy , Schwarz Emily , Savardekar Himanshu , Norman Ruthann , Kleiber Barbara , Wesolowski Robert , Otterson Gregory Alan , Verschraegen Claire F. , Carson William Edgar , Shah Manisha H. , Konda Bhavana , Owen Dwight Hall
Published: June 2022

4123

Background: LAG-3 is an immune checkpoint present on NK cells, activated T cells and myeloid cells that inhibit T cell responses. Recent evidence demonstrating the safety and efficacy of LAG-3 inhibition has increased interest in this pathway for the treatment of multiple malignancies but the role in NEN is unclear. We present results from correlative peripheral blood mass cytometry (CyTOF) performed in a phase 2 trial (NCT03728361) of the combination of NIVO and TMZ in pts with advanced NEN. Methods: Patients (pts) with progressive NEN of any grade or primary location and any line of therapy were eligible. Small cell lung cancer was excluded. Clinical results from NCT03728361 will be presented in a separate abstract. Study treatment consisted of NIVO 480 mg IV every 4 weeks and TMZ 150 mg/m2 for 5 consecutive days out of a 28-day cycle. Peripheral blood mononuclear cells (PBMCs) were available from 16 out of 28 patients at screening (baseline) and cycle 1, day 15 (C1D15) and analyzed via CyTOF. Antibody labelling was performed using a 37 marker Maxpar Direct Immune Profiling Assay (Fluidigm). Immune cell populations were compared using two sample t-tests between pts with partial response (PR) and non-partial response (non-PR). Results: At screening, no differences were observed in PD-1, TIM3, or KLRG1 positive T-cell populations between pts with PR or non-PR. Patients with a PR had a significantly lower % of LAG-3 expressing T cells (p=0.029). There was a trend towards a lower % CD8+LAG-3+ T cells in pts with PR (p=0.086). At C1D15: The % of CD8+ LAG-3+ T cells were significantly higher in PRs vs. non-PR (p = 0.015). In matched samples comparing T cell populations at screening to C1D15, LAG-3+ CD8+ T cells increased significantly in PRs when compared to non-PRs (p=0.021). Conclusions: The % of LAG-3+ T cell population at baseline associates with non-response to TMZ/NIVO in NENs. Among responders, there was a significant increase in CD8+ LAG-3+ T cells by Day 15 compared to baseline indicating a potential mechanism of immune escape and eventual resistance. Clinical trial information: NCT03728361. [Table: see text]
Genomic correlates of response to capecitabine and temozolomide (CAPTEM) in pancreatic neuroendocrine tumors.
Authors: Lee Patrick , Blais Edik Matthew , Gong Jun , Osipov Arsen , Moshayedi Natalie , Thomassian Shant , Ng Camille , Chuy Jennifer W. , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Hendifar Andrew Eugene
Published: June 2022

4124

Background: Despite the frequent use of capecitabine and temozolomide (CAPTEM) to treat metastatic, well-differentiated pancreatic neuroendocrine tumors (PNETs), no reliable genomic predictors of response currently exist. PNETs commonly harbor mutations in MEN1, ATRX, DAXX, and the PI3K/AKT/mTOR pathway. We sought to determine whether the mutational status of these genes correlates with response to CAPTEM. Methods: A retrospective cohort of PNET cases seen at Cedars-Sinai Medical Center or from Perthera’s Real-World Evidence Database included 23 patients who were treated with CAPTEM in 1st or 2nd line and had targeted next-generation sequencing (NGS) of their tumors available. Genomic alterations were correlated with progression-free survival (PFS) using multivariate Cox regression analysis. Results: We analyzed 23 PNET patients, 4 (17.4%) of whom had documented functional tumors. We identified MEN1 mutations as positively associated with CAPTEM response, but this effect was less pronounced for the subset with co-occurring DAXX mutations, which are commonly found alongside MEN1 alterations. With and without accounting for line of therapy, we found that PFS on CAPTEM was significantly longer in MEN1-mutated, DAXX-wildtype tumors compared to other mutation profiles ( P < 0.01, see Table). ATRX (67%) and PTEN (33%) alterations were also enriched in the MEN1-mutated/ DAXX-wildtype subset; however, other PI3K/AKT/mTOR alterations were common across all MEN1-mutated cases. Conclusions: We describe a novel genomic signature ( MEN1 mut/ DAXX wt) that correlates with PNET response to CAPTEM therapy and is exploratory in nature. Prospective validation of these associations is warranted while taking into account other therapies, histopathologic factors, and other genomic correlates. [Table: see text]
REGOMUNE: Phase II study of regorafenib plus avelumab in solid tumors—Results of the gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Portales Fabienne , Hollebecque Antoine , Metges Jean Philippe , Cassier Philippe Alexandre , Gomez-Roca Carlos A. , Bouteiller Fanny , Kind Michèle , Palussière Jean , Pernot Simon , Soubeyran Isabelle , Bessede Alban , Italiano Antoine
Published: June 2022

4125

Background: There is no standard treatment for patients (pts) with advanced extra-pulmonary neuroendocrine tumors (NET) and carcinomas (NEC) after failure of chemotherapy in the metastatic setting. PD-1/PD-L1 expression is frequent in these tumors. Combining anti-PD1/PDL1 agents with anti-angiogenics has been shown to be synergistic in several tumor models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in pts with advanced or metastatic grade 2 or 3 (G2/3) gastroenteropancreatic (GEP)-NET or GEP-NEC. The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between May 2019 and Apr. 2021, 46 pts were enrolled in 6 centers. Median age was 63 (range 31 – 80). 10 pts presented with a NEC and 36 pts with a G2/3 NET. Median follow-up was 6.5 months (95% CI: 5.3 - 9.6). Median number of previous treatment lines was: 2 (range 0 – 8). 39 (84.8%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were : Hypertension (13% of pts), fatigue (13%), and diarrhea (11%). One death was related to the treatment. Among the 42 assessable pts, 7 (16.7%) achieved a partial response: 6 pts with a G2/3 NET and 1 patient with a NEC. 22 (52.4%) pts demonstrated stable disease, 22 (52.4%) pts had tumor shrinkage and 10 (23.8%) pts had progressive disease. 3 (7.1%) pts were inevaluable as per RECIST. The median duration of response was 15.5 months (95%CI: 3.7 - not reached (NR)). The median PFS and OS were 5.5 months (95% CI: 3.6 – 9.2) and NR respectively. One year OS rate was 69.4 % (95% CI: 45.1 % – 84.5 %). Conclusions: REGOMUNE is the largest prospective study ever conducted in pts with grade 2/3 GEP-NET or GEP-NEC refractory to cytotoxic chemotherapy. The R+A combination has significant clinical activity in pts with refractory disease. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
Targeted alpha-emitter therapy with 212Pb-DOTAMTATE in neuroendocrine tumor subjects who progressed following prior 177Lu/90Y-PRRT.
Authors: Delpassand Ebrahim , Esfandiari Rouzbeh , Tworowska Izabela , Torgue Julien , Hurt Jason Daniel , Nunez Rodolfo
Published: June 2022

4128

Background: Targeted Alpha-Emitter Therapy (TAT) with 212Pb-DOTAMTATE has been shown to be safe and effective in subjects with neuroendocrine tumors (NET) who have not received previous PRRT, however, data is lacking for the use of TAT once progression occurs. Herein, we present the safety and efficacy of 212Pb-DOTAMTATE in subjects with recurrent NETs following prior 177Lu/90Y-PRRT. Methods: Subjects with biopsy-proven unresectable or metastatic SSTR expressing NETs from different primary sites with at least one measurable lesion who had received progressed after receiving prior PRRT were enrolled and received up to four 8-week cycles of 212Pb-DOTAMTATE at 67.6 μCi/kg/cycle. Response to treatment was measured per RECIST 1.1 criteria and by 68Ga/64Cu-DOTATATE PET/CT. Safety parameters were also obtained. Results: A total of 11 PRRT subjects were enrolled regardless of primary tumor location (pancreas (4), small bowel (3), midgut (1), ileum (1), thymus (1), and lung (1)). 8/11 subjects (73%) completed all four cycles. The mean cumulative dose was 20.9 mCi. As of January 2022, an objective radiological response (ORR) was demonstrated in 30% of evaluable subjects (1CR, 2PR, and 7 SD). In addition, 70% (7/10) evaluable subjects demonstrated a response per 68Ga/64Cu-DOTATATE PET/CT SSTR imaging. One hundred forty-five AEs were reported, with Grade 1 (79%). There were 23 (16%) Grade 2 AEs and 5 (3%) Grade 3/ 4 AEs. Of the AEs reported, 84 (58%) were considered possibly related, and 61 (42%) were considered not related or unlikely related. The most frequent AEs (reported in ≥ 4 subjects) include: alopecia (100%), fatigue (100%), nausea (91%), anemia (36%), alanine aminotransferase increased (36%), aspartate aminotransferase increased (36%) and lymphopenia (46%). Three SAEs were reported (achalasia, asthma exacerbation, and septic shock) one of which resulted in the death of the subject (septic shock). No SAEs were considered related to study drug. Conclusions: This is the first clinical trial of 212Pb-targeted alpha-emitter therapy in subjects with NETs who progressed following prior PRRT. The use of 212Pb-DOTAMTATE in the recurrent setting is highly effective with manageable toxicity and warrants further investigation. Clinical trial information: NCT03466216.
Do we need postoperative chemotherapy after preoperative FOLFIRINOX in resected borderline or locally advanced pancreatic cancer? A retrospective analysis.
Authors: Mari Roxane , Garnier Jonathan , Lapeyre-Prost Alexandra , Rochigneux Philippe , Dahel Yanis , Caillol Fabrice , Giovannini Marc , Turrini Olivier , Mitry Emmanuel , Chanez Brice
Published: June 2022

4150

Background: Pancreatic ductal adenocarcinoma (PDAC) has poor outcome and surgical resection remains the only curative treatment. Post-operative (Post-Op) chemotherapy (CT) improves survival and FOLFIRINOX (FFX) regimen is the standard of care. Increasing number of patients with borderline resectable (BL) or locally advanced (LA) disease are treated with pre-operative (Pre-Op) CT with FFX. However, the benefit of Post-Op CT after Pre-Op FFX remains unclear. The aim of this study was to analyze the impact on survival of Post-Op CT in patients with resected BL or LA PDAC after Pre-Op FFX CT. Methods: 116 consecutive patients treated at the Institut Paoli-Calmettes comprehensive cancer center between 2014 and 2020 were retrospectively analyzed. All patients underwent pancreatectomy after Pre-Op FFX for a BL or LA PDAC. Patients who progressed or died within 3 months after surgery were excluded from the analysis. We compared median relapse-free survival (mRFS) and median overall survival (mOS) defined by time from surgery to relapse or death in patients who received or not Post-Op CT. Results: 116 patients (80% BL, 20% LA) were included: 82 received Post-Op CT (CT+) and 34 did not (CT-). The median number of Pre-Op FFX cycles was 4 in the CT+ group vs 6 in the CT- group. 24 (29.3%) patients received Post-Op FFX, 37 (45.1%) received Gemcitabine, 9 (11%) received Gemcitabine + Capecitabine, and 9 (11%) received a 5FU-based CT. Median time between surgery and first Post-Op CT cycle was 63 days. No difference in mRFS nor in mOS were found between CT+ and CT- groups: mRFS 15.0 vs 13.6 months, HR 1.1 [IC95% 0.69–1.77] and mOS 33.8 vs 36.1 months, HR 0.94 [IC95% 0.55–1.60]. Among patients with pathologic node positive disease (N+) (n = 79), mRFS was 13.9 months in the CT+ group vs 6.9 months in the CT- group (HR 0.68 [IC 0.35 – 1.19]), and mOS was 31.8 months in the CT+ group vs 16.5 months in the CT- group (HR 0.96 [IC95% 0.51-1.81]). Patients who received peri-operative (Peri-Op) FFX (n = 24) experienced longer mOS compared to patients who received Gemcitabine Post-Op CT: NR vs 33.8 months, HR 0.45 [IC95% 0.25-1.02]. Patients who received Peri-Op CT for a total of six months or more (n = 31) had increased mOS (55 vs 32 months, HR 0.61 [IC 95% 0.37- 1.11] and mRFS (16 vs 14 months HR 0.80, [IC95% 0.50 -1.31]) than patients receiving less than 6 months Peri-Op CT (n = 85) Conclusions: Post-Op CT does not clearly impact survival in BL or LA pancreatic cancer pretreated with Pre-Op FFX. We observed a trend in the N+ population for a survival benefit. Peri-Op FFX was associated with longer survival than Gemcitabine Post-Op regimen. Further randomized data are needed to assess the impact of Peri-Op FFX for these patients
Cross-trial validation of molecular subtypes in patients with metastatic clear cell renal cell carcinoma (RCC): The JAVELIN Renal 101 experience.
Authors: Saliby Renee Maria , Jammihal Tejas , Labaki Chris , Xie Wanling , Motzer Robert J. , Powles Thomas , Rini Brian I. , Albiges Laurence , Pal Sumanta K. , McKay Rana R. , Signoretti Sabina , Shukla Sachet A. , Van Allen Eliezer Mendel , Braun David A. , Choueiri Toni K.
Published: June 2022

4531

Background: Vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (IO) combinations are a standard in mRCC. Molecular clusters of patients have been identified and correlated with outcomes in the phase 3 IMmotion151 (IM151) trial of atezolizumab + bevacizumab (IO+VEGF) vs. sunitinib (Sun) (Motzer, Cancer Cell 2020 & JAMA Oncol 2021). Avelumab+axitinib (AA) is an approved IO+VEGF combination in mRCC. This work aims to evaluate these clusters in patients from the phase 3 JAVELIN Renal 101 (JR101; NCT02684006 ) trial of AA vs. Sun. Methods: Bulk RNA-sequencing of primary and metastatic samples and clinical data (data cutoff: 28 January 2019) from JR101 were obtained. A random forest model designed to predict molecular clusters based on transcriptomic data was trained on the IM151 dataset. Using this model, patients from JR101 study were categorized into previously defined molecular subgroups. We then evaluated treatment outcomes including progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) from JR101 in relation to molecular subgroups. Results: The proportion of patients in each molecular subtype and across MSKCC risk groups were largely comparable between the 2 trials (accuracy: 81.6%; p=0.2). AA was generally superior to Sun. for PFS and ORR across all molecular subsets, including angiogenic and immune-based clusters (Table). Combining immune and/or cell cycle-enriched clusters 4+5 resulted in improved PFS (HR: 0.65; 95% CI: 0.44-0.97) for AA vs. Sun. Conclusions: We were able to largely validate the molecular clusters classification and some of the associations with survival outcomes from IM151 in the JR101 clinical trial cohort. Biomarkers of specific VEGF+IO combinations in mRCC should be prospectively validated in randomized trials. [Table: see text]
First-line therapy for elderly patients with advanced renal cell carcinoma (aRCC): A systemic review and network meta-analysis.
Authors: Fujiwara Yu , Miyashita Hirotaka , Liaw Bobby Chi-Hung
Published: June 2022

4532

Background: Multiple regimens incorporating tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI), either alone or in combination, confer a significant OS benefit in 1L metastatic clear cell RCC. However, guidance for optimal treatment selection in elderly patients remains limited. A network meta-analysis (NMA) was performed to compare the efficacy of 1L treatments for elderly patients with aRCC. Methods: Database search was performed through Pubmed, Embase, Web of Science, and Scopus. Eligible studies were randomized controlled trials (RCTs) evaluating first-line regimens for patients with aRCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Indirect comparisons of available regimens were estimated using a random-effects NMA. Results: 14 RCTs with more than 2,100 patients and 5 RCTs with 1,529 patients were eligible for PFS and OS analyses, respectively. Compared with sunitinib (Sun), the pembrolizumab (Pem) + axitinib (Axi) (HR 0.68, 95% CI 0.48-0.97) and Pem + lenvatinib (Len) (HR 0.61, 95% CI 0.4-0.94) regimens were associated with significantly improved OS. In comparing the TKI-ICI combinations with dual ICI nivolumab (Niv) + ipilimumab (Ipi), no significant OS differences were observed (Pem + Len: HR 0.71, 95% CI 0.40-1.27; Pem + Axi: HR 0.79, 95% CI 0.47-1.34; Avelumab (Ave) + Axi: HR 1.03, 95% CI 0.58-1.85; Niv + cabozantinib [Cab]: HR 1.03, 95% CI 0.57-1.93, using Niv + Ipi as a reference). Pem + Len, Niv + Cab, Pem + Axi, and Cab alone each showed improved PFS over Sun (Table). Among these, Pem + Len showed a PFS advantage compared to Pem + Axi (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared with the other regimens (vs Niv + Cab: HR 0.63, 95% CI 0.39-1.03; vs Cab alone: HR 0.84, 95% CI 0.40-1.77). Conclusions: Pem + Len and Pem + Axi provided the largest OS benefit in elderly patients for 1L aRCC. Pem + Len showed improved PFS compared with Pem + Axi, but no difference compared with Niv + Cab or Cab alone. Further validation using real-world data is needed to confirm the efficacy and safety of first-line regimens for the geriatric population with aRCC.[Table: see text]
Prognostic value of the lung immune prognostic index in patients with untreated advanced renal cell carcinoma (aRCC) receiving nivolumab plus ipilimumab (N+I) or sunitinib (SUN) in the CheckMate 214 trial.
Authors: Carril-Ajuria Lucia , Motzer Robert J. , Tannir Nizar M. , McDermott David F. , Hammers Hans J. , Plimack Elizabeth R. , Donskov Frede , Rini Brian I. , Jiang Ruiyun , Lee Chung-Wei , Desilva Heshani , Albiges Laurence
Published: June 2022

4538

Background: The Lung Immune Prognostic Index (LIPI), defined by lactate dehydrogenase (LDH) and derived neutrophil to lymphocyte ratio (dNLR), has been shown to correlate with outcomes of immune checkpoint inhibitor therapy in patients (pts) with lung and other cancers, including pts with previously treated aRCC receiving nivolumab in the phase 2 NIVOREN GETUG-AFU 26 trial. We report an analysis of LIPI in pts with previously untreated aRCC receiving N+I or SUN in the randomized phase 3 CheckMate 214 trial with 5 years minimum follow-up. Methods: Data were used from CheckMate 214 comparing N+I (N 3 mg/kg + I 1 mg/kg) vs SUN (50 mg) for untreated aRCC (N = 1096). Pts with available LIPI data were categorized into 3 LIPI groups (good [LG], dNLR ≤ 3 and LDH ≤ upper limit of normal [ULN]); intermediate [LI], dNLR > 3 or LDH > ULN; and poor [LP], dNLR > 3 and LDH > ULN). This analysis focused on the prognostic value of LIPI using overall survival (OS) outcomes. Univariable analyses (UVAs) were conducted to evaluate LIPI groups alongside known risk factors including age, sex, IMDC risk, baseline PD-L1 status, prior nephrectomy, and baseline tumor burden. Variables that were statistically significant in UVAs ( P < 0.1) were included in the full multivariable analyses (MVAs), from which a reduced model was generated. Results: A total of 1085 pts were evaluable for LIPI (N+I, n = 542; SUN, n = 543). Pts were distributed evenly between treatment arms for all 3 LIPI groups, but distribution between LIPI groups was unbalanced, with most pts grouped as LG (Table). OS outcomes were improved with N+I over SUN across all LIPI groups. Moreover, pts in the LG group had better OS outcomes vs pts in the LI or LP groups regardless of treatment, but with more distinct differences between LIPI groups in the SUN arm (Table). Final MVA results showed the LIPI correlated with OS for LI vs LG in the N+I arm and for LI vs LG and LP vs LG in the SUN arm (Table). Conclusions: These results from CheckMate 214 indicate the potential prognostic value of the LIPI in pts with untreated aRCC receiving N+I or SUN. Additional analyses are ongoing to further investigate the prognostic value of LIPI in this pt population and its impact on other clinical outcomes. Clinical trial information: NCT02231749. [Table: see text]
Racial differences in treatment patterns and outcomes of first-line (1L) therapies for advanced renal cell carcinoma (aRCC) in the real-world (RW) setting.
Authors: Geynisman Daniel M. , Kish Jonathan K. , Falkenstein Angelica , Huo Stephen , Del Tejo Viviana , Rosenblatt Lisa , Guttenplan Sarah , Balanean Alexandrina , Feinberg Bruce A.
Published: June 2022

4548

Background: In 1L therapy for aRCC, nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) have demonstrated significantly improved clinical outcomes versus sunitinib in phase III trials. African American/Black (AA) patients are grossly underrepresented in all aRCC trials. Little is known about the impact of racial differences on the use of 1L therapies and clinical outcomes in the RW setting. Methods: This retrospective chart review included AA and White American (WA) patients diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) intermediate/poor (I/P)-risk aRCC who initiated on 1L NIVO+IPI, PEM+AXI, or tyrosine kinase inhibitor (TKI) monotherapy with sunitinib, pazopanib, or cabozantinib. Patients’ demographic/clinical characteristics and outcomes were abstracted from medical charts by treating oncologists. Use of 1L therapy, treatment discontinuation, and clinical outcomes including disease response, landmark progression-free survival (PFS), landmark overall survival (OS), and treatment-related adverse event (TRAE) rates were assessed descriptively by race. Results: Of 473 patients, 95 (20.1%) were AA, and 378 (79.9%) were WA patients. Median follow-up was 10.9 months. A higher proportion of AA vs. WA patients had received 1L TKI monotherapy (21.1% vs. 16.1%). Treatment discontinuation rate was higher in AA vs. WA patients (49.5% vs. 43.4%). Treatment response was lower in AA than WA patients (overall response rate [ORR]: 58.8% vs. 74.8%; complete response [CR]: 8.2% vs. 11.4%). The TRAE rate was slightly lower in AA vs. WA patients (25.3% vs. 32.5%). Stratified clinical outcomes including landmark PFS and OS rates at 6 and 9 months are shown in the Table. Conclusions: In this RW I/P-risk aRCC cohort, fewer AA patients were treated with standard of care immune-oncology (IO)-based therapy vs. WA patients, which may contribute to differences in therapy discontinuation and survival outcomes. Also, even with short follow-up, clinically meaningful ORR differences are noted in AA and WA patients. [Table: see text]
Association of antibiotic therapy and treatment efficacy in patients with renal cell carcinoma receiving immune checkpoint inhibitors.
Authors: Braun Avery , Deng Mengying , Handorf Elizabeth A. , Abbosh Philip
Published: June 2022

4556

Background: There is growing evidence indicating that gut microbiome content is associated with the effectiveness of immune checkpoint inhibitory (ICI) therapy in various cancer types. Antibiotic therapy (ABT) induces significant changes in gut microbiota; however, the effects of ABT on oncologic outcomes with ICI therapy has only been explored in small, single-institution studies. We aimed to investigate the relationship between ABT on overall survival (OS) and real-world progression free survival (rwPFS) in subjects with advanced renal cell carcinoma (RCC) treated with ICI utilizing a national database. Methods: We queried the nationwide electronic health record (EHR)-derived de-identified FlatIron Health (FIH) database after Institutional Review Board approval was obtained and included a waiver of informed consent to select 1809 subjects who received ICI therapy. Patient characteristics were described and compared between those with known ABT use and without known ABT use (in the 3 months pre/post ICI initiation) using ANOVA and Chi-square tests. rwPFS and OS were calculated from date of initiation of ICI to date of real-world progression/date of death. Three-month landmark Kaplan Meier and log-rank tests were used to compare rwPFS and OS between groups defined by ABT use (any ABT, and ABT in 3 months pre-ICI vs 3 months post-ICI initiation). Cox proportional models were used to investigate the association between rwPFS, OS, and antibiotic use, adjusting for patient characteristics. Results: Patients receiving ABT group were younger (p = 0.007) and more likely female (p = 0.024) but similar in other measured demographic variables. rwPFS (median: 9.03 vs 11.6 months; p = 0.015) and OS (median: 23.7 vs 31.8 months; p = 0.019) were significantly shorter in the with-ABT group than in the without-ABT group. When assessing ABT use 3 months prior to initiation of ICI (vs ABT during/no known ABT use), neither rwPFS (median: 9.53 vs 11.66, p = 0.38) nor OS (median: 23.7 vs 22.6 months; p = 0.38) were significantly different. However, rwPFS (median: 23.5 vs 14.0 months vs not reached; p = 0.004) and OS (median: 36.2 vs 22.5 vs 31.8; p = 0.007) were statistically significantly different when stratifying based on exposure and timing of ABT amongst pre-ICI initiation ABT, post-ICI initiation ABT and no ABT groups, respectively. Multivariable analysis identified as a significant predictor of rwPFS (HR = 0.725, CI = 0.579-0.908; p =.005) and OS (HR = 0.722, CI = 0.573-0.911; p = 0.006). Conclusions: This study identifies a significant negative prognostic association of ABT administration on survival in advanced RCC treated by ICI in the first line setting. These results are consistent with the growing body of evidence suggesting that alterations in gut microbiome secondary to antibiotics appear to blunt efficacy of ICI treatment and emphasize the importance of antibiotic stewardship.
Maturation of overall survival (OS) in TIVO-3 with long-term follow-up.
Authors: Rini Brian I. , Pal Sumanta K. , Escudier Bernard , Atkins Michael B. , McDermott David F. , Verzoni Elena , Porta Camillo , Kasturi Vijay , Hutson Thomas E.
Published: June 2022

4557

Background: Maturity of survival data is a consideration in the value assessment and confident clinical application of oncology drugs based on trial evidence. TIVO-3 supported FDA-approval of tivozanib (TIVO) in relapsed/refractory (R/R) advanced RCC, meeting the primary endpoint of significantly improved PFS over sorafenib (SOR) (HR: 0.73, 95% CI, 0.56-0.95). Long-term follow-up analyses demonstrate that the PFS rate at 3-years with TIVO is >5x higher than with SOR (12% vs 2%, respectively), yet a significant OS benefit for TIVO has not been observed to date. Here we report the contribution of event accumulation and data maturation on the stability of KM survival estimates. Methods: Intent-to-treat analyses of Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for OS in the TIVO-3 trial at prespecified (2-years after last-patient-in [LPI]; ≥251 events) and exploratory extended follow-up timepoints (≥270 events; database closure). Patients were followed for survival until death, consent withdrawal, or loss to follow-up. Results: 350 patients were randomized 1:1 to TIVO (n=175) or SOR (n=175). 2-years post LPI and a mean follow-up of 17.9 months (data cut-off August 2019), 65% of patients experienced an event (HR: 0.99, 95% CI, 0.76-1.29). Subsequent analyses are reported at 20.3 (May 2020), 21.9 (January 2021), and 22.8 (May 2021) months follow-up. Accumulation of events and HR over time is shown in the Table. After almost 23 months of follow-up and realization of 80% of events, OS HR has decreased to below 0.90, in favor of TIVO. Conclusions: Serial OS analyses using KM estimates are subject to increased curve reliability with decreased censoring and limited residual patients at risk for death. Long-term follow-up of TIVO-3 suggests early and consistent PFS benefit with TIVO over SOR is associated with an OS HR decline over-time with more events. Clinical trial information: NCT02627963. [Table: see text]
Prognostic impact of bone metastasis in patients with metastatic urothelial carcinoma (mUC) treated with durvalumab (D) with or without tremelimumab (T) in the DANUBE study.
Authors: Stecca Carlos , Abdeljalil Osama , Lu Cindy , Zhang Han , Goluboff Erik T. , Sridhar Srikala S.
Published: June 2022

4564

Background: In mUC, bone metastases (BM) are associated with significant morbidity and mortality, but their independent impact on outcomes is not well established, especially in the current era of immune checkpoint inhibitors (ICIs). This post-hoc analysis assessed the impact of BM, as well as PD-L1 status (within the same BM category) on outcomes of patients with mUC treated with ICIs. Data was derived from the Phase 3 DANUBE study, which compared D, D+T, and standard chemotherapy (SoC). Methods: Patient characteristics, disease characteristics, treatments, and outcomes were collected. Patients were categorized as having BM or no BM. Outcomes included median overall survival (OS) and median progression-free survival (PFS) (in months [mo]), estimated by the Kaplan-Meier method. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay. Results: Overall, 1032 patients were included; 266 had BM (D, 80; D+T, 97; SoC, 89), and 766 had no BM (D, 262; D+T, 249; SoC, 255). Among all patients, those with BM had a lower OS than those with no BM (HR, 1.67; 95% CI, 1.43-1.92; nominal P< 0.0001) when controlling for cisplatin eligibility, PD-L1 expression, presence of visceral metastases, and treatment. Similarly, patients with BM had lower PFS compared to those without BM (HR, 1.52; 95% CI, 1.30-1.75; nominal P< 0.0001) Within each treatment arm, median OS was lower for patients with BM compared to patients with no BM for all patients, regardless of PD-L1 status (Table). Patients with BM and PD-L1–high expression, treated with either D or D+T, had numerically higher median OS compared to those with PD-L1 low; this difference was also seen in patients with no BM. In contrast, there was no difference in median OS, for BM or no BM, based on PD-L1 expression for patients treated with SoC (Table). Conclusions: In this post-hoc analysis, presence of BM was significantly and consistently associated with worse outcomes in patients with mUC across all treatment arms of the DANUBE study. PD-L1–high expression was associated with higher median OS in patients treated with D or D+T, regardless of presence of BM. These data reinforce the negative prognostic impact of BM in mUC and the role for PD-L1 expression in predicting benefit for patients treated with ICIs. Funding: AstraZeneca. Clinical trial information: NCT02516241. [Table: see text]
CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).
Authors: Li Roger , Steinberg Gary D. , Uchio Edward M. , Lamm Donald L. , Shah Paras , Kamat Ashish M. , Bivalacqua Trinity , Packiam Vignesh T. , Chisamore Michael Jon , McAdory John , Grandi Paola , Hnat Nataliya , Burke James
Published: June 2022

4597

Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.
Chromosomal instability (CIN) in circulating tumor cells (CTC) predicts for taxane sensitivity in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Keegan Niamh M. , Arfe Andrea , Barnett Ethan , Cohn Erica Dayan , Zhao Jimmy , Carbone Emily , Zanone Michelle , Anderson Amanda , Wenstrup Rick , Scher Howard I.
Published: June 2022

5026

Background: Few clinically validated biomarkers can inform therapy (tx) sequencing in mCRPC. Previously, we credentialed a biomarker of CIN in individual CTCs using phenotypic identification of cells with ≥9 large scale transitions (LSTs) and classification of CIN as high when detected in ≥3 CTC/mL (CIN3+). CIN3+ was associated with shorter radiographic progression survival (rPFS) and overall survival (OS) following taxane (T) or androgen receptor signaling inhibitor (ARSi) tx in mCRPC. Similarly, high CIN defined as ≥1 CTC/mL with ≥9 LSTs (CIN1+) predicts worse rPFS and OS following ARSi. Here, we explored if CIN1+ or CIN3+ predicted differential outcomes in pts on-tx with T or ARSi for mCRPC. Methods: We analyzed 208 banked CTC samples from 173 mCRPC pts collected within 30 days prior to starting a new tx with either T (n=88) or ARSi (n=120) in 2012-2017. CTCs were detected using Epic Sciences platform and CIN defined using the phenotypic classifier (PMID 32816908). Retrospective clinical annotation was completed for OS, defined as time from index tx start date to death, and rPFS, defined as index date to date of new or/and increasing lesion size in on-tx radiology report or death. Associations with rPFS and OS were studied according to samples’ CIN1+ and CIN3+ status. T vs. ARSi comparisons were adjusted using Cox models that incorporated pre-tx covariates, i.e. prior T or ARSi txs, total CTC count, presence of visceral disease, and prognostic lab values. Results: The median (range) follow-up from tx start to date of death or last follow-up was 7 (5-9) years. There were 53/120 (44%) pts starting ARSi that had prior ARSi txs and 41/88 (46%) pts starting taxane that had prior taxane txs. CTCs were detected in 184 (88%) samples, CIN1+ in 73 (35%; 64% pre-T, 36% pre-ARSi), and CIN3+ in 47 (22%; 60% pre-T,40% pre-ARSi). Compared to CIN1+, model results (Table) suggest that CIN3+ predicts a longer rPFS (p<0.01), and possibly OS (p=0.05), with T therapy. Compared to CIN1-, CIN3- also predicts a longer OS with ARSi therapy (p=0.04). Conclusions: CIN3+ CTC may be a more discriminating predictive biomarker than CIN1+ to help guide selection of T or ARSi tx in pts with mCRPC. Adequately powered prospective studies are planned. [Table: see text]