bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive detection of esophageal carcinoma by integrative analysis of low-pass whole methylome sequencing of plasma cell-free DNA.
Authors: Liu Dan , Jiang Bin , Chen Weizhi , Nie Peiyao , Xie Hongyu , Han Tiancheng , Yang Shunli , Huang Yu S. , Lv Fang , He Shuying , Yang Ying , LI Yulong , Hong Yuanyuan , Yu Jianing ,   Genecast Biotechnology Co.,Ltd., Beijing, China
Published: June 2022

4067

Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect esophageal carcinoma. Methods: Plasma cfDNA sampels from 85 patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 60 cancer patients and 398 healthy individuals and the independent testing cohort includes 25 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =96.25% in the discovery cohort and AUC =91.15% in the independent testing cohort. Under a specificity of 95.29% (CI: 87.64% - 100.00%), sensitivity was 72.00% (CI: 56.00% - 92.00%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect esophageal carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Regional subgroup analysis of the phase 3 TOPAZ-1 study of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC).
Authors: Vogel Arndt , Chen Li-Tzong , He Aiwu Ruth , Kim Jin Won , Chen Ming-Huang , McNamara Mairead Geraldine , Shimizu Satoshi , Gillmore Roopinder , Rey Felipe , Kim Hyosung , Xiong Julia , Makowsky Mallory , Rokutanda Nana , Cohen Gordon , Oh Do-Youn
Published: June 2022

4075

Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of D + GC as first-line treatment for patients (pts) with advanced BTC. D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC (Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Methods: A pre-specified subgroup analysis was performed for efficacy outcomes including OS for pts enrolled in Asia (China, Hong Kong, India, Japan, South Korea, Taiwan, Thailand) or the rest of the world (RoW; Europe [Bulgaria, France, Italy, Poland, Russia, Turkey, United Kingdom], North America [NA; USA], and South America [SA; Argentina, Chile]). Post hoc country level analyses were also performed to better characterize outcomes in different countries and regions. Pts with BTC were randomized 1:1 to D (1500 mg once every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on Days 1 and 8, Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from a Cox proportional hazards model. Results: Pt numbers were balanced across regions (Asia, n=374 [54.6%]; RoW, n=311 [45.4%]). Baseline characteristics were balanced between regions with the exception of modest differences in important pre-defined prognostic factors, including disease status: recurrent disease (Asia 23%; RoW 14.5%), ECOG performance status 1 (Asia 59.1%; RoW 41.2%), and metastatic disease (Asia 89.3%; RoW 82%). In the PBO arm, more pts in Asia received subsequent anti-cancer therapies than pts in RoW (53.6% vs 43.9%). Median duration of follow-up in censored pts was about 2 months (mo) longer in Asia versus RoW (14.8 vs 13.0 mo in D + GC; 13.8 vs 12.1 mo in PBO + GC). Regional level analysis (Table) showed outcomes were similar and approximated the overall population for Asia, Europe, and NA. Grade 3/4 adverse events were similar for Asia (D + GC 78.5%; PBO + GC 78.6%) and RoW (D + GC 72.7%; PBO + GC 76.7%). Conclusions: Despite some regional differences in prognostic characteristics, OS trends favored D + GC versus PBO + GC for pts enrolled in both Asia and RoW, supporting the use of D + GC as a potential new treatment option for all pts with BTC. Country-specific and regional outcomes continue to be explored. Clinical trial information: NCT03875235. [Table: see text]
A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary cancer.
Authors: Shen Jie , Kong Weiwei , Zhu Sihui , Liu Baorui
Published: June 2022

4077

Background: To evaluate anlotinib combined with toripalimab for advanced biliary cancer that failed or without the will of standard first-line treatments. Methods: Open single arm phase II study were conducted, eligible patients (pts) were advanced biliary without the chance of operation and failed or without the will of standard first-line treatments. Pts received anlotinib 12mg po qd in 21-day cycles and toripalimab 240mg i.v. every 3 weeks. The main outcome measure was the objective response rate (ORR) of the target lesions evaluated by researchers based on the RECIST 1.1 standard, the secondary outcome measures were progress free survival (PFS) and treatment-related adverse event (TRAE). Results: As of Jan, 2022, 15 pts were enrolled including 9 the intrahepatic cholangiocarcinoma, 3 hilar Cholangiocarcinoma, and 3 the gall bladder carcinoma. 11 (73.3%) pts failed standard first-line treatments, and 4 pts were without the will of standard first-line treatments. The median follow-up was 254 days and 15 pts were all evaluated. 4PR, 9SD and 2PD were achieved. The ORR and DCR for irradiated target lesions was 26.7% and 86.7%, respectively. PFS for first line treatment was 139 days, and for second line treatment as 171 days. By this strategy, 1 ps was successfully transferred to operation after 3 cycle treatment. TRAEs (all grades) occurred in 14 (93.3%) pts. Grade 3 related AEs were fatigue (13.3%). Grade 1-2 related AEs were white blood cell count decreased (53.3%), hypertension (20.0%), thrombocytopenia (60.0%), fatigue (13.3%), hypothyroidism (6.7%), and fever asthenia (6.7%). Conclusions: The combination of anlotinib and toripalimab were demonstrated promising anti-tumor activity in advanced biliary cancer. Clinical trial information: ChiCTR2000037847.
High atezolizumab antidrug antibody levels are associated with unfavorable clinical outcomes and diminished T cell responses following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Chon Hong Jae , Kim Chan , Yang Hannah , Kim Ilhwan , Kang Beodeul , Kim Hyeyeong , Kim Hyunho , Lee Won Suk , Jung Sanghoon , Lim Ho Yeong , Cheon Jaekyung
Published: June 2022

4105

Background: Systemic administration of humanized monoclonal antibodies can be immunogenic and trigger unwanted anti-drug antibody (ADA) responses. In the IMbrave 150 study, 29.6% of advanced hepatocellular carcinoma (HCC) patients developed atezolizumab ADAs after atezolizumab and bevacizumab (atezo/bev) treatment. ADAs could impair the action of the therapeutic antibody by reduction of serum concentration or neutralization. We determined the clinical and immunological implications of high ADA levels in advanced HCC patients after atezo/bev treatment. Methods: Advanced HCC patients (n = 132) treated with first-line atezo/bev were prospectively enrolled (discovery cohort: 50 from an institute; validation cohort: 82 from four institutes). Serum levels of atezolizumab ADA at baseline and three weeks (C2D1) and atezolizumab concentrations at C2D1 were measured by competitive ELISA. The effects of ADA on T cell immunity were examined by multiplex flow cytometry. Results: Strong ADA (≥ 1000 ng/ml) responses at C2D1 were observed in 17.4% of advanced HCC patients. ADA elevation after atezo/bev at C2D1 was evident in non-responders but not significant in responders. In the discovery cohort, patients with high ADA at C2D1 showed a decreased response rate (ADA-high: 11% and ADA-low: 34%) and shorter progression-free survival (PFS) and overall survival (OS) with atezo/bev compared to those with low ADA levels ( P = 0.004 for PFS; P = 0.009 for OS). In the validation cohort, patients with high ADA at C2D1 showed reduced response rate than those with low ADA (ADA-high: 7% and ADA-low: 29%). PFS and OS were worse in ADA-high group than in ADA-low group ( P = 0.001 for PFS; P < 0.001 for OS). In multivariate Cox regression analysis, the clinical significance of high ADA levels was independently associated with shorter PFS and OS after adjustment for age, sex, ECOG performance status, Child-Pugh score, AFP, macroscopic vascular invasion, extrahepatic spread, and neutrophil-to-lymphocyte ratio (PFS: HR 2.27, P = 0.006; OS: HR 3.04, P = 0.006). The atezolizumab serum concentrations were 29.8% lower in patients with high ADA levels than in ADA-negative patients. Atezolizumab concentration at C2D1 was inversely correlated with ADA levels. Moreover, patients with high ADA lacked CD8+ T cell proliferative responses to atezo/bev treatment. Furthermore, patients with high ADA had decreased secretion of effector cytokines such as IFN-γ and TNF-α from CD8+ T cells compared to those with low ADA. Conclusions: Highly elevated ADA at C2D1 is associated with unfavorable clinical outcomes in advanced HCC patients treated with atezo/bev. High ADA levels were associated with reduced atezolizumab exposure and could limit the drug’s anti-cancer efficacy.
IMMUNIB trial (AIO-HEP-0218/ass): A single-arm, phase II study evaluating safety and efficacy of immunotherapy nivolumab in combination with lenvatinib in advanced-stage hepatocellular carcinoma (HCC).
Authors: Vogel Arndt , Siegler Gabriele Margareta , Siebler Jurgen , Lindig Udo , Schultheiß Michael , Müller Tobias , Simon Henry , Jöckel Christiane , Mueller Daniel Wilhelm , Al-Batran Salah-Eddin , Saborowski Anna , De Toni Enrico N
Published: June 2022

4107

Background: The field of systemic options in HCC therapy has significantly evolved in recent years, and first line options now include sorafenib, lenvatinib and bevacizumab plus atezolizumab. Nivolumab is a recombinant human IgG4 mAb targeting PD-1 with clinically meaningful activity in about 15-20% of HCC patients, but the confirmatory phase III trial Checkmate 459 failed to demonstrate superiority over sorafenib. VEGF signaling is not only a driver of tumor angiogenesis, but also contributes to the formation of an immunosuppressive microenvironment. Combinations of anti-angiogenic multikinase inhibitors, specifically lenvatinib, and PD-1/PD-L1 inhibitors have demonstrated remarkable antitumor activity and manageable toxicity in several tumor types, including HCC. We therefore aimed to evaluate the efficacy of nivolumab in combination with lenvatinib as first line treatment in patients with advanced HCC. Methods: This investigator-initiated single-armed phase II trial (NCT03841201) recruited 50 patients (pts) at 8 sites in Germany between 07/2019 and 05/2021. Primary endpoints were objective response rate (ORR) according to investigator assessed RECIST 1.1 and safety/tolerability. Secondary endpoints included ORR according to iRECIST, time to progression (TTP), progression free survival (PFS) and overall survival (OS). Recruitment of the trial was completed in 05/2021. At the time of analysis, 4 patients remained on treatment. Results: 50 pts (24 BCLC B, 24 BCLC C, 2 not evaluable) were enrolled and received at least one dose of the combination treatment. ORR by RECIST 1.1 was 28% (CR: 6.0%, PR: 22.0%, SD: 46.0%, PD: 12.0%). Median PFS was 9.0 mo (26 events). Median TTP was 11.5 mo (0.69 at 6 mo, 0.45 at 12 mo, 0.36 at 18 mo) and median OS was 27.1 mo (8 events). 45 (91.8%) pts experienced at least one TRAE, of which 29 pts (59.1%) encountered at least one TRAE ≥ grade 3. 17 (34.7%) pts had one or more SAE related to the study medication, whereof 15 pts (30.6%) experienced at least one treatment related SAE ≥ grade 3. Conclusions: No new safety signals were observed for the combination of nivolumab and lenvatinib. Although the study failed to reach its prespecified ORR of at least 40%, the high activity in all efficacy endpoints with a mOS of 27.1 mo supports the further investigation of the combination in HCC. Clinical trial information: NCT03841201.
Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma (aHCC): 3-year follow-up of the phase 2 KEYNOTE-224 study.
Authors: Borbath Ivan , Van Laethem Jean-Luc , Karwal Mark , Verslype Chris , Van Vlierberghe Hans , Kardosh Adel , Bergamo Francesca , Stål Per , Sarker Debashis , Palmer Daniel H. , Edeline Julien , Cattan Stéphane , Kudo Masatoshi , Cheng Ann-Lii , Ogasawara Sadahisa , Siegel Abby B. , Hatogai Ken , Wang Anran , Vogel Arndt
Published: June 2022

4109

Background: Pembrolizumab monotherapy showed durable antitumor activity and a manageable safety profile in patients with sorafenib-treated (cohort 1) and treatment-naive (cohort 2) aHCC in the open-label, phase 2 KEYNOTE-224 (NCT02702414) study. Longer term data from KEYNOTE-224 after ̃3 years of follow-up for patients with treatment-naive aHCC are reported. Methods: Eligible patients in cohort 2 had histologically, cytologically, or radiologically confirmed aHCC, Barcelona Clinic Liver Cancer stage C or B not amenable or refractory to locoregional therapy and not amenable to curative treatment, Child-Pugh A liver function, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (̃2 years). Primary end point was ORR assessed per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS, all assessed per RECIST v1.1 by BICR, OS, and safety/tolerability. Results: All 51 patients enrolled in cohort 2 received ≥1 dose of pembrolizumab. Median follow-up, defined as the time from first dose to the data cutoff (October 1, 2021), was 35 months (range, 31-37). ORR was 16% (95% CI, 7-29). Median DOR was not reached (NR; range, 3 to 24+ months); 58% of responders were estimated to have a response duration ≥18 months. Best overall response was 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; no CRs were observed and response was not evaluable for 2 patients (4%) and not assessed for 3 patients (6%). DCR was 57% (95% CI, 42-71). ORR was generally consistent among patients with a viral and nonviral etiology for HCC, although sample sizes were small. The median TTP was 4 months (95% CI, 3-9). Median PFS was 4 months (95% CI, 2-8). Estimated PFS rate at 24 months was 15%. Median OS was 17 months (95% CI, 8-23). Estimated OS rate at 24 months was 34%. No new or unexpected adverse events (AEs) occurred. Treatment-related AEs were reported in 28 patients (55%; grade 3-5, 8 [16%]). Conclusions: Updated results from cohort 2 of the KEYNOTE-224 study continued to demonstrate durable antitumor activity, promising OS, and manageable safety for pembrolizumab monotherapy in patients with aHCC and no prior systemic therapy. These data, together with recent positive results from KEYNOTE-394, underscore the broad applicability of pembrolizumab in patients with aHCC both as monotherapy and in combination with other therapies. Clinical trial information: NCT02702414.
Early detection of hepatocellular carcinoma using cfDNA signatures from cirrhotic patients with nodules.
Authors: Fan Rong , Chen Lei , Wang Yingchao , Wei Weiwei , Qian Yunsong , Du Lutao , Fan Xiaotang , Yu Yanlong , Jiang Guoqing , Huang Yangqing , Bai Honglian , Gao Yanhang , Wang Chunying , Deng Guohong , Zhang Qingzheng , Wang Chuanxin , Liu Jingfeng , Wang Hongyang , Hou Jinlin
Published: June 2022

4113

Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Early detection of HCC patients is related to favorable survival. Nodules in liver cirrhosis (LC) are at higher risk of developing into HCC. There is an urgent clinical need for development of an accurate and affordable non-invasive method for early HCC diagnosis among LC patients with nodules. Methods: We have previously shown that the genome-wide HIFI (5-Hydroxymethylcytosine/motIf/ Fragmentation/nucleosome footprInt) method held a solid diagnostic value in differentiating HCC from LC. In this study, we leverage this knowledge to diagnose early HCC (BCLC 0/A) in cirrhotic nodules using copy number variation (CNV) to replace 5-Hydroxymethylcytosine to simplify NGS protocol and decrease cost. The updated method generates a score that reflects the presence of tumor-derived cfDNA in 10 ml blood via low coverage (2x) whole-genome sequencing (WGS). We applied it in a retrospective cohort (validation set 1, n = 171) and a prospective cohort (validation set 2, n = 156), both of which involved patients with newly diagnosed early stage HCC (BCLC 0/A) as well as individuals with cirrhotic nodules. Results: The updated method showed excellent performance for early HCC detection both in the validation set 1 (84 HCC and 87 cirrhotic nodules; AUC: 0.951, 82.1% sensitivity at 90.8% specificity) and validation set 2 (71 HCC and 85 cirrhotic nodules; AUC: 0.958, 81.7% sensitivity at 91.8% specificity) (Table). The AUC values for distinguishing early HCC from cirrhotic nodules could reach 0.951 (80.9% sensitivity at 91.0% specificity) and 0.947 (74.7% sensitivity at 92.1% specificity) among patients with AFP < 400 μg/L and those with nodular size < = 2 cm, respectively. More importantly, our model also maintained consistent performance in detecting very early stage HCC (BCLC 0) with AUC of 0.941 (74.7% sensitivity at 91.3% specificity). Conclusions: These findings provide an accurate, affordable, excellent clinical potential model integrating four cfDNA molecular signatures for detecting early stage HCC from cirrhotic nodules using low-coverage WGS of plasma cfDNA samples. [Table: see text]
Socioeconomic factors associated with a late-stage pancreatic cancer diagnosis: An analysis of the national cancer database.
Authors: Gallegos Jillian Marie , Verplancke Kiana , Taylor Alexandra , McMahon Kevin , Silberstein Peter T. , Dahl Mary Elizabeth
Published: June 2022

4135

Background: Pancreatic cancer is an aggressive, lethal cancer that is the 4th leading cause of cancer death in the United States. It is often asymptomatic until later stages, thus it is critical to assess the socioeconomic factors associated with diagnosis at early vs. late stages. Using the National Cancer Database, we aim to identify associations between socioeconomic factors of patients that present with early stage (0-I) pancreatic cancer in comparison to late-stage disease (stage IV) at diagnosis. Methods: In this study, 256,822 patients from the National Cancer Database who were diagnosed with NCDB Analytic Stage Group stage 0-I and stage IV pancreatic cancer were analyzed based on age, race, sex, ethnicity, insurance type, income, geographic location, education and Charlson-Deyo score. Demographic factors of patients that presented with early and late-stage disease were analyzed using chi square and multivariate analysis. All patients included in the study were diagnosed with pancreatic cancer between 2004 and 2018. Results: We identified significant ( P <0.05) associations between race, sex, insurance status, education, income, and geographic location with diagnosis of advanced-stage disease. A greater percentage of males were diagnosed with late-stage cancer than early-stage (52.8% vs 47.9%). Females were more likely to have an earlier-stage diagnosis and were 15% less likely to have late-stage diagnosis than males (p < 0.001 and 95% CI = 0.839-0.875). African Americans were 10% more likely to have a late-stage diagnosis than Caucasians (p < 0.001 and 95% CI = 1.069-1.144). For insurance status, private and Medicaid insurance had higher percentages of late-stage diagnosis than early-stages, and all types of insurance had lower rates of late-stage diagnosis than patients without insurance (p < 0.001). Patients from a zip-code associated with < $38,000 median household income and zip-codes with lower levels of high school diplomas had higher rates of late-stage diagnosis (p < 0.025). Conclusions: Factors associated with increased likelihood of pancreatic cancer presentation at advanced stage compared to early stage include race, sex, insurance status, education, median income, comorbidity score, and geographic location.
Phase I dose escalation and expansion study of defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment-refractory pancreatic cancer.
Authors: wang-gillam Andrea , Lim Kian-Huat , McWilliams Robert R. , Suresh Rama , Lockhart A. Craig , Brown Amberly , Herndon John , Pedersen Katrina Sophia , Tan Benjamin R. , Boice Nicolas , Abdiannia Mina , Gao Feng , Yoon Harry H. , Zhu Mojun , Trikalinos Nikolaos A. , Ratner Lee , Aranha Olivia , Hawkins William G. , Herzog Brett , DeNardo David G.
Published: June 2022

4146

Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.
Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study.
Authors: Pal Sumanta K. , Agarwal Neeraj , Singh Parminder , Necchi Andrea , McGregor Bradley Alexander , Hauke Ralph J. , Powles Thomas , Suárez Cristina , Van Herpen Carla M.L.- , Vaishampayan Ulka N. , Sudhagoni Ramu , Curran Dominic , Andrianova Lana , Loriot Yohann
Published: June 2022

4504

Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors (ICIs). COSMIC-021, a multicenter phase 1b study, is evaluating C + A (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). C + A demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients (pts) with UC previously treated with platinum-containing chemotherapy (chemo) (Pal S et al. ASCO 2020. Abstract 5013). Outcomes of C + A from 3 other UC cohorts (C3, C4, C5) are presented. Methods: Pts with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG PS 0‒1 were eligible. Pts enrolled in C3 and C4 had no prior therapy and were cisplatin-based chemo ineligible (C3) or eligible (C4). C5 enrolled pts with one prior ICI and no prior VEGFR-TKI therapy. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints: safety, duration of response (DOR), PFS, and OS. Results: Thirty pts each were enrolled in C3 and C4, and 31 in C5. Baseline characteristics for C3, C4, and C5, respectively: median age, 74 y, 66 y, 68 y; male, 67%, 73%, 55%; ECOG PS 1, 63%, 57%, 74%; lung/liver metastasis; 33%/17%, 40%/20%, 58%/23%; ≥3 tumor sites, 30%, 43%, 45%; bladder as primary site, 67%, 70%, 71%. As of Nov 30, 2021, the median follow-up for C3, C4, and C5 was 27.9, 19.1, and 32.9 mo, respectively, with 1, 6, and 1 pts on treatment. C + A demonstrated clinical benefit across all cohorts (Table). Most common treatment-related adverse events (TRAEs) of any grade across C3, C4, and C5, respectively, were diarrhea (43%, 33%, 35%), nausea (27%, 17%, 26%), fatigue (27%, 27%, 48%), and decreased appetite (33%, 27%, 39%); grade 3/4 TRAEs occurred in 63%, 43%, and 45%, and there was no grade 5 TRAE. Conclusions: C + A demonstrated encouraging clinical activity with manageable toxicity in inoperable locally advanced/metastatic UC as first-line systemic therapy in cisplatin-based chemo eligible/ineligible pts and as second- or later line in pts who received prior ICI. Clinical trial information: NCT03170960. [Table: see text]
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell (ccRCC) carcinoma who have received front-line treatment (NCT04300140).
Authors: Shah Neil J. , Beckermann Katy , Vogelzang Nicholas J. , Mao Shifeng S. , Ornstein Moshe Chaim , Hammers Hans J. , Gao Xin , McDermott David F. , Haas Naomi B. , Yan Hongxia , Esquibel Vanessa , Rangwala Reshma A. , Campbell Matthew T
Published: June 2022

4511

Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in both VHL-deficient and hypoxic tumor cells and plays a critical role in the metastatic phenotype of ccRCC. Batiraxcept is a recombinant fusion protein containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating highly potent, specific AXL inhibition. Methods: Batiraxcept at doses of 15 and 20 mg/kg, plus cabozantinib 60 mg daily, was evaluated using a 3+3 dose escalation study design. The primary objective was safety; secondary and exploratory objectives included identification of the recommended phase 2 dose (RP2D), overall response rate (ORR), and duration of response (DOR). Correlation of serum soluble AXL (sAXL)/GAS6 with ORR was evaluated. Key eligibility criteria include previously treated (2L+) ccRCC patients; prior treatment with cabozantanib was not allowed. sAXL/GAS6 was evaluated at baseline. Results: Data as of 4-February-2022, Phase 1b enrolled 26 patients, 16 patients treated with 15 mg/kg and 10 patients with 20 mg/kg dose of batiraxcept. Baseline characteristics: median age 60 (40-81); male 22 (85%); median prior line of therapy 1 (1-5); IMDC risk group of favorable 6 (23%); prior VEGF inhibitor 15 (58%); 100% with prior immunotherapy. At median follow up of 4.9 months, 92% (n=24) patients remained on the study. No dose limiting toxicities were observed at either 15 mg/kg or 20 mg/kg dose. Batiraxcept and cabozantinib related adverse events (AEs) occurred in 17 subjects (65%). Most common related AE include decreased appetite 31% (n=8), diarrhea and fatigue 23% (n=6). Grade 3 related AEs occurred in 4 patients (15%) including diarrhea, thromboembolism, hypertension, small bowel obstruction, and thrombocytopenia (n=1, 4% each) being most common. No grade 4 or 5 related AEs were observed. The ORR was 46% (n=12, partial response [PR]; Table). No patients had primary progressive disease. Among the patients who had baseline sAXL/GAS6 ratio of ≥ 2.3, the ORR was 67% (12/18). Regardless of baseline sAXL/GAS6 ratio, 3-month DOR was 100%; and 6-month progression free survival was 79%. Batiraxcept PK levels were similar across both doses and GAS6 levels suppressed through the dosing period. Conclusions: Batiraxcept plus cabozantinib is well tolerated. The RP2D of batiraxcept was identified as 15 mg/kg. Early efficacy signals were observed including 100% DOR at 3 months. Baseline sAXL/GAS6 may serve as a potential biomarker to enrich the population. Clinical trial information: NCT04300140. [Table: see text]
Landscape analysis of urothelial carcinoma (UC) by telomerase reverse transcriptase (TERT) alterations.
Authors: Stewart Tyler F. , Dosset Magalie , Brodskiy Pavel , Xiu Joanne , Rezazadeh Arash , Mar Nataliya , Darabi Sourat , Demeure Michael J. , Barata Pedro C. , Geynisman Daniel M. , Ghatalia Pooja , Joshi Monika , Ramamurthy Chethan , Nabhan Chadi , Heath Elisabeth I. , Carter Hannah , Zanetti Maurizio , McKay Rana R.
Published: June 2022

4524

Background: TERT is a catalytic subunit of telomerase, the unique enzyme that confers immortality to cells and is expressed in >90% of cancer cells. Mutations in the TERT promoter region (pTERTmut) are the most prevalent noncoding mutations in cancer. Recent data suggest pTERTmut are associated with improved outcomes in patients with UC treated with immune checkpoint inhibitors. We evaluated the molecular and immune landscape of UC with and without pTERTmut. Methods: UC tissue samples were analyzed for DNA alterations (NextSeq, 592 Genes; NovaSeq, WES) and mRNA expression (NovaSeq, WTS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). PD-L1 expression was assessed by immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by fragment analysis, IHC and NGS. TMB-H was based on a cut-off of > 10 mut/MB. We compared alterations between samples with and without detected pathogenic pTERTmut. Significance was determined by Mann–Whitney U, X2, and Fischer-Exact and p adjusted for multiple comparisons (q) was < 0.05 using Benjamini-Hochberg. Results: Overall, 1686 UC samples were analyzed, 1166 from primary lesions and 499 from a lymph node or metastatic site. pTERTmut was present in 68% of primary and 61% of metastatic tumors, and correlated with modest increase of TERT expression (1.18 fold, p=0.015). pTERTmut was associated with less frequent alterations in TP53, KMT2D, CCND1, MYC, KEAP1 and less MSI/dMMR. By contrast, pTERTmut was associated with more frequent alterations in ARID1A, TSC1, PIK3CA and TMB-H (all q<0.05). Over 41% of pTERTmut were TMB-H. TERTp mutations were not associated with FGFR alterations. The frequency of co-occurring mutations was similar by specimen site. In evaluating the immune landscape (Table), pTERTmut was associated with higher expression of PD-L1 (IHC, mRNA), PD-L2 (mRNA) and TIM3 (mRNA) in tumors from primary sites (all p and q<0.05), but not in metastatic sites. Investigation of tumor-associated immune cells demonstrated that pTERTmut correlated with higher percentage of M1-macrophages and CD8+ T cells in primary tumors, and was inversely-correlated with NK cells in metastatic sites (all q<0.05). Conclusions: This is the largest analysis looking at the molecular and immune landscape of pTERTmut UC tumors. We observed differential patterns of DNA alterations and tumor immune microenvironment based on pTERTmut status. Further work is needed to understand differences in these molecular cohorts and the association of these data with clinical outcomes. [Table: see text]
Phase II randomized double blind trial of axitinib (Axi) +/- PF-04518600, an OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in metastatic renal cell carcinoma (mRCC).
Authors: Sadeghi Sarmad , Parikh Rahul Atul , Tsao-Wei Denice D. , Groshen Susan G. , Li Ming , Appleman Leonard Joseph , Tagawa Scott T. , Nanus David M. , Molina Ana M. , Kefauver Cheryl , Ornstein Moshe Chaim , Rini Brian I. , Dreicer Robert , Quinn David I. , Lara Primo "Lucky" N.
Published: June 2022

4529

Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P < 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]
Impact of steroid use among patients with renal cell carcinoma (RCC) who develop immune-related adverse events (irAE).
Authors: Zang Peter , Resnick Karen , Larsen Travis , Ye Shirley , Choi April , Yu Xiao , Brady Kevin , Tulpule Varsha , D'souza Anishka , In Gino Kim
Published: June 2022

4530

Background: Immune checkpoint inhibitor (ICI) therapy has become a standard therapy in the treatment of advanced renal cell carcinomas (RCC). This has led to a proportional increase in the frequency of immune related adverse events (irAE), however. While increasing evidence suggests that irAE may be correlated with benefit from ICI, the impact of steroids to mitigate irAE’s remains unclear. Methods: We analyzed records of patients with RCC treated with an ICI at the USC Norris Comprehensive Cancer Center, Keck Hospital of USC, and LAC+USC Hospital from 2015-2021. Statistical analysis was performed using R. The Kaplan-Meier model was used to calculate progression free survival (PFS) and overall survival (OS). A log-rank test was used to determine if differences in PFS/OS were statistically significant. Results: Out of a total 841 cancer patients treated with ICI, 107 RCC patients were identified. The median age was 60 (range 20-91). The two most common represented ethnicities were 48 Hispanic/Latino (44.9%) and 37 Caucasian (34.6%). The patient population include 64 male patients (59.8%) versus 43 female patients (40.2%). Most had metastatic disease (74.8%) versus local disease (25.2%), and most patients (80.4%) received ICI therapy as initial therapy. Only 6 patients (5.6%) were given combination ICI therapy. The three most common systems affected by irAE were endocrine (18.7%), dermatologic (16.8%), and renal (14.0%). Of the irAE that occurred, 21.5% were categorized as CTCAE grade III or higher. The median PFS of the irAE group was 51.8 months (95% CI 10.0 – 51.8) versus 11.2 months (95% CI 2.7 – 13.8) in the no irAE group. The median OS of the irAE group was 55.0 months (95% CI 23.9 – 55.0) versus 15.6 months (95% CI 13.5 – 23.5). The occurrence of irAE was associated with both statistically significantly increased PFS (p = 0.02) and OS (p = 0.007). The median PFS of patients receiving steroids to treat irAE was 6.5 months (95% CI 3.9 – 9.2) compared to 12.5 months (95% CI 10.4 – 12.5) in the group with irAE who did not receive steroids. The use of steroids was associated with statistically significant worse PFS (p = 0.04) and worse OS but not at statistical significance (p = 0.2). Conclusions: The occurrence of irAE was associated with improved PFS and OS in RCC patients treated with ICI. Furthermore, the use of steroids among patients with irAE was associated with worsened PFS, but not OS. Although steroids should still be used as clinically indicated for the management of irAE, clinicians should be judicious as they may blunt tumor response to ICI treatment.
The prognostic value of peripheral blood inflammatory indices early variation in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (Δ-Meet-URO analysis).
Authors: Rebuzzi Sara Elena , Signori Alessio , Buti Sebastiano , Banna Giuseppe Luigi L. , Stellato Marco , Santini Daniele , Basso Umberto , De Giorgi Ugo , Chiellino Silvia , Salfi Alessia , Zucali Paolo Andrea , Masini Cristina , Naglieri Emanuele , Procopio Giuseppe , Milella Michele , Boccardo Francesco , Fratino Lucia , Pipitone Stefania , Porta Camillo , Fornarini Giuseppe ,   Meet-URO: Italian Network For Research In Urologic-Oncology
Published: June 2022

4534

Background: Immunotherapy has improved the treatment landscape of mRCC pts and identifying biomarkers for patients’ selection is clinically needed. Inflammatory indices from peripheral blood showed a prognostic value in different tumors and therapies, including immunotherapy. These biomarkers are inexpensive and readily available in clinical practice. We aimed to assess the prognostic role of the dynamic evaluation of these indices in immunotherapy-naïve pretreated mRCC pts. Methods: The Meet-URO 15 multicentric retrospective study enrolled 571 pretreated mRCC pts receiving nivolumab. The Δ-Meet-URO was a secondary analysis on the early variation through the first four cycles of therapy compared with baseline (difference, delta - Δ) of white blood cells, platelets and inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, platelets x NLR), their comparison with baseline values and correlation with treatment response, overall (OS) and progression-free survival (PFS). The baseline and Δ cut-offs were identified by ROC curves for OS. Results: The analysis was performed on 422 mRCC pts (74% of the entire cohort). Patients with ΔNeutrophils < 730 at 2nd, 3rd and 4th cycles were more responders ( p < 0.001, p = 0.003 and p < 0.001) with longer mPFS (11 vs 6.1 months, p = 0.033) and mOS (46.9 vs 20.8 months, p = 0.046) compared to ΔNeutrophils ≥ 730. There was a significant interaction between baseline and ΔNeutrophils on PFS ( p = 0.047). Pts with baseline neutrophils ≥ 4330/mm3 had longer mPFS when ΔNeutrophils < 730 ( p = 0.002), whilst no difference was observed in those pts with baseline neutrophils < 4330/mm3 according to ΔNeutrophils ( p = 0.46). Similar non-significant trends were observed in mOS. Patients with ΔNLR < 0.5 at 3rd and 4th cycles were more responders ( p = 0.004 and p = 0.001, respectively) with doubled mPFS (12.1 vs 6.4 months, p = 0.007) and mOS (46.9 vs 21.7 months, p = 0.062) compared to ΔNLR ≥ 0.5. No significant interaction between baseline NLR and ΔNLR was observed in PFS and OS, suggesting a similar association between ΔNLR and PFS or OS, regardless of the baseline NLR cut-off of 3.2. The multivariable analyses confirmed all these results. Conclusions: The early assessment of NLR and neutrophils variations during immunotherapy for mRCC pts is a promising, affordable and non-invasive prognostic tool. Prospective and external validation analyses are warranted.
The prognostic role of nephrectomy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with immunotherapy according to the novel prognostic Meet-URO score: Subanalysis of the Meet-URO 15 study.
Authors: Rebuzzi Sara Elena , Signori Alessio , Banna Giuseppe Luigi L. , Buti Sebastiano , Rescigno Pasquale , Gemelli Maria , Panni Stefano , Massari Francesco , Sorarù Mariella , Santoni Matteo , Cortellini Alessio , Prati Veronica , Soto Parra Hector Josè , Atzori Francesco , Di Napoli Marilena , Caffo Orazio , Messina Marco , Morelli Franco , Prati Giuseppe , Fornarini Giuseppe ,   Meet-URO: Italian Network For Research In Urologic-Oncology
Published: June 2022

4535

Background: Most of mRCC pts with favorable and intermediate prognosis, according to the IMDC classification, are offered a nephrectomy. However, in the immunotherapy era, the role of nephrectomy is still unclear. In the Meet-URO 15 study we reported the higher prognostic accuracy of the Meet-URO score compared to the IMDC score, by the addition of the neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases to the IMDC score, identifying five categories with progressively worse prognosis. For this reason, we aimed to explore the prognostic impact of the previous nephrectomy (PN) on mRCC pts receiving immunotherapy and according to the Meet-URO score groups. Methods: The Meet-URO 15 study was a multicentric retrospective analysis on 571 pretreated mRCC pts receiving nivolumab. Univariable analysis of the correlation between PN and overall survival (OS) and multivariate analysis adjusted for IMDC score, therapy line, NLR and metastatic sites were performed. The interaction of PN with the Meet-URO prognostic groups was then evaluated. Results: 503/571 pts (88%) underwent PN. A reduced risk of death (HR = 0.44; 95% CI: 0.32-0.60; p< 0.001) and higher mOS and OS rate were observed in pts with PN than without (mOS: 36 vs 13 monhts; 1-year-OS 72% vs 52% and 2-year-OS 57% vs 24%, respectively). The reduced risk of death for pts who underwent PN was confirmed at the multivariate analysis (HR = 0.69; 95% CI: 0.49-0.97; p= 0.032). The percentage of pts receiving PN progressively reduced through the five Meet-URO prognostic groups (PN: group 1: 98%, group 2: 95%, group 3: 84%, group 4: 79%, group 5: 59%). No significant interaction was observed between the PN and Meet-URO score when all the five groups were considered ( p= 0.17). A significant interaction was observed when the Meet-URO groups 1,2 and 3 were taken together (HR = 0.40; 95% CI: 0.25-0.63; p< 0.001), highlighting the significant protective role of the PN on OS for these three groups. For the Meet-URO groups 4 and 5, the interaction was indeed not significant (HR = 0.81; 95% CI: 0.51-1.30; p= 0.39). Conclusions: PN has a favourable prognostic impact on pretreated mRCC pts receiving immunotherapy. This benefit may be limited to mRCC pts with more favorable diseases as belonging to Meet-URO prognostic groups 1, 2 and 3. Further analysis of the type of PN (i.e., radical vs cytoreductive) is ongoing and confirmatory prospective evaluations are warranted.
Real-world treatment patterns in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC): Costs of tumor reduction procedures and their complications.
Authors: Sundaram Murali , Song Yan , Freimark Jonathan , Berman Richard , Nguyen Ha , Signorovitch James , Jonasch Eric
Published: June 2022

4539

Background: VHL disease is an inherited condition associated with tumors in multiple organs; RCC may affect up to 70% of patients with VHL. Patients often need many tumor reduction procedures (TRP) to manage renal neoplasms. This study evaluated TRP treatment patterns, costs, and complications among patients with VHL-RCC. Methods: Using an algorithm based on VHL manifestations, patients with VHL were identified from the Optum Clinformatics claims database. Patients were then selected with a prior RCC diagnosis. Minimum continuous enrollment of 12 months before and 3 months after first observed RCC diagnosis was required. TRPs for RCC included nephrectomy, renal ablation, and cryotherapy. Time to first TRP from initial observed RCC diagnosis was estimated using Kaplan-Meier analysis. Mean hospitalization costs per TRP type were estimated. Costs associated with TRP complications were estimated via linear regression; the explanatory variable was the presence of a given complication. Short-term complications were evaluated for 4 weeks post-TRP; long-term ones were evaluated over 6 months. Renal function was evaluated using chronic kidney disease (CKD) stages before and after TRPs, using diagnosis codes and eGFR lab values. Results: 160 patients with VHL-RCC were identified; mean follow-up time was 34.1 months. 115 (71.8%) patients incurred ≥1 RCC TRP over their study period. 68.4% had a TRP in the first year after RCC diagnosis and 76.5% had TRPs by year 5. Of the 125 observed TRPs, 97 (77.6%) were nephrectomies and 28 (22.4%) were ablation/cryotherapy. The mean costs for nephrectomy were nominally higher vs. ablation/cryotherapy ($29,313 vs. $18,290). The most common short-term complications were respiratory related (20.8%) and vascular injury/anemia (13.6%). The most common long-term complications were CKD stage 1-5 (24.0%) and end-stage renal disease (chronic dialysis dependence) (4.0%). The most expensive complications were related to impaired renal function: acute renal failure ($21,013 over 4 weeks), CKD ($26,032 over 6 months) and end stage renal disease ($65,338 over 6 months). At baseline, the proportion of patients with a diagnosis of CKD ≥ stage 3 was similar between patients who had TRPs (n = 115) and those who did not have TRPs (n = 45): 24.3% and 24.4%, respectively. After the first TRP, the proportion of patients with CKD ≥ stage 3 increased from 24.3% to 41.7%. Conclusions: Patients with VHL-RCC incur a significant clinical and economic burden related to TRPs for managing their renal tumors. This is in addition to the burden that VHL-RCC patients incur from the management of other VHL tumors. This study underscores the need for novel effective therapies to prevent or delay the recurrence of VHL-related renal neoplasms to mitigate the burden of morbidity and long-term medical management related to VHL.