bluuebunny/crossref_metadata_2025 huggingface dataset:
Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: An international study.
Authors: Casadei-Gardini Andrea , Rimini Margherita , Rimassa Lorenza , Burgio Valentina , Kudo Masatoshi , Tada Toshifumi , Shimose Shigeo , Suda Goki , Yoo Changhoon , Cheon Jaekyng , Pinato David J. James , Scartozzi Mario , Cascinu Stefano
Published: June 2022

4069

Background: Recently, several evidences have suggested that patients with a no-viral hepatocellular carcinoma (HCC) might be less responsive to immunotherapy and more response to Lenvatinib. Methods: The study population derived from prospectively collected retrospectively analyzed data of patients treated with atezolizumab plus bevacizumab (AB) or lenvatinib (L) or sorafenib (S) as first-line treatment for advanced HCC or intermediate HCC deemed not eligible for loco-regional therapies. The overall cohort included Western and Eastern patient populations from 36 centers located in 4 countries(Italy, Japan, Republic of Korea, and United Kingdom) undergoing treatment with L or AB or with S. The primary endpoint was OS of AB versus L; the secondary endpoints were OS of AB versus S. Results: 569 patients received L, 190 patients received AB and 210 received S. In the whole population OS was 17.8 months (95%CI:15.8-43.8) for patients receiving L, and 12.1 months(95%CI:11.1-16.8)for patients treated with AB (HR 0.71; 95% CI:0.50-1.06; p=0.1028); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.65; 95% CI:0.44-0.95; p=0.0268), compared AB. In the population affected by NASH/NAFLD, 254 patients were treated with L and 82 patients were treated with AB. OS was 21.2 months (95% CI:18.4-30.6) for patients receiving L, and 12.2 months (95% CI:10.0-16.8) for patients treated with AB (HR 0.46; 95% CI:0.25-0.88; p = 0.0181); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.46; 95% CI:0.26-0.84; p=0.031),compared AB. In the cohort of no viral and no NASH/NAFLD patients, no statistically significant differences were reported in terms of OS between patients treated with L versus AB. All these results were confirmed following propensity score matching analysis. By comparing patients receiving AB versus S, no significant differences were found in terms of OS in the whole population, in the NASH/NAFLD population and in no viral/no NASH/NAFLD population. Conclusions: The present analysis conducted on a large number of non-viral HCC patients showed for the first time a significant survival benefit from lenvatinib over atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
Patient-reported outcomes from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.
Authors: Sangro Bruno , Galle Peter R , Kelley Robin Kate , Charoentum Chaiyut , De Toni Enrico N , Ostapenko Yuriy , Heo Jeong , Cheng Ann-Lii , Vogel Arndt , Marcovitz Michelle , Abraham Jayne , Patel Nikunj , Negro Alejandra , Abou-Alfa Ghassan K.
Published: June 2022

4074

Background: In the Phase 3 HIMALAYA study (NCT03298451) of patients (pts) receiving first-line treatment for unresectable hepatocellular carcinoma (uHCC), a single priming dose of tremelimumab (T; anti-CTLA-4) plus durvalumab (D; anti-PD-L1) in the STRIDE regimen significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S for OS (Abou-Alfa et al. J Clin Oncol 2022;40[suppl 4]. Abs 379). Methods: A pre-planned secondary objective of HIMALAYA was to assess pt-reported outcomes (PROs) in pts receiving STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]; N=393) or D (1500 mg Q4W; N=389) vs S (400 mg twice daily; N=389). The European Organisation for Research and Treatment of Cancer (EORTC) 30-item Quality of Life (QoL) Questionnaire and the EORTC 18-item HCC QoL questionnaire were used to assess disease-related symptoms, physical functioning (PF), and Global Health Status (GHS)/QoL. Time to deterioration (TTD), defined as time from randomization to first clinically meaningful deterioration (worsening ≥10 points) confirmed at a subsequent visit or death, was assessed in pts with baseline scores ≤90 for symptoms or ≥10 for PF and GHS/QoL. Results: Across treatment arms, compliance rates for PROs were >77% at baseline and >70% overall. Baseline scores were comparable across treatment arms. TTD in fatigue, appetite loss, abdominal pain, PF, and GHS/QoL were significantly longer for both STRIDE and D vs S (Table). TTD in nausea and abdominal swelling were significantly longer for STRIDE vs S. Conclusions: The positive OS outcomes for STRIDE and D in pts receiving first-line treatment for uHCC in HIMALAYA were associated with clinically meaningful, pt-centered benefits, demonstrated by delayed worsening of disease-related symptoms, PF, and GHS/QoL vs S. Median TTD in months (95% CI) in PROs for STRIDE and D vs S. Clinical trial information: NCT03298451. [Table: see text]
Phase 1b results of a multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin +/- CPI-613 as first-line therapy for patients with advanced biliary tract cancer (BilT-04).
Authors: Sahai Vaibhav , Zhen David Bing , Crysler Oxana V. , Beg Shaalan Shaalan , Enzler Thomas , Griffith Kent A. , Zalupski Mark
Published: June 2022

4094

Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Gemcitabine (G) and cisplatin (C) is a standard first-line systemic therapy with a reported overall response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (mo). CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: An investigator-initiated, multi-institutional phase 1b/2 trial is underway across 10 sites in the US investigating the combination of G 1000 mg/m2, C 25 mg/m2 and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m2) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) was to determine the recommended phase 2 dose (RP2D). The primary objective of the ongoing phase 2 portion (n = 48-58 pts; 2:1 randomization with Bayesian control arm) is to determine the best ORR with an alternative hypothesis of 43% (null of 25%); with 80% power and one-sided alpha of 0.05. Secondary objectives include evaluation of progression-free survival (PFS), OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis using tissue, and metabolomic analysis using plasma (pre-, on- and post-treatment). Results: 20 pts were enrolled on phase 1b; median age 65 years (range 43-75), ECOG PS 0/1 (9/11), male/female (11/9), Caucasian (85%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (9/5/3/3), and metastatic/locally advanced stage (15/5). CPI-613 dose level assignments were 1 pt each for (-1) and (1), 2 pts on (2), and 16 pts on (3). Median follow-up was 9.4 mos and median number of cycles was 9. Only 1 pt had dose-limiting toxicity (grade 2 creatinine elevation). RP2D for CPI-613 was 2000 mg/m2. In phase 1b, ORR was 40% (7 PR, 1 CR). Median PFS not estimable (NE) but probability of PFS at 9 months was 68.1% [95% CI, 38.1%-85.8%]. Median OS is 16.3 months [95% CI, 9.1-NE]. One locally advanced pt was resected with pathologic CR. Conclusions: The combination of GCD was well tolerated and demonstrates encouraging efficacy with ORR, PFS and OS in phase 1b. The randomized phase 2 portion of the trial is open and accruing patients. Clinical trial information: NCT04203160.
A multicenter, non-randomized, controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF-Cohort Trial): Analysis of overall survival.
Authors: Yamashita Tatsuya , Kawaguchi Yoshikuni , Kaneko Shuichi , Takayama Tadatoshi , Izumi Namiki , Yamanaka Naoki , Kudo Masatoshi , Shimada Mitsuo , Inomata Masafumi , Baba Hideo , Koike Kazuhiko , Omata Masao , Makuuchi Masatoshi , Matsuyama Yutaka , Kokudo Norihiro , Hasegawa Kiyoshi
Published: June 2022

4095

Background: We conducted a multicenter prospective study (SURF trial) to compare the efficacy of surgery vs. radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC). SURF trial consisted of a randomized controlled trial (SURF-RCT) and a non-randomized prospective observational study (SURF-Cohort), including patients who did not consent to randomization. The initial report of the SURF-Cohort trial showed that recurrence-free survival (RFS) did not differ significantly between patients undergoing surgery and RFA. The focus of the present report was to assess the efficacy for overall survival (OS). Methods: The SURF-Cohort trial was a prospective multicenter study conducted in 49 institutions in Japan. Patients (aged between 29 and 79 years) with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. Before the enrollment, both liver surgeons and hepatologists who perform RFA confirm that all the patients can be treated using both surgery and RFA. The co-primary endpoints were RFS and OS. OS was assessed at 5 years after the last accrual as per the protocol. Inverse probability of treatment weighted (IPTW) analysis was used to balance the characteristics of the groups. This trial is registered in UMIN000001796. Results: During 2009–2015, 782 patients were enrolled. After excluding ineligible patients, the surgery and RFA groups included 382 and 371 patients, respectively. In the surgery group, median platelet count (13.7x104 vs. 11.5x104, P< 0.01) was significantly greater, and the median largest HCC diameter was significantly greater (2.0 cm vs. 1.8 cm, P< 0.01) than in the RFA group. The median (range) follow-up period was 6.8 years in the surgery group and 6.7 years in the RFA group. The IPTW-adjusted OS did not differ significantly between the surgery and RFA groups: the 5-year OS, 79.7% vs. 79.3%; HR 0.98; 95% CI 0.75–1.30; P= 0.906. The analysis after long-term follow-up in the current report showed that RFS was not significantly different between the surgery and RFA groups: the 5-year RFS, 44.6% vs. 39.3%; HR 0.86; 95% CI 0.71–1.06; P= 0.155. Conclusions: SURF-Cohort trial revealed that OS and RFS after the IPTW adjustment were not significantly different between patients undergoing surgery and RFA for early stage HCC (≤ 3 cm and 3 nodules). Clinical trial information: UMIN000001796.
Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma.
Authors: Yang Xu , Lian Baofeng , Li Yiran , Xue Jinnan , Wang Yunchao , Wang Yanyu , Xun Ziyu , Zhang Nan , Sun Huishan , Long Junyu , Song Zhijian , Lu Leilei , Pan Jie , Zhao Lin , Guan Mei , Yang Xiaobo , Mao Yilei , Sang Xinting , Wang Kai , Zhao Hai-Tao
Published: June 2022

4101

Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P<0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P<0.001, HR=0.17, P <0.001) and high clinical benefit (CBR) (OR=8.16, P <0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P<0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.
A descriptive study on the treatment and outcomes of patients with platinum-sensitive, advanced, BRCA- or PALB2-related pancreatic cancer who have progressed on rucaparib.
Authors: Brown Timothy J , O'Hara Mark H. , Teitelbaum Ursina R. , Karasic Thomas Benjamin , Schneider Charles John , Izgur Natallia , Nathanson Katherine L. , Domchek Susan M. , Reiss Kim Anna
Published: June 2022

4131

Background: We recently reported the results of a single arm phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic variant in BRCA1, BRCA2, or PALB2 (NCT 03140670; Reiss, JCO 2021). However, optimal treatment following progression on PARP inhibitors (PARPi) has not been defined. Here, we report a descriptive study of post-progression treatment and outcomes of this patient population. Methods: Patients with advanced pancreatic cancer and germline or somatic BRCA1, BRCA2, or PALB2mutations treated with at least 16 weeks of platinum-based chemotherapy without progression were enrolled and treated with rucaparib until progression or unacceptable toxicity. At the time of progression, patients were treated with physician-choice chemotherapy. Here we evaluate the objective response rates (ORR) by RECIST 1.1. Overall survival (OS) and time to second progression (PFS2) calculated from trial enrollment and progression free survival on chemotherapy (PFS) by regimen were secondary endpoints. Time-to-event was analyzed by the Kaplan-Meier method and censored at date of last clinic visit, with a cutoff date of 12/10/21. Results: The trial enrolled 42 patients; 31 patients had progressed. Of these, 22 received second-line chemotherapy: nine were treated with an oxaliplatin-based regimen, nine were treated with a cisplatin-based regimen, and four were treated with non-platinum regimens. Demographics were balanced between those who received platinum versus non-platinum. All patients who received second-line chemotherapy regimens met the PFS2 endpoint and all but one patient had died at time of data cutoff. No patients had a complete response, five patients had a partial response (PR). By regimen, 1/9 patients treated with cisplatin had a PR, 3/9 treated with oxaliplatin had a PR, and 1/4 patients treated with non-platinum had a PR. OS, PFS2, PFS, and ORR results by regimen are shown in the table. Conclusions: In this small sample of patients with advanced pancreatic cancer with progressive disease on PARPi, chemotherapy retains some activity. Further study to identify predictors of response and/or resistance to post-PARPi treatment are underway. [Table: see text]
Responses to immune checkpoint inhibition among MSI-H pancreatic ductal adenocarcinoma: A multi-institutional case series.
Authors: Coston Tucker , Starr Jason S. , Sonbol Bassam Bassam , Babiker Hani M. , Mahipal Amit , Chakrabarti Sakti , McWilliams Robert R. , Bekaii-Saab Tanios S. , Desai Aakash , Jones Jeremy Clifton , Ma Wen Wee
Published: June 2022

4145

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence <2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for >5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.
Discrimination of mucinous pancreatic cysts using an enzymatic turnover assay to improve clinical diagnostic accuracy.
Authors: Sheik Daniel , Suresh Vallabh , Byers Kaleb , Rajesh U. Chinna , Caiazza Francesco , Zhu Gina , Craik Charles , Kirkwood Kimberly S. , Davisson V. Jo
Published: June 2022

4151

Background: One impact of medical imaging technology has been an approximately 3-fold increase in the incidental detection of pancreatic cysts during routine clinical examinations. To reduce burden on the healthcare system and patients, clinicians desire accurate classification of pancreatic cysts into benign non-mucinous or potentially malignant, mucinous populations. Using EUS-FNA, fluid from these cysts can provide molecular biomarkers of predictive value. However, current in vitro diagnostics lack the desired sensitivity and specificity for clinicians to accurately stratify patients for risk of pre-malignant cancers. This situation can be improved by introducing new biomarkers and novel assay platforms. An enzymatic biomarker, pepsin C, has shown high accuracy for diagnosing mucinous cysts. The use of enzymatic activity assays is applicable to clinical workflows without disruption of current standards of care. Methods: A pepsin C activity assay using a magnetic bead-based platform was developed, with both fluorescent and surface-enhanced Raman spectroscopy (SERS) readouts. The assay platform utilizes selective peptide substrates, and a dimeric Rhodamine-6G-based dye, which allows ultrasensitive detection and significantly decreases the sample volume requirement for analysis, down to 1 µL of cyst fluid. The dye-labeled substrate is immobilized on magnetic beads and reacted with enzyme-containing samples to produce a quantitative assay signal that is standardized and expressed in true enzyme activity units. Results: While both readouts were quantitative and produced linear standard curves, SERS-based analysis was more robust against established biological matrix effects than fluorescence. Nevertheless, both assay modes successfully differentiated mucinous and non-mucinous cysts in a retrospective cohort of 69 cyst fluid samples. Compared with the standard of care CEA assay, this activity-based assay displays much improved sensitivity in diagnosing mucinous pancreatic cysts (Table). Conclusions: This pepsin c activity assay differentiates between mucinous and non-mucinous cysts better than the CEA assay and provides a quantifiable standardized readout. This work establishes a path to a true rule-out assay enabling clinicians to better stratify patients into low risk vs. potential malignancy thus impacting treatment and monitoring plans. [Table: see text]
Supportive care (SC) utilization for patients with locally advanced pancreatic cancer: Review of the National Cancer Data Base (2004-2018).
Authors: Cann Christopher G , Shen Chan , LaPelusa Michael Brian , Agarwal Rajiv , Cardin Dana Backlund , Eng Cathy
Published: June 2022

4154

Background: Pancreatic cancer is a formidable malignancy, with an estimated 62,000 new cases in 2022 and approximately 50,000 deaths. Five-year overall survival remains low at 11%; 14.4% for locally advanced disease. Nearly one-third of newly diagnosed patients (pts) present with locally advanced pancreatic cancer (LAPC) and only a minority of pts (<25%) are eligible for surgical resection. Given the significant morbidity and mortality associated with LAPC, timely integration of SC into the treatment care plan is vital. Methods: Pts diagnosed with Stage II-III LAPC (2004-2018) recorded in the National Cancer Data Base were included, stratified by stage and use of SC (defined as procedures or therapy provided for palliative intent symptom control) from time of diagnosis throughout the disease trajectory. Analyses included tumor characteristics, demographics, and socioeconomic parameters. Multivariate logistic regressions were performed on three sets of data: Stage II, Stage III, and Stage II/III combined. Results: 158,340 pts were included in the cohort [stage II (70.6%); stage III (29.4%)]. Only a minority of pts (2.9%) received SC treatment despite > 65% of pts receiving care at an academic program; 95% living in or near a metro area, and nearly 60% living < 20 miles of their primary treatment center (p <0.001). Medicare (58%) and private insurance (32.8%) was consistent across both stages and SC use. The table depicts selected significant factors and the respective adjusted odds of receiving SC from the three logistic regressions. Conclusions: Our analysis demonstrates the underutilization of SC in LAPC population over the past decade and potential specific demographic/social areas of unmet need. Future work should focus on practice patterns across cancer centers and the significant impact SC has on both survival and quality of life outcomes for LAPC pts. SC should be an integral component incorporated early on in the care of pancreatic cancer regardless of stage. [Table: see text]
Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Powles Thomas , Sonpavde Guru P. , Loriot Yohann , Duran Ignacio , Lee Jae-Lyun , Matsubara Nobuaki , Vulsteke Christof , Castellano Daniel E. , Mamtani Ronac , Wu Chunzhang , Matsangou Maria , Campbell Mary S. , Petrylak Daniel P.
Published: June 2022

4516

Background: Enfortumab vedotin (EV), an antibody-drug conjugate directed against Nectin-4, demonstrated longer overall survival (OS) and progression-free survival (PFS) in the confirmatory phase 3, randomized, open-label EV-301 trial at the prespecified interim analysis. The longer-term clinical profile of EV is unknown. Data from 12 additional months of follow-up in EV-301 are presented. Methods: In EV-301 (NCT03474107), patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had received a prior platinum-containing chemotherapy and had disease progression during or after PD-1/L1 inhibitor treatment were randomized 1:1 to receive either EV 1.25 mg/kg on Days 1, 8, and 15 of each 28-day cycle or investigator-chosen standard chemotherapy with docetaxel, paclitaxel, or vinflunine. The primary endpoint was OS; secondary endpoints included investigator-assessed PFS per RECIST v1.1, as well as safety and tolerability. Efficacy and safety findings from July 30, 2021, approximately 1 year after the interim analysis (July 15, 2020), are reported. Results: Overall, 608 patients with la/mUC were randomly assigned to EV (n = 301) or chemotherapy (n = 307). As of July 30, 2021, 444 deaths had occurred (EV, n = 207; chemotherapy, n = 237). After a 23.75-month follow-up, median OS was significantly prolonged by 3.97 months with EV compared with chemotherapy (median OS: 12.91 vs 8.94 months, respectively; HR = 0.704 [95% CI: 0.581-0.852], 1-sided P= 0.00015). Additionally, the OS benefit of EV was retained in the majority of prespecified subgroups. PFS also was improved with EV (median 5.55 months) vs chemotherapy (median 3.71 months) (HR = 0.632 [95% CI: 0.525-0.762]; 1-sided P< 0.00001). Rates of treatment-related adverse events (TRAEs; 93.9% vs 91.8%), including serious TRAEs (22.6% vs 23.4%), were comparable between the EV and chemotherapy groups. Rates of grade ≥3 TRAEs were ̃50% in both groups. Conclusions: EV continues to show significant and consistent survival advantage over standard chemotherapy in patients with treatment-experienced la/mUC. No new safety signals were identified. With robust clinical benefit and a tolerable safety profile, EV maintains its place as a standard of care for this aggressive disease. Clinical trial information: NCT03474107.
Association of DNA damage response (DDR) gene mutations (mts) and response to neoadjuvant cisplatin-based chemotherapy (chemo) in muscle-invasive bladder cancer (MIBC) patients (pts) enrolled onto SWOG S1314.
Authors: Iyer Gopa , Tangen Catherine , Sarfaty Michal , Regazzi Ashley Marie , Lee I-Ling C. , Choi Woonyoung , Dinney Colin P.N. , Flaig Thomas W. , Thompson Ian M , McConkey David James , Rosenberg Jonathan E.
Published: June 2022

4522

Background: Neoadjuvant cisplatin-based chemo followed by radical cystectomy (RC) is a standard of care treatment for pts with MIBC. DDR gene mts, including within ERCC2, a DNA helicase implicated in cisplatin sensitivity in MIBC, have been associated with higher pathologic (path) downstaging ( < pT2) and complete response (pT0) at RC and improved overall survival (OS) in retrospective series. S1314 randomized pts to one of 2 chemo regimens (dose dense MVAC or Gem/Cis) followed by RC. We sought to correlate ERCC2 and other DDR gene mts with response and survival in MIBC pts enrolled onto this prospective trial. Methods: Tumor and matched germline DNA from evaluable pts enrolled onto S1314 underwent exon capture sequencing of 505 cancer-associated genes (MSK-IMPACT). Both deleterious (del) mts and any mts in 9 DDR genes (ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, ATM, ATR, RAD51C, FANCC) were correlated with clinical outcomes. The prespecified analyses included the association of mts with < pT2 and pT0 by logistic regression analysis and with progression-free survival (PFS) and OS by Cox proportional hazards regression. Results: 179 patients (median 61 years, 85% male, 87% white, and 87% clinical stage T2) who received >2 cycles of chemo and were evaluable for path response were included in the analysis. The pT0 rate was 28% and < pT2 was 41%. Del mts in ERCC2 were detected in 26 (14%) pts followed by ATM (n = 12, 7%), ATR (n = 3) and BRCA2 (n = 2). ERCC2 mts were associated with statistically significantly higher path responses with a 54% pT0 rate and 62% downstaging rate. Patients with any del mts had higher path response rates (51% pT0, 56% < pT2) and better PFS (Table) with a median follow-up of 53 months. There was a non-significant trend towards improved OS. Conclusions: In pts managed with neoadjuvant chemo and RC on S1314, both ERCC2 mts and del DDR gene mts correlated with pathologic response. Any del DDR gene mt was associated with improved PFS. These results are in line with retrospective analyses displaying a correlation between DDR gene mts and neoadjuvant chemosensitivity in MIBC and support ongoing genomically-informed organ sparing trials.[Table: see text]
Monitoring efficacy of neoadjuvant sunitinib in metastatic renal cell carcinoma using a personalized and tumor informed ctDNA assay.
Authors: Peterson Christine B. , Kalashnikova Ekaterina , Feeney Jordan , Koyen Malashevich Allyson , Sethi Himanshu , Aleshin Alexey , Jonasch Eric
Published: June 2022

4525

Background: Approximately 30% of renal cell carcinoma (RCC) cases present as stage IV at the time of diagnosis. Metastatic RCC (mRCC) is associated with poor outcomes, with a five-year survival rate below 50%. Tools to evaluate the efficacy of novel systemic regimens are needed. Biomarkers like ctDNA can accurately and non-invasively assess molecular residual disease (MRD) in response to therapy and monitor disease status over time to predict disease progression. Here, we aimed to determine the feasibility of performing personalized and tumor-informed ctDNA testing in mRCC patients enrolled on a study integrating systemic therapy with surgical cytoreduction, as well as to measure patient response to sunitinib by assessing ctDNA dynamics. Methods: We analyzed a cohort of 21 mRCC patients with median age of 59.5 (43-76) years who were treated with sunitinib, and had planned cytoreductive nephrectomy during their second cycle of therapy. Baseline and post-first cycle ctDNA levels were measured using a personalized and tumor-informed ctDNA assay (SignateraTM bespoke mPCR NGS assay). Changes in ctDNA levels from baseline to the best response time point were correlated with disease status as assessed by radiological imaging. Results: In this cohort, baseline ctDNA was detected in 81% (17/21) of patients, with higher ctDNA concentrations observed in patients who presented with multiple distant metastases (n = 11) compared to the 10 cases with a single metastatic mass (median 5.8 vs 1.3 mean tumor molecules/mL, not statistically significant). Of those with baseline ctDNA measurement, 12% (2/17) cleared their ctDNA, 24% (4/17) had a decrease in ctDNA, and 59% (10/17) had an increase in ctDNA after 4 weeks of sunitinib. During the course of treatment, patients whose ctDNA concentration increased from baseline were more likely to experience a disease progression (HR: 3.9 95% CI 1.13-13.7; p = 0.032) compared to those whose ctDNA decreased. In addition, higher ctDNA concentration before surgery after initial treatment with sunitinib correlated with shorter time to progression (p = 0.04). Conclusions: Our results demonstrate the feasibility and prognostic value of personalized and tumor-informed ctDNA testing for determining response to systemic therapy in patients with mRCC. Early signs of unfavorable ctDNA kinetics can provide rationale for modification of systemic therapy in order to enhance response. Future work exploring the clinical utility of ctDNA testing in larger mRCC cohorts is warranted.
Estimating clear cell renal cell carcinoma transcriptomic signatures using machine learning and histopathology images.
Authors: Hassanpour Saeed , Tomita Naofumi , Kotecha Ritesh , Lee Chung-Han
Published: June 2022

4533

Background: Gene expression signatures derived from RNA sequencing data have been associated with treatment outcomes for renal cell carcinoma (RCC) patients. Incorporating these RNA biomarkers into clinical practice is promising, yet its real-world applicability is heavily limited as RNA profiling is expensive, time-consuming, and requires specialized expertise for data analysis. In this study, we applied a deep neural network framework to identify the correlation between standard pathology images and underlying RNA signatures using hematoxylin and eosin (H&E) stained formalin-fixed paraffin-embedded (FFPE) whole slides of clear cell kidney tumors from The Cancer Genome Atlas (TCGA). Methods: We collected 496 H&E stained FFPE clear cell RCC whole-slide images and the RNA gene signatures for 496 patients from the TCGA database. We partitioned 496 slides into training (N = 245, 50%), development (N = 49, 10%), and test (N = 202, 40%) sets. We used this dataset to train and evaluate our weakly-supervised deep learning model. The model was iteratively trained using extracted patches from a slide and processed the patches through a convolutional neural network (CNN), pre-trained for the RCC subtypes classification task, to represent features. The features were aggregated and summarized to predict angiogenesis, myeloid infiltration, and adenosine gene signature (AdenoSig) scores. Performance was assessed by computing Pearson’s correlation coefficients. 95% confident intervals (CI) are computed using the Fisher Z transformation. Results: The median angiogenesis score was 6.98 (range: 1.77-8.40), the median myeloid score was 0.54 (range: -4.59-5.96), and the median AdenoSig score was 268.31 (range: -4988.71-7621.57). A total of 202 slides were included in the test set. On this test set, the results of our weakly supervised method achieved a Pearson’s correlation of 0.65 (95% CI: 0.57-0.73), 0.10 (95% CI: -0.04-0.23), and 0.10 (95% CI: -0.04-0.23) with angiogenesis, myeloid, and AdenoSig scores from gold-standard RNA sequencing data, respectively. Conclusions: We proposed using deep learning-based AI techniques to process digitized histopathological images and estimate actionable signatures of angiogenesis, myeloid, and AdenoSig from H&E stained slides. Our model showed promising results for predicting angiogenesis scores compared to myeloid and AdenoSig scores. These results suggest the feasibility of this approach for estimating digital biomarkers from H&E histopathology images and offering a rapid and cost-effective alternative to conventional RNA sequencing.
Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with non-chromophobe RCC (nonchrRCC): Impact of FLCN genomic alteration (GA) status.
Authors: Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Danziger Natalie , Ross Jeffrey S.
Published: June 2022

4550

Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with nonchrRCC. Methods: 109 chrRCC and 5,862 nonchrRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female (37 [34%] vs. 1,817 [31%]) and younger than pts with nonchrRCC (median age 58 vs 62 years, p <.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in the nonchrRCC cases only at 2.3% with 37% of the GA being germline. 1/109 (0.9%) of chrRCC featured a germline FLCN GA. GA/tumor were slightly higher in nonchrRCC vs chrRCC (3.6 vs 2.4; NS). There were no significant differences in gLOH, genomic signatures or ancestry between the groups. GA more frequent in chrRCC included TP53, RB1, PTEN. GA more frequent in the nonchrRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Biomarkers of immune checkpoint inhibitor (ICPI) drug response revealed higher mean TMB, TMB ≥10 mutations/Mb and PBRM1 inactivating mutation frequencies in the nonchrRCC than the chrRCC indicating possible differences in IO drug response. Conclusions: FLCN mutations that are associated with familial incidence of chrRCC are rarely associated with sporadic chrRCC. Sporadic chrRCC has a substantially different genomic profile from nonchrRCC and appears to harbor fewer opportunities for both targeted and immunotherapies. [Table: see text]
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy.
Authors: Pérez-Valderrama Begoña , Powles Thomas , Sridhar Srikala S. , Caserta Claudia , Loriot Yohann , Gupta Shilpa , Bellmunt Joaquim , Sternberg Cora N. , Wang Jing , Costa Nuno , Laliberte Robert J , Di Pietro Alessandra , Park Se Hoon , Grivas Petros
Published: June 2022

4559

Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy. We report exploratory analyses in subgroups defined by response to 1L chemotherapy (complete response [CR], partial response [PR], or stable disease [SD]) after ≥2 years of follow-up. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC (n = 350) or BSC alone (n = 350), stratified by best response to 1L chemotherapy (CR/PR vs SD) and visceral vs nonvisceral disease at start of 1L chemotherapy. Results: At data cutoff (June 4, 2021), median follow-up in both arms was ≥38 months. OS and PFS were longer in the avelumab + BSC vs BSC alone arm in all subgroups (Table). Median duration of study treatment and incidence of grade ≥3 treatment-emergent adverse events (TEAEs) in subgroups are shown in the Table. In the avelumab + BSC vs BSC alone arm, respectively, subsequent second-line anticancer drug therapy was received by: CR subgroup, 50.0% vs 74.2%; PR subgroup, 58.3% vs 71.8%; and SD subgroup, 46.4% vs 70.4%. Conclusions: Long-term follow-up from JAVELIN Bladder 100 continues to show prolonged OS and PFS with avelumab + BSC vs BSC alone irrespective of response (CR, PR, or SD) to 1L chemotherapy and despite a higher proportion of pts in the BSC alone arm receiving subsequent therapy. Long-term safety was consistent across subgroups. These findings further support avelumab 1L maintenance as standard of care for all pts with aUC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Real-world treatment patterns and clinical outcomes with first-line therapy in cisplatin-eligible and ineligible patients with advanced urothelial carcinoma.
Authors: Sonpavde Guru P. , Galsky Matt D. , Wright Phoebe , Hepp Zsolt , Chang Nancy N. , Willmon Candice , Sesterhenn Steven , Liu Yutong , Morgans Alicia K.
Published: June 2022

4565

Background: Advanced urothelial carcinoma (aUC) has a poor long-term prognosis. Despite new clinical trial data for novel therapies including PD-1/L1 inhibitors, data on real-world (RW) treatment patterns and overall survival (OS) in aUC patients (pts) treated with first line (1L) therapy are limited. Methods: This retrospective observational study describes the contemporary RW 1L treatment patterns and OS in aUC pts stratified by cisplatin (cis)-eligibility (based on accepted criteria) and treatment. Data were from the nationwide Flatiron Health longitudinal electronic health record-derived database, comprising de-identified patient-level structured and unstructured data. Eligible pts were adults diagnosed with aUC from May 2016-Oct 2020 and followed until death or end of data availability in July 2021. OS was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. Results: Of 4,300 aUC diagnosed pts, 3,311 (77.0%) received 1L treatment; 1836 (55.5%) cis-ineligible, 1475 (44.5%) cis-eligible. Differences between cis-ineligible and cis-eligible pts were observed, with cis-ineligible more likely to be older (mean age, 75.0 vs 69.0 yrs), have lower CrCl (median, 45.3 vs 80.7 mL/min), and worse ECOG-PS (2+, 29.2 vs 0%). Only 44.4% received 2L therapy: 38.3% cis-ineligible vs 52.0% cis-eligible. Median OS in all 1L treated pts was 11.0 (95% CI, 10.3 – 11.5) mo and was shorter in cis-ineligible than cis-eligible pts (8.6 [95% CI, 8.1 – 9.2] vs 14.4 [95% CI, 13.4 – 16.4]; hazard ratio [HR], 0.8 [0.7 – 1.0]). A number of cis-ineligible pts received cis, and many cis-eligible pts did not (Table), suggesting physicians consider clinical factors beyond conventional criteria to determine cis-eligibility. Cis + gemcitabine (gem) or MVAC was associated with longer OS vs other treatments regardless of cis-eligibility (Table). Conclusions: Clinical outcomes in 1L aUC pts were poor, particularly for cis-ineligible pts, which may be partly driven by the specific regimen administered. Many aUC pts did not receive 1L treatment and among those who did, less than half received 2L therapy. These data highlight the need for more effective and tolerable 1L therapy for all aUC pts. [Table: see text]
A phase 3 trial of SHR3680 versus bicalutamide in combination with androgen deprivation therapy (ADT) in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Ye Ding-Wei , Gu Weijie , Han Weiqing , Luo Hong , Zhou Fangjian , He Dalin , Ma Lulin , Guo Hongqian , Liang Chaozhao , Chong Tie , Jiang Jun , Chen Zhiwen , Wang Yong , Zou Qing , Tian Ye , Xiao Jun , Huang Jian , Yang Xinfeng , Li Junliang , Jin Chunlei
Published: June 2022

5005

Background: Both TITAN and ARCHES studies have demonstrated significant clinical benefits of second-generation androgen receptor inhibitors (ARIs) plus ADT versus placebo plus ADT in the treatment of mHSPC. However, first-generation ARIs plus ADT is also widely used in clinic and how superior second-generation ARIs is to first-generation ones remains to be determined. Here, we evaluated the efficacy and safety of SHR3680, a novel oral ARI, versus bicalutamide (Bica) in high-volume mHSPC. Methods: CHART is a randomized, open-label, phase 3 study (NCT03520478). Patients (pts) with mHSPC were randomized 1:1 to ADT plus either SHR3680 (240 mg/d) or Bica (50 mg/d). All pts had high-volume disease adapted from the CHAARTED study. The primary endpoints were radiographic progression-free survival (rPFS) assessed by independent review committee (IRC) and overall survival (OS). As of May 16, 2021, 209 rPFS events per IRC and 153 deaths occurred and a preplanned interim analysis for rPFS was done. Results: 654 pts were randomized to receive SHR3680 (n = 326) or Bica (n = 328). At data cutoff, the median follow-up duration was 22.1 mo in SHR3680 group and 20.4 mo in Bica group. SHR3680 significantly reduced the risk of radiographic progression or death than Bica (HR, 0.44; 95% CI, 0.33-0.58; p < 0.0001; median, not reached vs 25.1 mo). OS data were immature but an improved OS was observed in SHR3680 group compared to Bica group (HR, 0.58; 95% CI, 0.42-0.80; p = 0.0009). All secondary efficacy endpoints favored SHR3680 plus ADT (Table). Frequencies of adverse events of any cause in any grade were similar between groups. Grade ≥3 treatment-related adverse events occurred in 19.2% and 13.9% of pts in SHR3680 and Bica groups, respectively. No seizure occurred in SHR3680 group. Conclusions: SHR3680 plus ADT significantly improved rPFS versus Bica plus ADT in pts with high-volume mHSPC, with a desirable safety profile. New drug application has been submitted to seek approval based on the data presented here. Clinical trial information: NCT03520478. [Table: see text]
Defining germline genetics of germ cell tumor: Implications for genetic testing and clinical management.
Authors: Truong Hong , Ravichandran Vignesh , Kemel Yelena , Knezevic Andrea , Gleeson Jack Patrick , Benfante Nicole , Bromberg Maria , Bolos Mary , Joseph Gabriella , Matulewicz Richard , Sheinfeld Joel , Funt Samuel Aaron , McHugh Deaglan Joseph , Bajorin Dean F. , Donoghue Mark , Stadler Zsofia Kinga , Feldman Darren R.
Published: June 2022

5007

Background: Epidemiologic studies on germ cell tumors (GCT) in men have shown GCT has a high heritability. Yet, the genetic mechanisms underlying development of GCT in men remain unknown. We sought to determine the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in cancer predisposition genes in men with GCT and identify clinical and pathologic factors associated with the presence of P/LP variants. Methods: We retrospectively identified men with testicular (T) or mediastinal (M) GCT who underwent matched tumor--germline sequencing of ≥ 310 genes as part of an institutional genomic profiling initiative from 04/2015 to 12/2020. Presence of germline variants in clinically actionable genes associated with hereditary cancer syndromes were analyzed. Clinicopathologic characteristics, including primary site, histology and family history were assessed by the presence of P/LP variants and compared using Fisher’s exact test. Results: The study included 480 men, 70 (15%) with M-GCT and 410 (85%) with T-GCT. The median age of diagnosis was 30 years (interquartile range 24 – 39). A total of 81% had non-seminoma; 5% had localized disease; 46%, 14%, and 34% had good, intermediate, and poor risk advanced disease, respectively; 6% had family history of GCT. Among men with T-GCT, 4% had bilateral T-GCT. P/LP variants in clinically actionable genes were identified in 58 (12%) men in the entire cohort. Men with M-GCT had higher frequency of P/LP variants compared to those with T-GCT (15/70 [21%] vs 43/410 [10%], p = 0.02). A total of 7 (10%) men with M-GCT and 20 (5%) with T-GCT had P/LP variants in moderate or high penetrance cancer predisposition genes (p = 0.09). Most P/LP variants in both M-GCT (11/15, 73%) and T-GCT (33/43, 77%) were in genes involved in DNA damage repair pathways. The spectrum of moderate or high penetrance DNA damage repair genes identified is shown in the Table 1. Family history and histology (seminoma vs. non-seminoma) were not associated with the presence of a P/LP variants in the overall cohort (p = 0.8 and 0.7, respectively). Bilateral disease was not associated with the presence of P/LP variants in men with T-GCT (p = 0.4). Conclusions: Approximately 1 in 5 men with M-GCT carried a P/LP variant in a clinically actionable cancer susceptibility gene and 10% had a P/LP variant in a high-risk gene such as TP53 and PMS2. As men with GCT tend to develop disease in early adulthood, identification of germline P/LP variant has significant implications for enhanced cancer screening and surveillance, cascade testing for at-risk family members, and potential preconception genetic counseling. [Table: see text]