bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.
Authors: Murthy Pranav , Zenati Mazen S , AlMasri Samer S. , Singhi Aatur D. , DeSilva Annissa , Paniccia Alessandro , Lee Kenneth K. , Simmons Richard L. , Bahary Nathan , Lotze Michael T. , Zureikat Amer H.
Published: June 2021

4126

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.
Circulating cell free tumor DNA detection as a prognostic tool in advanced pancreatic cancer.
Authors: Botrus Gehan , Uson Junior Pedro Luiz Serrano , Raman Puneet , Kaufman Adrienne , Kosiorek Heidi E. , Sonbol Mohamad Bassam , Borad Mitesh J. , Ahn Daniel H. , Chang Isabela , Drusbosky Leylah , Starr Jason S. , Mody Kabir , Bekaii-Saab Tanios S.
Published: June 2021

4130

Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.
Impact of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC).
Authors: Mehdi Maahum , Kamgar Mandana , George Ben , Szabo Aniko , Annunzio Kaitlin , Taylor Bradley W , Shreenivas Aditya Varnam , Chakrabarti Sakti , Thomas James P. , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Clarke Callisia , Hall William Adrian , Erickson Beth , Ahmed Gulrayz , Thapa Bicky
Published: June 2021

4136

Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]
Genetic and immune divergence in pancreatic cancer lesions at the time of metastatic relapse compared to primary tumor.
Authors: Gebregziabher Bereket , Oldridge Derek A. , Furth Emma E. , Feldman Michael D. , Rech Andrew J. , Vonderheide Robert H.
Published: June 2021

4140

Background: Relapse of pancreatic ductal adenocarcinoma (PDA) is common even after complete resection and adjuvant therapy. Compared to the resected tumor, the biological characteristics of metastatic tumors at the time of first relapse are poorly understood. Methods: Whole-exome sequencing (WES) (250x) and bulk RNA sequencing were performed on samples from 30 patients with PDA. Paired primary tumor samples were obtained after R0 or R1 resection, and metastatic tumor samples were obtained by biopsy at the time of first relapse. 74.1% of patients had received adjuvant chemotherapy and radiation therapy, 7.4% had received adjuvant chemotherapy only, and 3.7% had received adjuvant radiation therapy only. Most common metastatic sites were liver and lung. The cohort was 60% male with a median age at diagnosis of 64 years. The vast majority of patients had stage IIA or IIB disease at diagnosis. Median disease-free survival was 481 days. Analysis used Freebayes (somatic variant calling), Kallisto (transcript quantification), Danaher et al. (cell type deconvolution), and antigen.garnish (neoantigen prediction). Results: High-quality WES and/or RNA sequencing were available for 27/30 patients. Among these were 16 pairs of primary and metastatic samples for WES and 15 paired samples for RNA sequencing. Median tumor purity was 32% (primary) and 42% (metastatic). KRAS mutations were present in 43/48 evaluable samples, with conserved KRAS mutations in 14/16 primary-metastatic pairs. Tumors were otherwise highly variable, with 13/16 patients developing oncogenic mutations in metastatic tumors that were undetected in primary tumors (BRCA1 [3/16], AKT3 [3/16], TP53 [2/16], ROS1 [2/16]). Overall, primary and metastatic tumors had similar tumor mutation burden and neoantigen production rate. However, neoantigens were highly variable at the peptide and gene level, with conservation rates of 2.73% and 11.57%, respectively, across primary-metastatic pairs. PDA transcriptomic subtype also differed across primary-metastatic pairs in all cases. Furthermore, metastatic tumors contained lower immune suppressive signal by transcripts and deconvolution (CTLA4: p = 0.0012, FOXP3: p = 0.0026, PDCD11: p = 0.012, regulatory T cells: p = 0.012), while myeloid cells were higher (CD33: p = 0.0067). Conclusions: With the exception of KRAS, metastatic PDA tumors at relapse contain new oncogenes, distinct neoantigens, and lower immune-suppressive signal compared to primary PDA tumors. These data suggest a potential clinical utility for tumor biopsies at the time of first metastatic relapse and caution against clinical decisions for relapsed, metastatic patients based solely on sequencing of the originally resected tumor.
Association of total neoadjuvant therapy with major pathologic response and survival in localized pancreatic cancer: A multi-institutional analysis of 504 patients.
Authors: Datta Jashodeep , Collier Amber , Kronenfeld Joshua , Wilson Gregory , Maduekwe Ugwuji , Snyder Rebecca A , Weber Sharon M. , Hawkins William G. , Kim Hong Jin Jin , Parikh Alexander A. , Hammill Chet , Kooby David A. , Abbott Daniel , Maithel Shishir K. , Hosein Peter Joel , Ahmad Syed A. , Merchant Nipun B.
Published: June 2021

4145

Background: Despite increased utilization of neoadjuvant therapy for pancreatic cancer (PC), a substantial proportion of patients never receive adjuvant therapy. We examined if total neoadjuvant therapy (TNT) would facilitate delivery of all prescribed (≥6 months) non-surgical therapy (NST: chemotherapy ± radiation) to improve oncologic outcomes. Methods: Patients receiving neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ±radiation followed by pancreatectomy at 7 centers were reviewed. Patients receiving TNT (≥6 months NST pre-resection) were compared to those receiving < 6 months ( < TNT). Primary outcomes were major (complete/near-complete) pathologic response (MPR) and overall survival (OS). Results: Of 504 patients, 105 (21%) were selected for TNT. TNT and < TNT patients had similar performance status and rates of borderline resectable/locally advanced disease (82% vs. 80%). TNT patients were significantly more likely to receive ≥6 months NST (100% vs. 31%; p < 0.001) vs. < TNT. While selection of chemotherapy regimen (FOLFIRINOX or gemcitabine/nab-paclitaxel) did not differ between TNT and < TNT cohorts, TNT patients were more likely to receive neoadjuvant radiation (44% vs. 25%, p < 0.001). Rates of vascular resection, postoperative complications, and mortality were similar between groups. TNT was associated with decreased rates of lymphovascular/perineural invasion (p = 0.002) and nodal positivity (p = 0.001), and increased rates of MPR (41% vs. 23%; p = 0.001) and pathologic complete response (13% vs. 6%; p = 0.02). TNT was associated with improved OS compared with < TNT (median 38 vs. 30 months; p = 0.039). Both MPR (median 38 [MPR] vs. 28 [limited response] months; p = 0.002) and ≥6 months NST (TNT or peri-operative) (median 38 [≥6m] vs. 26 [ < 6m] months; p = 0.001) were associated with improved OS. Addition of radiation was not associated with MPR or OS. Conclusions: The TNT approach allows more patients with localized PC to receive ≥6 months NST and is associated with improved rates of MPR and OS. TNT should be considered for all patients with operable PC when possible.
Vorolanib, everolimus, and the combination in patients with pretreated metastatic renal cell carcinoma (CONCEPT study): A randomized, phase 3, double-blind, multicenter trial.
Authors: Sheng Xinan , Ye Dingwei , Zhou Ai-Ping , Yao Xin , Luo Hong , He Zhisong , Wang Zengjun , Zhao Yingchao , Ji Zhigang , Zou Qing , He Chaohong , Guo Jianming , Tu Xinhua , Liu Ziling , Shi Benkang , Liu Ben , Chen Peng , Wei Qiang , Zhou Fang-Jian , Guo Jun
Published: June 2021

4512

Background: The combination of agents targeting both VEGF- and mTOR-mediated pathways has been investigated in renal cell carcinoma (RCC). We conducted the CONCEPT study to assess vorolanib, everolimus, or their combination as second-line treatment in Chinese patients (pts) with metastatic RCC. Methods: Pts with cytologically or histologically confirmed RCC who had disease progression after one prior VEGFR-TKI were eligible for participation in the study. They will be randomized by 1:1:1 ratio to receive matching placebo plus vorolanib or everolimus, or the combination. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2016 and June 2019, 399 pts (133 pts in each group) were enrolled. At the data cutoff (October 23, 2020), the median PFS in combination group was significantly longer than that in single-agent everolimus group (10.0 months [95% CI, 8.2-10.4] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.70 [95% CI, 0.52-0.94]; P = 0.0171), while the median PFS was similar between single-agent vorolanib group and single-agent everolimus group (6.4 months [95% CI, 4.6-8.3] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.94 [95% CI, 0.69-1.24]; P = 0.6856). An objective response was achieved by 33 (24.8%) of 133 pts allocated vorolanib plus everolimus compared with 11 (8.3%) of 133 who received single-agent everolimus and 14 (10.5%) of 133 pts assigned single-agent vorolanib. OS was immature with no significant difference between pts assigned vorolanib plus everolimus (30.4 months [95% CI, 16.5-NE]) and those allocated single-agent everolimus (25.4 months [95% CI 19.4-NE]) or single-agent vorolanib (30.5 months [95% CI, 22.8-NE]). Treatment-related adverse event (TRAE) occurred in 132 (99%) of 133 pts with vorolanib plus everolimus, 127 (96%) of 133 pts with single-agent vorolanib and 131 (99%) of 133 pts with single-agent everolimus, respectively. Grade 3 or higher TRAEs occurred in fewer patients who received single-agent vorolanib (52 [39%]) than in those who received single-agent everolimus (71 [53%]) or vorolanib plus everolimus (96 [72%]). Safety profiles of both agents were consistent with previous studies. Conclusions: This is the first phase 3 study of combination of mTOR- and VEGF-targeted agents in second-line treatments. Vorolanib plus everolimus showed a PFS benefit for patients with metastatic RCC who have progressed after one previous VEGF-targeted therapy with a safe tolerance profile. Clinical trial information: NCT03095040.
Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.
Authors: Fallah Jaleh , Gittleman Haley , Weinstock Chana , Bloomquist Erik , Chang Elaine , Suzman Daniel L. , Agrawal Sundeep , Ibrahim Amna , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Amiri-Kordestani Laleh
Published: June 2021

4516

Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]
Avelumab first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): Analysis of time to end of next-line therapy in JAVELIN Bladder 100.
Authors: Grivas Petros , Park Se Hoon , Voog Eric , Kopyltsov Evgeny , Gurney Howard , Muniz David Queiroz Borges , Rolland Frederic , Als Anne Birgitte , Valderrama Begoña P. , Wang Jing , Costa Nuno Matos , Laliberte Robert J , Di Pietro Alessandra , Powles Thomas , Bellmunt Joaquim
Published: June 2021

4525

Background: Avelumab 1L maintenance is approved in various countries for patients (pts) with advanced UC that has not progressed with 1L platinum-based chemotherapy based on significantly prolonged overall survival (OS) seen with avelumab + BSC vs BSC alone in the phase 3 JAVELIN Bladder 100 trial. OS was prolonged despite the more frequent use of subsequent anticancer therapy in the BSC alone arm (42.3% in the avelumab + BSC arm vs 61.7% in the BSC alone arm), most commonly with immune checkpoint inhibitors (6.3% vs 43.7%, respectively). To further characterize the efficacy benefits of avelumab 1L maintenance, we report a post hoc analysis of the time to end of next-line therapy (for any reason) in the randomized trial population. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without disease progression with 4 to 6 cycles of 1L gemcitabine + either cisplatin or carboplatin. The primary endpoint was OS from randomization, assessed in 2 populations: all pts and pts with PD-L1+ tumors (Ventana SP263). In this exploratory analysis, time from randomization until end of next-line treatment received after first progression (due to death or discontinuation) was assessed. Results: A total of 700 pts were randomized 1:1 to avelumab 1L maintenance + BSC or BSC alone. Among all randomized pts, time to end of next-line therapy was prolonged in the avelumab + BSC arm vs the BSC alone arm (Table). Time to end of next-line therapy was also longer in the avelumab + BSC arm vs the BSC alone arm in pts with PD-L1+ tumors (n = 358) or PD-L1− tumors (n = 270). Conclusions: Pts who received avelumab 1L maintenance + BSC had prolonged time to end of next-line treatment compared with those who received BSC alone, irrespective of PD-L1 status. These data provide further evidence of the efficacy of a maintenance approach with avelumab in pts with advanced UC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial.
Authors: Bellmunt Joaquim , Necchi Andrea , De Wit Ronald , Lee Jae-Lyun , Fong Lawrence , Vogelzang Nicholas J. , Climent Durán Miguel A. , Petrylak Daniel P. , Choueiri Toni K. , Gerritsen Winald R. , Gurney Howard , Quinn David I. , Culine Stephane , Sternberg Cora N. , Xu Jin Zhi , Homet Moreno Blanca , Godwin James Luke , Bajorin Dean F. , Vaughn David J. , Fradet Yves
Published: June 2021

4532

Background: Pembro was approved for the treatment of locally advanced or metastatic UC that progressed during or after a platinum-containing regimen, based on the phase 3 KEYNOTE-045 (NCT02256436) trial that showed significantly improved OS with use of pembro. Updated results are presented from KEYNOTE-045 after >5 y of follow-up since the last patient (pt) was randomized. Methods: KEYNOTE-045 is a randomized, multisite, open-label, phase 3 trial. Pts with histologically or cytologically confirmed UC, progression after platinum-containing chemo, ECOG PS 0-2, measurable disease per RECIST v1.1, and ≤2 prior lines of systemic therapy were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary end points are PFS (RECIST v1.1, blinded central review) and OS. ORR and duration of response (DOR) were key secondary end points. Results: As of Oct 1, 2020, among 542 enrolled pts, median time from randomization to data cutoff was 62.9 mo (range 58.6-70.9). 9.4% and 0% of pts in the pembro and chemo arms, respectively, completed 2 years of therapy. Median OS was longer for pembro vs chemo (10.1 vs 7.2 mo; HR, 0.71 [95% CI, 0.59-0.86]) overall and in pts with CPS ≥10 (8.0 vs 4.9 mo; HR, 0.59 [95% CI, 0.40-0.86]). For pts with CR or PR, median OS was not reached and 16.4 (95% CI, 11.3-25.1) mo in the pembro and chemo arms, respectively (Table). OS rates at 48 mo were 16.7% for pembro and 10.1% for chemo; 60-mo OS rates were 14.9% and 8.7%, respectively. OS benefit with pembro vs chemo continued regardless of age, ECOG PS, prior therapy, liver metastases, baseline hemoglobin, time from last chemo, histology, risk factors, and chemo choice. Median DOR for responders was longer for pembro vs chemo (29.7 mo [1.6+ to 60.5+] vs 4.4 mo [1.4+ to 63.1+]), and a greater proportion of responses lasted ≥48 mo (40.9% vs 28.3%, Kaplan-Meier) and ≥60 mo (32.8% vs 28.3%). ORR was higher for pembro vs chemo (21.9% vs 11.0%; difference 10.8% [95% CI, 4.6-17.0]). Fewer pts given pembro vs chemo experienced a treatment-related AE of any grade (62.0% vs 90.6%) or grade ≥3 (16.9% vs 50.2%). Conclusions: After 5 y, pembro maintained clinically meaningful OS benefit vs chemo in pts with locally advanced or metastatic UC that progressed during or after platinum-based chemo. Pts who responded to pembro experienced a durable response (median >2 y). Clinical trial information: NCT02256436 .[Table: see text]
Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who receive second-line immunotherapy.
Authors: Miron Benjamin , Handorf Elizabeth A. , Zarrabi Kevin , Zibelman Matthew R. , Ghatalia Pooja , Anari Fern , Plimack Elizabeth R. , Geynisman Daniel M.
Published: June 2021

4535

Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cisplatin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Carbo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69-1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted.[Table: see text]
Use of neoadjuvant chemotherapy in elderly patients with muscle invasive bladder cancer: A population-based study, 2006 to 2017.
Authors: Posielski Natasza , Jung Nathan , Koenig Hannah , Ho On , Flores John Paul , Porter Christopher
Published: June 2021

4536

Background: Current guidelines recommend neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC). NAC has been shown to confer a survival benefit across all ages. Yet, many elderly patients are not offered NAC due to concern regarding physiologic reserve and postoperative complications. Our objective was to evaluate age-based disparity in treatment and outcomes of MIBC. Methods: Using the National Cancer Database, we identified patients with MIBC from 2006-2017. First, use of different treatments, RC, RC and adjuvant chemotherapy, RC with NAC (“optimal treatment”), chemo-radiation, and no treatment, was compared between age groups. A second analysis was performed in the cohort of elderly patients, ≥70, undergoing cystectomy. Propensity weighting was used to compare peri-operative and mortality outcomes in those who received NAC vs. no NAC. Results: In 70,911 patients with non-metastatic MIBC, use of RC with NAC was lower in patients ≥70, 7.2 vs. 20.9%, p<0.001 (Table). Patients receiving RC with NAC were younger, had private insurance, higher high school completion rate and median income, shorter distance to hospital, lower CCI, diagnosis in recent years, and higher stage disease. NAC use was also associated with pelvic lymph node dissection (OR 4.55, p<0.001). In patients ≥70 undergoing RC, NAC was associated with shorter length of stay (LOS) (8.5 vs 9.6 days, p<0.001), decreased 30-day readmission (8.6 vs 10.6%, p=0.003), lower 30- and 90-day mortality (1.9 vs 3.6%, p=0.01 and 4.9 vs 7.7%, p=0.004, respectively), and better overall survival (OS) (43.8% vs. 37.5%, p<0.001). Multivariate logistic regression found NAC as an independent predictor of shorter LOS, lower 30-and 90-day mortality, and improved OS. Conclusions: Despite increased omission of NAC in patients ≥70, NAC is not associated with worse peri-operative outcomes or mortality in elderly patients. Advanced age in properly selected patients should not preclude offering NAC prior to radical cystectomy.[Table: see text]
Impact of recurrence on health-related quality of life in patients at high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma (MIUC): Results from the phase 3 CheckMate 274 trial.
Authors: Galsky Matt D. , Witjes Johannes Alfred , Gschwend Jürgen , Braverman Julia , Broughton Edward , Nasroulah Federico , Alhasani Hasan , Maira-Arce Mario , Ye Xiaomei , Shi Ling , Hamilton Melissa , Bajorin Dean F.
Published: June 2021

4540

Background: Patients (pts) undergoing radical surgery for MIUC face a high risk of disease recurrence. Recurrence is associated with worse survival, but its effect on health-related quality of life (HRQoL) is unclear. This post hoc analysis assessed the impact of recurrence on HRQoL using data from the phase 3 CheckMate 274 trial. Methods: Pts who had undergone radical surgery for high-risk MIUC (≤ 120 days previously) were randomized 1:1 to nivolumab 240 mg Q2W or placebo for ≤ 1 year. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D-3L every 4–6 weeks during treatment; 35 and 115 days after the last dose; and every 3 months after that until the end of the study (EQ-5D-3L only). The analysis included pts with a valid HRQoL assessment at baseline and at ≥1 post-baseline visits. Confirmed deterioration in HRQoL was defined as worsening exceeding an a priori points threshold (± 10 for the EORTC QLQ-C30 domains, –7 for the EQ-5D visual analogue scale [VAS]) at ≥ 2 consecutive visits. Recurrence was classified as local only or distant (with or without local recurrence). The effect of recurrence on HRQoL deterioration was assessed by Cox proportional hazards regression with recurrence as a time-dependent covariate. The models controlled for treatment arm and baseline HRQoL score, and were stratified by PD-L1 expression, pathologic nodal status, and use of neoadjuvant cisplatin-based chemotherapy. Results: The analysis included 645 pts for EORTC QLQ-C30, of whom 71 (11%) had local recurrence only and 136 (21%) had distant recurrence during the HRQoL assessment period; and 648 pts for EQ-5D-3L. with recurrence had a significantly higher risk of confirmed deterioration in all HRQoL domains than those without recurrence (see table). However, hazard ratios were consistently greater for distant recurrence than for local recurrence across all HRQoL domains. For local recurrence only, a higher risk of confirmed deterioration in HRQoL compared to no recurrence was observed only for global health status/QoL. Conclusions: Recurrence, particularly distant recurrence, had a significant, negative impact on HRQoL. This suggests that treatment delaying recurrence after radical surgery for high-risk MIUC may prevent or delay HRQoL deterioration in these pts. Clinical trial information: NCT02632409. [Table: see text]
Survival outcomes in patients receiving immune checkpoint inhibitor (ICI) for metastatic small cell urothelial cancer (SCUC).
Authors: Alhalabi Omar , Wilson Nathaniel , Navai Neema , Campbell Matthew T , Shah Amishi Yogesh , Gao Jianjun , Corn Paul G. , Aparicio Ana , Czerniak Bogdan , Guo Charles , Logothetis Christopher , Tannir Nizar M. , Choi Seungtaek , Siefker-Radtke Arlene O.
Published: June 2021

4543

Background: The prognosis in patients with metastatic SCUC (mSCUC) remains poor with median survival around 1 year with systemic chemotherapy. We aimed to investigate the impact of ICI on survival of patients with mSCUC. Methods: Patients who received systemic therapy at MD Anderson Cancer Center (MDACC) for de novo or metachronous mSCUC after completing local management. within 12 months of neoadjuvant or adjuvant chemotherapy were included in this cohort, with overall survival (OS) calculated from the time of receipt of initial chemotherapy. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using logrank test. Results: 102 patients with mSCUC received systemic therapy at MDACC between April 2006 and June 2020. Median age was 66 (range 24 – 86 years), male to female ratio was 5. Bladder was the primary site in 85 (83%), 45 (44%) had prior cystectomy and 9 (9%) had prior nephroureterectomy. Histologies included 51 (50%) with predominant small cell (SC) features, 28 (27%) with focal SC features, 20 (20%) with pure SC, and 3 (3%) mixed with large cell component. Thirty-nine (38%) received ICI during their disease course: 29 (28%) following front-line chemotherapy (15 of whom within 12 months of neoadjuvant/adjuvant platinum therapy), 5 (5%) combined with front-line chemotherapy, and 5 (5%) received ICI front-line (two of whom were able to receive second-line chemotherapy). ICI agents used included anti-PD-1 (n=19), anti-PD-L1 (n=12), anti-PD-1/anti-CTLA-4 (n=5), anti-PD-1/anti-TIM3 (n=1), anti-PD-1/anti-STAT3 (n=1), anti-PD-L1/PARPi (n=1). Those who received ICI at any time had an improved median OS compared to those treated with chemotherapy alone (20.1 vs 12 months), [HR=0.45, 95% CI 0.27-0.72, p=0.003]. When we limited the analysis to those with de novo mSCUC (n=36), those who received ICI at any time (n=13) had an improved median OS compared to those treated with chemotherapy alone (n=23) (not reached vs 9.41 months), [HR=0.28, 95% CI 0.12-0.68, p=0.03]. Among patients who received ICI (n=39), median OS in those with liver metastases (n=11) was numerically shorter than those without (n=28) (13.1 vs 21.6 months), [HR=1.83, 0.59-5.7, p=0.21]. Conclusions: ICI improves OS for patients with mSCUC. Although clinical trials remain difficult in these rare variants, further prospective studies are indicated to confirm this finding.
Association of C-reactive protein (CRP) with efficacy of avelumab + axitinib (A + Ax) in advanced renal cell carcinoma (aRCC): Long-term follow-up results from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Larkin James , Venugopal Balaji , Haanen John B. A. G. , Kanayama Hiro-Omi , Eto Masatoshi , Grimm Marc-Oliver , Fujii Yosuke , Umeyama Yoshiko , Mariani Mariangela , Di Pietro Alessandra , Choueiri Toni K.
Published: June 2021

4548

Background: CRP is an important prognostic and predictive factor in patients with aRCC receiving various therapies, such as cytokines and tyrosine kinase inhibitors. In this extended follow-up to the phase 3 JAVELIN Renal 101 trial (NCT02684006), we report the association of CRP levels at baseline (BL) and early after treatment with the efficacy of A + Ax or sunitinib (S). Methods: CRP levels were assessed at screening and day 1 of each 6-week cycle. Patients were categorized into CRP normal (BL CRP < 10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to < 10 mg/L during 6 weeks of treatment), and non-normalized (CRP ≥10 mg/L at BL and during 6 weeks of treatment) groups. Multivariate analysis of BL characteristics, including CRP for efficacy, was also conducted. Progression-free survival (PFS) and best overall response per independent central review (RECIST 1.1) from the second interim analysis (IA2) of overall survival (OS) and OS from the third interim analysis (IA3) were assessed. Results: Minimum duration of follow-up for IA2 and IA3 were 13 and 28 months, respectively. The table shows objective response rate (ORR), PFS, and OS by CRP group. Efficacy outcomes in the normal and normalized groups were favorable compared with the non-normalized group with both A + Ax and S. In the A + Ax arm, the complete response rate was 11.8% (normalized group), 3.8% (normal group), and 0.9% (non-normalized group). With A + Ax, the PFS in the normalized group was longer than in the normal group, but this was not observed with S. In each CRP group, all efficacy outcomes were favorable with A + Ax vs S. In the multivariate analysis, normalized or non-normalized CRP was an independent predictive factor of ORR or OS with A + Ax. Conclusions: Normal and normalized CRP levels were associated with improved A + Ax efficacy. A + Ax demonstrated favorable efficacy across CRP groups. OS in this study was immature; follow-up for the final analysis is ongoing. Further research in defining predictive value of CRP is warranted. Clinical trial information: NCT02684006. [Table: see text]
The impact of antibiotic (Ab) exposure on clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or VEGF targeted therapy (VEGF-TT).
Authors: Ernst Matthew Scott , Abou Alaiwi Sarah , Dizman Nazli , Labaki Chris , Nuzzo Pier Vitale , Adib Elio , Schmidt Andrew Lachlan , Meza Luis A , Gan Chun Loo , Wells J Connor , Bakouny Ziad , Pal Sumanta K. , Choueiri Toni K. , Heng Daniel Yick Chin , Dudani Shaan
Published: June 2021

4552

Background: Retrospective studies have shown an association between Ab exposure and inferior clinical outcomes in patients receiving ICI across various tumor types, including mRCC. However, it is unclear whether Ab exposure has a unique interaction with ICI or is an independent prognostic marker, regardless of treatment. We sought to examine Ab exposure and its association with clinical outcomes in patients with mRCC treated with ICI compared to VEGF-TT. Methods: We identified patients treated with ICI (anti-PD-L1 alone or in combination with VEGF or CTLA4 inhibitor) or VEGF-TT alone in first to fourth line settings from 2009-2020 across 3 academic centers in North America. Ab exposure was defined as administration of Ab within 60 days prior to initiation of systemic therapy. Outcomes of interest were response rate (RR), time to treatment failure (TTF) and overall survival (OS). Multivariable Cox regression was performed to control for imbalances in International mRCC Database Consortium (IMDC) risk factors, histology, and treatment line. Results: We identified 748 patients. Among the ICI (n=427) and VEGF-TT (n=321) cohorts, 13% vs 15% (p=0.47) had Ab exposure and 57% vs 48% (p=0.046) were treated in the first line setting. The proportion of favorable, intermediate, and poor risk disease by IMDC criteria differed between Ab exposed and unexposed patients in the ICI (14% vs 18%, 47% vs 62%, 39% vs 21% p=0.03) and VEGF-TT (7% vs 13%, 43% vs 60%, 50% vs 27%, p=0.01) cohorts. RR, TTF and OS results are displayed in Table 1. Multivariable analysis did not show a significant independent association between Ab exposure and OS in both the ICI (HR 1.13, p=0.62) and VEGF-TT (HR 1.32, p=0.16) cohorts. Treatment modality (ICI vs VEGF-TT) did not modify the effect of Ab exposure on OS (p=0.84). Conclusions: Ab exposure was associated with higher IMDC risk scores in both the ICI and VEGF-TT cohorts as well as inferior OS on univariable analysis. After adjusting for IMDC risk factors, histology and treatment line, we were unable to find an independent association between Ab exposure and OS in multivariable analysis for either cohort.[Table: see text]
Outcomes of first-line (1L) ipilimumab and nivolumab (IPI-NIVO) and subsequent therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Gan Chun Loo , Wells J Connor , Schmidt Andrew Lachlan , Powles Thomas , Tran Ben , Meza Luis A , Labaki Chris , Lee Jae-Lyun , Wood Lori , Shapiro Julia , Ernst D. Scott , Kapoor Anil , Canil Christina M. , Yuasa Takeshi , McKay Rana R. , Beuselinck Benoit , Donskov Frede , Dudani Shaan , Choueiri Toni K. , Heng Daniel Yick Chin
Published: June 2021

4554

Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p<0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p<0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p<0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p<0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7-5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO.[Table: see text]
Phase II trial of stereotactic ablative radiation (SAbR) for oligoprogressive kidney cancer.
Authors: Hannan Raquibul , Christensen Michael , Garant Aurelie , Hammers Hans J. , Arafat Waddah , Courtney Kevin Dale , Bowman Isaac Alex , Cole Suzanne , Sher David , Ahn Chul , Timmerman Robert D. , Brugarolas James
Published: June 2021

4564

Background: Metastatic renal cell carcinoma (mRCC) patients on systemic therapy may experience oligoprogression. SAbR has been demonstrated to be safe and is associated with high local control rates in mRCC. In this prospective phase II single arm trial, we investigated SAbR to control oligoprogressive mRCC. Methods: Patients with mRCC who demonstrated response to systemic therapy with subsequent radiographic evidence of three or fewer sites of progression were treated with SAbR to all progressive sites. Systemic therapy was held during SAbR at the discretion of the treating oncologist. Follow-up included radiographic imaging at three-month intervals. Sequential SAbR for continued oligoprogression was allowed. The primary objective was extension of ongoing systemic therapy by >6 months in 40% of the patients. Progression was defined by any of these 3 criteria: (1) local failure at a radiated site; (2) progression ineligible for additional SAbR (>3 sites) or involving >30% of metastasis; or (3) progression as clinically determined by treating physicians. An exact binomial test was used to test the probability of postponing systemic therapy. Secondary endpoints focused on overall survival (OS), local control (LC) rates, toxicity, and health-related quality of life (QOL). Results: The trial completed accrual with enrollment of 20 patients who received SAbR to a total of 36 sites. At enrollment four, twelve, three, and one patients were on first, second, third, and fourth line of systemic therapy, respectively. Eleven were on immunotherapy and nine on a tyrosine-kinase inhibitor. Three patients required repeat SAbR to a new site for sequential disease control. At a median follow-up of 8.3 months (interquartile range 3.9 – 15.1), SAbR extended the duration of the ongoing systemic therapy by >6 months in 12 out of 17 patients (70.6%, 95% CI: 48.9%-92.3%). Thirteen out of 20 patients progressed with a median PFS of 8.7 months (95% CI: 3.2-12.4). Five patients died and the OS did not reach the median. LC was 36/36 (100%). Treatment related grade 1 and grade 2 toxicity was experienced by three and one patient, respectively; no grade 3 toxicities were reported. When compared to baseline, no significant decline in QOL was detected. Conclusions: SAbR extended PFS of ongoing systemic by >6 months in oligoprogressive patients with mRCC. SAbR was safe and did not adversely affect QOL. These data support further evaluation of SAbR for oligoproressive mRCC in a prospective randomized setting. Clinical trial information: NCT03696277.