bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early response marker during pembrolizumab treatment in metastatic urothelial cancer: Temporal shift in peripheral CD4 T cells expressing chemokine receptors.
Authors: Rijnders Maud , Balcioglu Hayri Emrah , Robbrecht Debbie , Boormans Joost L. , Aarts Maureen J.B. , Hamberg Paul , Voortman Jens , Westgeest Hans , De Wit Ronald , Lolkema Martijn P. , Van Der Veldt Astrid Aplonia Maria , Debets Reno 
Published: May 2020

5033 Background: Approval of PD1 blockade greatly improved treatment possibilities for patients with platinum-resistant metastatic urothelial cancer (mUC), however the current response rate for pembrolizumab is less than 25%. Since PD-L1 expression does not have predictive value in this setting, the aim of this study was to identify new markers to improve patient selection. Methods: Between Sept 2017 and Jan 2020, 84 mUC patients received pembrolizumab in a prospective biomarker discovery study (NCT03263039). Peripheral blood samples (n = 22) taken prior to and at 6 and 12 weeks after start of treatment were analyzed for frequencies of CD4 and CD8 T cells expressing co-inhibitory, co-stimulatory and chemokine receptors using multiplex flow cytometry. Plasma chemokine levels were determined using ELISA (n = 38), and fresh tumor biopsies obtained prior to and during treatment (n = 26) were analyzed for densities and phenotypes of T cells using multiplex immunofluorescence staining. T cell receptor clonality was analyzed in peripheral blood (n = 10) and tumor biopsies (n = 6) using RNA sequencing. Patients were classified as responder (complete or partial response) or non-responder (progressive disease) according to RECIST v1.1 after 12 weeks of treatment. Results: Longitudinal sampling revealed that upon treatment the frequency of CXCR3+ CD4 T cells decreased in responders, whereas the frequency of CXCR3+ CCR1+ CD4 T cells drastically increased in non-responders. Before treatment, the frequency of CD4 T cells co-expressing CXCR3 and CCR1 was already decreased in responders. Notably, in responders, the treatment-related decrease in frequency of CD4 T cells expressing chemokine receptors was accompanied by a decrease in the frequency of CD4 T cells expressing the co-inhibitory receptor PD1, whereas an increase in the frequency of CD4 T cells expressing the co-stimulatory receptor 4-1BB was observed. These findings will be complemented with chemokine levels in plasma, contexture of T cells in tumor biopsies, and T cell receptor clonality analysis. Conclusions: mUC patients responding to pembrolizumab treatment demonstrated an on-treatment decrease in frequency of CD4 T cells expressing chemokine receptors that is accompanied by a changed frequency of co-signaling receptor expressing CD4 T cells. These data show that dynamic immune phenotyping can distinguish effective from less effective immune activation by pembrolizumab, and may provide early markers for benefit from PD1 blockade in mUC patients.
Atezolizumab (atezo) therapy for locally advanced/metastatic urinary tract carcinoma (mUTC) in patients (pts) with poor performance status (PS): Analysis of the prospective global SAUL study.
Authors: Castellano Daniel , Gedye Craig , Fornarini Giuseppe , Fay Andre P. , Voortman Jens , Mego Michal , Bamias Aristotelis , Lester Jason Francis , Huddart Robert A , Matouskova Michaela , Gurney Howard , Mellado Begona , Ong Michael , Carneiro Filipa , Seseke Florian , Milesi Laura , Shariat Shahrokh F. , Fear Simon , de Ducla Sabine , Sternberg Cora N. 
Published: May 2020

5035 Background: Pts with PS > 1 have a poor prognosis and are often excluded from clinical trials. The single-arm SAUL study (NCT02928406) evaluated atezo in a ‘real-world’ population. Overall, safety and efficacy were consistent with prior trials. However, ECOG PS 2 pts had worse overall survival (OS) but fewer adverse events (AEs) than ECOG PS 0/1 pts [Sternberg, 2019], likely reflecting shorter treatment duration and warranting exploration. Methods: Pts with mUTC received atezo 1200 mg q3w until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Post hoc analyses compared baseline factors, AEs and efficacy in pts with ECOG PS 2 vs 0/1. In this analysis, AE incidences were restricted to the first 45 days of atezo to adjust for differing treatment exposure. Results: None of the baseline factors explored was significantly associated with worse OS or disease control rate (DCR) in ECOG PS 2 pts. However, pts with visceral metastases and ECOG PS 2 had particularly poor outcomes. Safety appeared similar between subgroups. Conclusions: ECOG PS 2 pts have a dismal prognosis. The higher proportion with poor prognostic factors despite similar age in ECOG PS 2 vs 0/1 pts may suggest that poor PS was related to disease rather than comorbidities. Risk/benefit should be considered especially carefully when treating pts with ECOG PS 2 due to high-burden/visceral disease. Clinical trial information: NCT02928406 . [Table: see text]
Impact of renal impairment on clinical outcomes in patients (pts) with locally advanced or metastatic (LA/M) urinary tract carcinoma (UTC) treated with atezolizumab (atezo): Analysis of the international SAUL study.
Authors: Retz Margitta , Seseke Florian , Banna Giuseppe Luigi , De Giorgi Ugo , Powles Thomas , Basso Umberto , McDermott Raymond S. , Llado Anna , Su Wen-Pin , Cebotaru Cristina Ligia , Puente Javier , Montesa Alvaro , De Greve Jacques , Kahan Zsuzsanna , Anido Herranz Urbano , de Ducla Sabine , Pavlova Julie , Fear Simon , Sternberg Cora N. 
Published: May 2020

5036 Background: Atezo, which targets PD-L1, is an approved therapy for LA/M urothelial carcinoma based on the IMvigor210 and IMvigor211 trials. The single-arm SAUL study (NCT02928406) showed consistent activity and safety in a broader population, including understudied scenarios, eg pts with renal impairment or other IMvigor211 exclusion criteria. Methods: Pts with LA/M UTC received atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and overall survival (OS). Post hoc analyses explored outcomes in pts classified as: chemotherapy (CT) ineligible (calculated creatine clearance [CrCl] 15– < 30 mL/min); cisplatin ineligible and carboplatin eligible (CrCl 30– < 60 mL/min); or cisplatin eligible (CrCl ≥60 mL/min). Results: Of 1004 enrolled pts, 46 (5%) were classified as CT ineligible and 420 (42%) as cisplatin ineligible. Results are summarized below. Conclusions: These post hoc analyses suggest pts typically considered cisplatin or CT ineligible are candidates for atezo. Pts with renal impairment achieved similar ORR and DCR to pts with CrCl ≥60 mL/min, without increased toxicity. Imbalances in pt characteristics may explain numerical differences in OS. Clinical trial information: NCT02928406 . [Table: see text]
Ipilimumab challenge/re-challenge in metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors treated with cabozantinib+nivolumab (CaboNivo) or cabozantinib+nivolumab+ipilimumab (CaboNivoIpi).
Authors: Niglio Scot Anthony , Girardi Daniel da Motta , Mortazavi Amir , Lara Primo , Pal Sumanta K. , Saraiya Biren , Cordes Lisa M. , Ley Lisa , Sierra Ortiz Olena , Cadena Jacqueline , Diaz Carlos , Bagheri Mohammadhadi H. , Steinberg Seth M. , Costello Rene , Streicher Howard , Wright John , Parnes Howard L. , Ning Yang-Min , Bottaro Donald P. , Apolo Andrea B. 
Published: May 2020

5039 Background: We investigated challenging/re-challenging pts with ipilimumab (ipi) after progression on CaboNivo or CaboNivoIpi. Methods: In a phase I expansion study, patients with mUC post-platinum chemotherapy and other GU tumors patients who progressed on Cabo 40 mg daily plus nivolumab, 3 mg/kg every 21 days (CaboNivo) alone or with ipi, 1 mg/kg every 21 days for 4 cycles (CaboNivoIpi)-and achieved a PR or SD≥6 mo, were challenged/re-challenged with ipi, 1 mg/kg every 21 days for up to 4 cycles. Restaging scans were done every 6 wks for the first 12 wks, then every 8 wks and evaluated by RECIST 1.1. Results: In total, 24 patients were evaluated: 18 pts (8 UC (5 bladder and 3 upper tract), 4 clear cell renal cell carcinoma (RCC), 3 urachal adenocarcinoma (adeno), 2 bladder adeno, and 1 sarcomatoid clear cell RCC) who progressed on CaboNivo were challenged with ipi. In the challenge group, median (m) follow-up was 21.2 months. One pt achieved a PR in the LNs, but was found to have brain metastases before the next restaging, 13 had SD and 4 had PD. Median duration of PR or SD was 3.6 months (95% CI: 1.4 – 7.8 months). The mOS from start of ipi challenge was 13.9 months (95% CI: 5.8 months- not estimable); mPFS was 4.6 months (95% CI: 1.9 – 8.7 months). Grade 1/2 treatment related adverse events (AEs) occurred in all 18 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 11 pts (61%). The most common G≥3 AEs were hypophosphatemia (22%), hypertension (6%), adrenal insufficiency (6%), increased AST (6%), and ALT (6%). Six patients (3 bladder UC, 1 penile squamous cell (SCC) carcinoma, 1 urethral SCC, and 1 clear cell RCC with sarcomatoid features) who progressed on CaboNivoIpi were re-challenged with Ipi. On re-challenge, mfollow-up was 20.9 months. There were no PRs, 3 SDs and 3 PDs. mOS from start of re-challenge was 4.0 months (95% CI: 2.2 – 23.3 months) and mPFS was 1.9 months (95% CI: 1.1 – 2.6 months). Grade 1/2 treatment related AEs occurred in all 6 pts (100%) and ≥Grade 3 (G≥3) AEs occurred in 2pts (33%). G≥3 AEs included 1 hypertension (17%) and 1 hyperphosphatemia (17%). Conclusions: Ipi challenge/re-challenge showed low response rates in pts previously treated with CaboNivo or CaboNivoIpi. However, pts treated with CaboNivo who were challenged with ipi had a better OS than patients who had progressed on CaboNivoIpi and were re-challenged with ipi. Larger trials are warranted testing the ipi challenge in pts progressing on CaboNivo. Clinical trial information: NCT02496208 .
ALTERNATE: Neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106.
Authors: Ma Cynthia X. , Suman Vera J. , Leitch A. Marilyn , Sanati Souzan , Vij Kiran R. , Unzeitig Gary Walter , Hoog Jeremy , Watson Mark , Hahn Olwen Mary , Guenther J. Michael , Caudle Abigail Suzanne , Dockter Travis , Korde Larissa A. , Weiss Anna , Hunt Kelly , Hudis Clifford A. , Winer Eric P. , Partridge Ann H. , Carey Lisa A. , Ellis Matthew James ,   Alliance
Published: May 2020

504 Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .
Study EV-103: Durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Flaig Thomas W. , Friedlander Terence W. , Milowsky Matthew I. , Srinivas Sandy , Petrylak Daniel Peter , Merchan Jaime R. , Bilen Mehmet Asim , Carret Anne-Sophie , Yuan Nancy , Sasse Carolyn , Hoimes Christopher J. 
Published: May 2020

5044 Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with locally advanced or mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. EV is investigational in the 1L setting. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cisplatin-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 1L or previously untreated mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% ≥G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo); the 12-month DOR rate was 53.7% (95% CI, 27.4, 74.1). The median PFS was 12.3 mo (95% CI, 7.98, -); the 12-month PFS rate was 50.1% (95% CI, 33.0, 65.0). The median OS was not reached (range 0.66 to 19.2+ mo); the 12-month OS rate was 81.6% (95% CI, 62.0, 91.8). Conclusions: In 1L cisplatin-ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545 .
Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial).
Authors: Khan Qamar J. , O'Dea Anne , Bardia Aditya , Kalinsky Kevin , Wisinski Kari Braun , O'Regan Ruth , Yuan Yuan , Ma Cynthia X. , Jahanzeb Mohammad , Trivedi Meghna S. , Spring Laura , Makhoul Issam , Wagner Jamie L. , Winblad Onalisa , Amin Amanda Leigh , Blau Sibel , Crane Gregory James , Elia Manana , Hard Mia , Sharma Priyanka 
Published: May 2020

505 Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]
Clinicogenomic predictors of extreme responses to anti-PD1/PDL1 checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC).
Authors: Teo Min Yuen , Whiting Karissa , Mota Jose Mauricio , Li Han , Regazzi Ashley Marie , Solit David B. , Aggen David Henry , Lee Chung-Han , Funt Samuel Aaron , Bajorin Dean F. , Ostrovnaya Irina , Iyer Gopa , Rosenberg Jonathan E. 
Published: May 2020

5050 Background: Only a subset of mUC patients (pts) derives benefit from CPI. We sought to evaluate potential clinical and genomic predictors, with additional focus on extreme outcomes. Methods: CPI-treated mUC with tumor sequencing with MSK-IMPACT (up to 468 genes) were identified. Pre-CPI clinical variables (including hemoglobin [hgb], lymphocyte [lymph], neutrophil [neut] and eosinophil [eos] counts) were extracted. Endpoint was time on treatment (ToT). Poor responders were defined as ToT ≤9 weeks and overall survival ≤3 months; exceptional responders had ToT >20 months. A multivariate Cox model for ToT was performed with clinical variables chosen by stepwise selection minimizing Akaike information criterion. Genomic analyses were adjusted for multiple testing. Results: 166/171 identified mUC were evaluable. Median age was 68 years, 78% were male. 72% had bladder primary, while 17%, 35% and 28% had liver, lung and bone metastases (mets). 67% had prior platinum chemo. 24 pts (14%) were poor and exceptional responders, respectively. In univariate analysis, liver mets were associated with shorter ToT while DNA damage repair (DDR) gene alterations, higher body mass index (BMI), eos, hgb and tumor mutation burden (TMB) were associated with longer ToT. No specific genomic alterations achieved q<.05. In multivariate model, prior chemo (HR 1.6, p=.01), liver mets (HR 2.4, p<.01) and high neut were associated with shorter ToT while urethral primary (HR 0.1, p<.01), higher TMB (HR 0.9, p<.01) and higher eos (HR 0.1, p<.01) were independently associated with ToT. Univariate logistic regression to identify poor and exceptional responders are tabulated. Multivariate results will be reported. Conclusions: In addition to validation of various known mUC prognosticators, we observed potential non-linear influence of clinical and genomic factors on extreme outcomes. [Table: see text]
Model to predict brain metastasis (BM) in patients with metastatic germ-cell tumors (mGCT).
Authors: Ashkar Ryan , Althouse Sandra K. , Cary Clint , Masterson Timothy A. , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: May 2020

5057 Background: BM is an independent adverse prognostic factor that can lead to treatment complications and failure in pts with mGCT. We aimed to establish an effective and practical model for prediction of BM in mGCT. Methods: 2,256 consecutive pts with mGCT treated at Indiana University between January 1990 and September 2017 were identified. Pts were divided into 2 categories: BM present (N = 144) and BM absent (N = 2112). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated 50/50 into training and validation datasets with equal numbers of events in each. Results: Baseline characteristics for 2 groups are listed in Table. 2-yr PFS and OS for pts with vs without BM: 17% vs 66% (p < 0.001) and 62% vs 91% (p < 0.001) respectively. Among the 144 pts with BM, 64 (44%) had radiation only (whole-brain radiotherapy or gamma knife), 21 (15%) had BM-surgery only, 14 (10%) had both radiation and BM-surgery. 45 pts (31%) did not receive local therapy for BM. A stepwise selection was used to determine the best model with p < 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis≥40 (1 point), presence of pulmonary metastases (3 points), bone metastasis (1 point), pre-chemotherapy hCG≥5000 (1 point), and choriocarcinoma predominant histology (1 point). Patients with 0 points had a 0.4% probability of BM, 1 point: 1%, 2 points: 2.6%, 3 points: 7%, 4 points: 16%, 5 points: 32%, 6 points: 56%, and 7 points: 77%. Details regarding analysis in training and validation datasets will be presented. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence and can be used by clinicians to identify high-risk pts. [Table: see text]