bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes of patients with resectable pancreatic cancer treated with upfront surgery versus neoadjuvant chemotherapy: A retrospective tertiary care center experience.
Authors: Liu Fang , Mirsky Matthew , Wu Sulin , Fu Pingfu , Cao Shufen , Shanahan John , Kyasaram Ravi Kumar , Jain Prantesh , Hardacre Jeffrey , Ammori John Brian , Winter Jordan Michael , Bajor David Lawrence
Published: May 2020

4623

Background: The role of neoadjuvant chemotherapy (NAC) for resectable pancreatic cancer (RPC) remains controversial. We sought to compare the outcomes of NAC with upfront surgery (UFS). Methods: The study retrospectively enrolled patients with RPC who had UFS or received neoadjuvant FOLFIRINOX (FFX) or gemcitabine plus albumin-bound paclitaxel (GA). Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher’s exact test for categorical variables. The overall survival (OS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method with Wilcoxon test for the difference between groups. The effects of NAC vs. UFS on OS and RFS were further estimated using Cox regression controlling the effects of age and CA 19-9. Results: Between 2011 and 2019, 131 patients with RPC underwent UFS followed by adjuvant chemotherapy (gemcitabine, n = 65; gemcitabine/capecitabine, n = 18; FFX, n = 9). Up to 32 patients (24.4%) could not receive adjuvant chemotherapy due to surgical complications or poor recovery. Total 50 patients with RPC received NAC (FFX, n = 32; GA, n = 18). Median of 5.5 cycles of FFX or 3 cycles of GA were given prior to surgery. Resection rate was 72% (FFX 62.5%; GA 88.9%). The rest (28%) were no longer surgical candidates due to disease progression rather than toxicities from NAC. On surgical pathological review, complete resection (R0) was achieved in 83.3% of resected cases after NAC (FFX 90%; GA 75%) and 79.4% with UFS. The tumor size distribution was: pT1 11.1%, pT2 41.7%, pT3 44.4% with NAC; pT1 5.4%, pT2 18.3%, pT3 76.3% with UFS. The nodal status distribution was: pN0 27.8%, pN1 55.5%, pN2 16.7% with NAC; pN0 23.7%, pN1 71.0%, pN2 5.3% with UFS. Median pre-treatment CA 19-9 was 321.95 unit/mL in the NAC group and 79.99 unit/mL in the UFS group (p = 0.009). Median age was 70.5 in the NAC group and 72 in the UFS group (p = 0.374). There was no significant difference in the performance status between the two groups. In Kaplan-Meier analysis, there was a significant difference of OS between UFS and NAC with median OS of 648 days under UFS versus 884 days under NAC (p = 0.029); the median of RFS was 390 days under UFS versus 392 days under NAC (p = 0.953). The hazard ratio (NAC vs UFS) adjusted for CA19-9 and age was 0.7 (p = 0.176) for OS and 0.98 (p = 0.918) for RFS. Conclusions: We observed a signal of tumor downstaging, higher R0 rate, and improved OS with NAC compared with UFS. Further prospective trials are needed to validate these results.
Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: Multicenter study of the Korean Cancer Study Group (KCSG).
Authors: Chon Hongjae , Park Hyung Soon , Kang Beodeul , Im Hyeon-Su , Lee Choong-kun , Kim Ilhwan , Kang Myoung Joo , Hwang Jun-Eul , Bae Woo Kyun , Cheon Jaekyung , Hong Jung Yong , Kang Jung Hun , Kim Jung Hoon , Lim Sung Hee , Kim Jin Won , Kim Ji-Won , Yoo Changhoon , Choi Hye Jin , Park Joon Oh
Published: May 2020

4624

Background: There is no clear consensus on the second-line treatment for patients with metastatic pancreatic cancer (mPC). The aim of this study was to compare the efficacy and tolerability between liposomal irinotecan (nal-IRI) plus fluorouralcil/leucovorin (FL) and FOLFIRINOX (oxaliplatin/irinotecan/leucovorin/fluorouracil) in patients who failed to first-line gemcitabine-based therapy. Methods: In this retrospective study, 378 mPC patients who received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as the second-line treatment across 11 institutions from January 2015 to August 2019 were analyzed. The primary end point was progression free survival (PFS), and secondary end points were overall survival (OS), overall response rate, and tolerability. Results: There were no significant differences between the two groups in terms of baseline characteristics, except first-line regimen (previous gemcitabine/nab-paclitaxel, nal-IRI/FL, 85.6% vs. FOLFIRINOX, 51.5%; previous gemcitabine monotherapy, 5.8% vs. 24.5%). The median follow-up time was 6.0 months. The median PFS (nal-IRI/FL, 3.7 months vs. FOLFIRINOX, 5.0 months) and OS (nal-IRI/FL, 7.7 months vs. FOLFRINOX, 9.7 months) were comparable between two groups (P = 0.40 and 0.13, respectively). The overall response rate was not significantly different between two groups (nal-IRI/FL, 14% vs. FOLFRINOX, 16%; P = 0.644). In multivariate analysis, poor ECOG status, presence of liver metastasis, high NLR, and high CA19-9 were independent prognostic factors for PFS and OS, but chemotherapy regimen (nal-IRI/FL vs. FOLFRINOX) was not. In a subgroup analysis of patients with liver metastasis, FOLFIRINOX exerted significant PFS (median: 2.1 months vs. 4.1 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.02) and OS (median: 6.7 months vs. 8.4 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.04) benefit compared with nal-IRI/FL. Grade 3 neutropenia or higher were more frequently observed in FOLFIRINOX (47.2%) than nal-IRI/FL (35%) (P = 0.033). Grade 3 peripheral neuropathy was also common in FOLFIRIONX (5.9%) group compared with nal-IRI/FL (1.0%) (P = 0.049). Conclusions: In second-line setting for mPC after progression on gemcitabine-based therapy, both nal-IRI/FL and FOLFIRINOX regimen showed comparable efficacy and acceptable safety outcomes. FOLFIRINOX regimen might be preferentially considered in patients with liver metastasis.
Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C), and paricalcitol (P)neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Borazanci Erkut Hasan , Jameson Gayle S. , Snyder Courtney Edwards , Tsai Frank Yung-Chin , Gordon Michael S. , Sharma Sunil , Guarnieri Carol , Thosani Amar , Rahmanuddin Syed , Korn Ronald Lee , Sckolnik Steven , Salontai Sharon , Wyman Rachel , Haag Susan , Gosselin Kevin , Von Hoff Daniel D. , Amini Albert
Published: May 2020

4631

Background: Localized PDAC management has recently evolved. Due to concerns over micro metastases at diagnosis the use of neoadjuvant chemotherapy for PDAC has become more common. Typical therapies involve the use of multiagent systemic chemotherapies with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. We conducted a prospective, phase 2 clinical trial of patients with resectable (R), BR, and LA PDAC utilizing a regimen combining A + G + C + paricalcitol (P) with the primary endpoint of CA 19-9 normalization (NCT03138720). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2, P at a fixed dose of 25 µg on days 1, 8 of a 21-day cycle (all treatment IV). Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate, and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date 24 of the planned 24 patients have been enrolled. 13 male, 11 female; age range 49 to 84 yo. Patient classifications is 8 R; 7 BR; 9 LAPC. Median baseline CA 19-9 156 (range 45-3674). Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 29%, gr 4 25%, anemia gr 3 45.8%, gr 4 4.2%, and hypophosphatemia gr 3 8.3%. CA 19-9 normalization occurred in 50% (12/24) who have completed at least 1 cycle of treatment. To date, 14 individuals went to surgery, with 13/14 achieving R0, (1 pCR). Overall response rate in measurable patients is 38% (1 CR, 8 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+P resulted in a CA 19-9 normalization rate in 50% of individuals. The study is ongoing and OS data is maturing. Clinical trial information: NCT03138720 .
Interim data: Phase I/IIa study of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682 (E-EDV-D682) with immunomodulatory adjuvant EDVs carrying α-galactosyl ceramide (EDV-GC) in patients with recurrent, metastatic pancreatic cancer.
Authors: Lundy Joanne , Marx Gavin M. , MacDiarmid Jennifer , Brahmbhatt Himanshu , Ganju Vinod
Published: May 2020

4632

Background: Targeted EDV nanocells loaded with doxorubicin and microRNA16a have shown excellent safety profiles in Phase I trials in recurrent glioma and mesothelioma. This planned safety analysis of an ongoing first-in-human, open label Phase I/IIa study in patients with treatment-refractory metastatic pancreatic cancer, assesses safety, biologic and clinical activity of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682, designed to overcome drug resistance, combined with EDV nanocells carrying immunomodulatory adjuvant α-galactosyl ceramide, designed to stimulate anti-tumour immune response. Methods: 9 patients with advanced pancreatic cancer enrolled in the dose escalation phase to evaluate safety of the EDV combination. Doses gradually escalated from 2 x 109 EDVs/dose to a maximum of 7 x 109 EDVs/dose in Week 7, with subsequent dosing at the maximum dose achieved in Cycle 1. iRECIST criteria was used to assess tumour response after each cycle, and blood was collected each cycle for cytokine and PBMC analysis. Results: Combination EDVs were well tolerated with no DLTs, and no drug related SAEs. A minority of patients experienced G1 infusion reactions, which responded promptly to supportive treatment. PR or SD was achieved at 8 weeks in 8/9 patients (CBR 89%), with responses confirmed at 4 months in 4/5 evaluable patients (80%), with 2 durable responses seen beyond 6 months. Exploratory analyses have revealed elevation of IFN-α and IFN-γ in almost all evaluable patients (6/8). In addition, we observed elevated CD8+ T cells (2/8), iNKT, dendritic and NK cells (3/8), and a reduction in exhausted CD8+ T cells (3/8), suggesting activation of both innate and adaptive immune responses. Conclusions: EDVs carrying the cytotoxic drug and immune adjuvant are safe and well tolerated. Early signals point to durable responses, possibly related to the development of an innate and adaptive immune response along with cytotoxic effects on drug resistant tumour cells. The Phase IIa study plans to enrol an additional 35 patients to further evaluate safety and anti-tumour efficacy. Clinical trial information: ACTRN12619000385145 .
A phase Ib study of sEphB4-HSA combined with first-line chemotherapy in patients (pts) with advanced pancreatic (PC) and biliary cancers (BC).
Authors: Hanna Diana L. , Iqbal Syma , Habib Diane , Tsao-Wei Denice D. , Barzi Afsaneh , Thomas Jacob Stephen , Chiu Victor , Siddiqi Imran , Bhavsar Rishi D. , Jensen Nicole G. , DeLeon Cristina , Lenz Heinz-Josef , Gill Parkash S. , El-Khoueiry Anthony B.
Published: May 2020

4640

Background: EphB4, a receptor kinase expressed in most epithelial tumors, binds EphrinB2 to affect cancer cell growth, apoptosis and angiogenesis. EphB4 overexpression is associated with advanced stage and shorter survival in multiple cancers. sEphB4-HSA, the albumin-bound extracellular fragment of EphB4, is a first-in-class inhibitor which blocks EphB4-EphrinB2 bidirectional signaling and results in downstream suppression of KRAS, PI3K, and promotes recruitment of CD3 and CD8 T cells into the tumor. The RP2D of sEphB4-HSA is 10 mg/Kg IV q week. Here, we report on sEphB4-HSA in combination with standard first-line chemotherapy. Methods: Pts with advanced PC or BC and no prior therapy for metastatic disease were eligible and enrolled into separate cohorts. Pts with PC received gemcitabine 1,000 mg/m2 + nab-paclitaxel 125 mg/m2 on Days 1, 8, 15 of a 28-day cycle. Pts with BC received gemcitabine 1,000 mg/m2 + cisplatin 25 mg/m2 on Days 1, 8 of a 21-day cycle. sEphB4-HSA 10 mg/kg IV was given weekly starting in Cycle 2. Response was assessed every 2 cycles. Primary endpoint was safety and tolerability; secondary endpoints were objective response rate (ORR) by RECIST 1.1, PFS, OS. Expression of EphrinB2 and EphB4 in tumor was examined by IHC and classified as 1+ (weak staining); 2+ (moderate staining); 3+ (strong, uniform staining). Results: A total of 44 pts with advanced PC (n = 21) and BC (n = 23; 70% gallbladder cancer) were enrolled. Median age 66 yrs; ECOG 1 (70%), 52% male. Median number of cycles received were 5 (PC) and 7 (BC). Median PFS was 5.6 mo in PC and 5.8 mo in BC (95% CI: 3.1-8.1 [PC]; 2.7-7.0 [BC]). Median OS was 7.9 mo in PC and 9.1 mo in BC (95% CI: 6.5-15.0 [PC]; 5.4-15.0 [BC]). In response evaluable pts (20 PC, 22 BC), ORR was 40% in PC (95% CI: 21%, 63%) and 23% in BC (95% CI: 9%, 45%). Stable disease was noted in 48% of PC and 61% of BC pts. The most common grade 3 or 4 treatment-related AEs in ≥10% of pts in both cohorts combined were hypertension (n = 16; 36%), neutropenia (n = 15; 34%), anemia (n = 14; 32%), thrombocytopenia (n = 7, 16%), fatigue (n = 7, 16%). In the PC cohort, there was an association between EphB4 expression and objective response (p = 0.009). Conclusions: sEphB4-HSA has a manageable safety profile in combination with chemotherapy in pts with PC and BC. Clinical activity is manifested by a high disease control rate in both cohorts and a promising RR in PC. Additional biomarker analyses will be presented. Future studies combining chemoimmunotherapy with sEphB4-HSA in pancreatic cancer are planned. Clinical trial information: NCT02495896 .
Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426.
Authors: Plimack Elizabeth R. , Rini Brian I. , Stus Viktor , Gafanov Rustem , Waddell Tom , Nosov Dmitry , Pouliot Frédéric , Soulieres Denis , Melichar Bohuslav , Vynnychenko Ihor , Azevedo Sergio Jobim , Borchiellini Delphine , McDermott Raymond S. , Bedke Jens , Tamada Satoshi , Yin Lina , Chen Mei , Molife L. Rhoda , Atkins Michael B. , Powles Thomas
Published: May 2020

5001

Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here. Methods: Treatment-naive patients (pts) with clear cell aRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Primary end points were OS and PFS. Secondary end points were ORR, DOR, and safety. All P values are nominal. A post-hoc exploratory analysis was done to evaluate association of depth of response (maximum reduction from baseline in sum of diameters of target lesions) and OS using landmark analysis up to 6 mo after randomization. Results: 861 pts were randomly assigned (pembro + axi, n = 432; sunitinib, n = 429). Median (range) duration of follow-up for all pts was 27.0 mo (0.1-38.4). Pembro + axi improved OS (HR, 0.68 [95% CI, 0.55-0.85]; P < 0.001; 24-mo OS rate, 74% vs 66%) vs sunitinib. Median (95% CI) OS was not reached with pembro + axi and was 35.7 mo (33.3-NR) with sunitinib. Pembro + axi improved PFS (HR, 0.71 [95% CI, 0.60-0.84]; P < 0.001; 24-mo PFS rate, 38% vs 27%) vs sunitinib. For pembro +axi vs sunitinib respectively, median (95% CI) PFS was 15.4 (12.7-18.9) vs 11.1 mo (9.1-12.5); ORR was 60% vs 40% ( P < 0.0001); CR rate was 9% vs 3%; and median DOR was 23.5 mo (range 1.4+ to 34.5+) vs 15.9 mo (range 2.3-31.8+). In general, the pembro + axi benefit was observed in all subgroups tested, including IMDC risk and PD-L1 expression subgroups. Post-hoc landmark analysis at 6-mo showed that pts on pembro + axi with ≥80% target lesion reduction had OS similar to that of pts with CR per RECIST v1.1 based on Kaplan-Meier curves and HR [95% CI] estimates (0.20 [0.05-0.84] vs. 0.10 [0.01-0.76], respectively) vs pts with 0-30% target lesion reduction. No new safety signals were observed. Conclusions: Pembro + axi continued to demonstrate superior and durable antitumor activity vs sunitinib in pts with first-line aRCC with a 27-mo median follow up; no new safety signals were observed. Clinical trial information: NCT02853331 .
Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma.
Authors: Jonasch Eric , Donskov Frede , Iliopoulos Othon , Rathmell Wendy Kimryn , Narayan Vivek , Maughan Benjamin Louis , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Welsh Sarah J. , Thamake Sanjay , Park Eric Kristopher , Zojwalla Naseem J. , Perini Rodolfo F. , Linehan W. Marston , Srinivasan Ramaprasad
Published: May 2020

5003

Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target-toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788 .
DUTRENEO Trial: A randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signature.
Authors: Grande Enrique , Guerrero Félix , Puente Javier , Galante Isabel , Duran Ignacio , Dominguez Mario , Alonso Gordoa Teresa , Burgos Javier , Font Albert , Pinto Alvaro , Alvarez-Maestro Mario , Reig Oscar , Maroto José , Garcia del Muro Xavier , Galvan Patricia , Garcia Juan Fernando , Malats Nuria , Prat Aleix , Real Francisco X. , Castellano Daniel
Published: May 2020

5012

Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]
Phase II study of nivolumab and ipilimumab for advanced rare genitourinary cancers.
Authors: McGregor Bradley Alexander , Campbell Matthew T , Xie Wanling , Farah Subrina , Bilen Mehmet Asim , Sonpavde Guru , Kilbridge Kerry L. , Choudhury Atish Dipankar , Mortazavi Amir , Shah Amishi Yogesh , Venkatesan Aradhana M. , Bubley Glenn , Siefker-Radtke Arlene O. , McKay Rana R. , Choueiri Toni K.
Published: May 2020

5018

Background: Patients with rare genitourinary malignancies (Bladder cancer of variant histologies (BCVH), adrenal tumors, chemotherapy refractory germ cell tumors (CRGCT), penile carcinoma and prostate cancer of variant histology (PCVH)) have poor outcomes. Nivolumab and ipilimumab has demonstrated safety and efficacy in genitourinary malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluated the efficacy of nivolumab and ipilimumab in pts with advanced rare genitourinary cancers (NCT 03333616). Herein, we report the results of the fully accrued BCVH, adrenal and other cohorts. Methods: Eligible pts had a metastatic rare genitourinary malignancy, ECOG performance status of 0-2 and no prior immune checkpoint inhibitor exposure; aside from CRGCT pts could be treatment naïve. Eligible pts received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses with continued nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 56 pts were enrolled at 6 institutions between 4/2018 and 7/2019 in 3 cohorts: BCVH (N = 19), adrenal tumors (n = 18) and other tumors (n = 19). Median follow-up was 9.9 (range < 1~21) months. 28(50%) pts received all 4 doses of nivolumab and ipilimumab. 25 pts received nivolumab maintenance at a median of 4 (range 1-18) cycles. ORR in entire cohort was 16% (n = 9: 2 CR 7 PR, Table); 67% of responders (6/9) maintained response greater than 9 months. Median PFS was 2.8 (2.7-5.2) months. 22 pts (39%) developed treatment-related ≥ grade 3 toxicity; 23% required high dose steroids (≥40 mg prednisone or equivalent) and 15 (27%) pts discontinued treatment due to an AE. Grade 5 toxicity occurred in 3 pts; 1 death was treatment related. Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of pts with rare GU malignancies, especially in BCVH. Biomarkers are being evaluated and an additional cohort exploring the activity in genitourinary tumors with neuroendocrine differentiation is ongoing. This combination warrants further investigation in these pts with substantial unmet needs. Clinical trial information: NCT 03333616 . [Table: see text]
A phase Ib trial of neoadjuvant/adjuvant durvalumab +/- tremelimumab in locally advanced renal cell carcinoma (RCC).
Authors: Ornstein Moshe Chaim , Zabell Joseph , Wood Laura S. , Hobbs Brian , Devonshire Sarah , Martin Allison , Allman Kimberly D. , Rao Arpit , Gilligan Timothy D. , Campbell Steven , Krishnamurthi Venkatesh , Rini Brian I.
Published: May 2020

5021

Background: Effective neoadjuvant and adjuvant therapies are lacking in locally advanced RCC. Given robust activity of checkpoint inhibitors in mRCC, a phase Ib trial of perioperative Durvalumab (D) +/- Tremelimumab (T) in locally advanced RCC was conducted (NCT02762006). Methods: Pts with radiographic evidence of high risk localized RCC (clinical stage T2b-4 and/or N1, M0 disease), adequate performance status, and adequate laboratory values were eligible. Primary objective was safety and feasibility of neoadjuvant/adjuvant D +/- T. Results: Twenty-nine pts were enrolled. Cohorts, regimens, and immune-related adverse events (irAE) are detailed in the table. In total, 79% male, median age 61 (range, 42-84), 8%/88%/4% clinical T2/T3/T4, 27% positive clinical lymph nodes (LN+), and median time from neoadjuvant dose to surgery was 7 days. On surgical pathology: 5%/14%/77%/5% pathologic T1/T2/T3/T4, and 13% LN+. Median time from treatment to first grade (Gr) >3 irAE or any Gr irAE requiring corticosteroids was 99 days (range, 32-207). There were no treatment-related delays to nephrectomy or surgical complications. Although not meeting the protocol-defined MTD, given higher than expected irAEs, the study was suspended. Conclusions: Perioperative durvalumab in locally advanced RCC appears safe. The addition of tremelimumab is associated with higher rates of toxicity. Updated toxicity will be presented. Clinical trial information: NCT02762006 . [Table: see text]
Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.
Authors: Petrylak Daniel Peter , Tagawa Scott T. , Jain Rohit K. , Bupathi Manojkumar , Balar Arjun Vasant , Rezazadeh Arash , George Saby , Palmbos Phillip Lee , Nordquist Luke T. , Davis Nancy B. , Vogelzang Nicholas J. , Ramamurthy Chethan , Sternberg Cora N. , Loriot Yohann , Agarwal Neeraj , Hong Quan , Gladden Allison , Kanwal Charu , Goswami Trishna , Grivas Petros
Published: May 2020

5027

Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade ≥3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21-day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade ≥3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade > 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973 .
Association of molecular subtypes with pathologic response in a phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy (NAC) for localized, muscle-invasive bladder cancer (SWOG S1314; NCT02177695).
Authors: Lerner Seth P. , McConkey David James , Tangen Catherine , Meeks Joshua J , Flaig Thomas W. , Hua Xing , Daneshmand Siamak , Alva Ajjai Shivaram , Lucia M. Scott , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Choi Woonyoung , Bangs Richard Carlton , Gustafson Daniel , Thompson Ian Murchie
Published: May 2020

5028

Background: Cisplatin-based NAC is recommended for patients with MIBC prior to radical cystectomy (RC) but the majority will not have a pathologic response. To identify responders the COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed and in a prospective rPII clinical trial (SWOG S1314) the GC score was associated with path downstaging in the pooled arms. We investigated RNA based molecular subtypes as additional predictive biomarkers for response to NAC in patients treated in S1314. Methods: Eligibility required cT2-T4a N0 M0, predominant urothelial, > 5 mm tumor, cisplatin eligible, and plan for RC and PLND. 237 patients were randomized between 4 cycles of ddMVAC and GC. Based on Affymetrix transcriptomic data used to assign COXEN scores, we determined subtypes using 3 classifiers: TCGA (k=5), Consensus (k=6), and MD Anderson (MDA; k=3). Primary objective was to assess subtype association with pathologic response to NAC in the pooled arms and to determine any association with COXEN. TCGA and Consensus classifiers were collapsed into 3 groups for ROC analyses. We tested whether each classifier contributed additional predictive power when added to a model based on pre-defined stratification factors (PS 0 vs. 1; T2 vs. T3, T4a). Results: 161 patients had adequate tissue and gene expression results, received at least 3 of 4 cycles of NAC and had pT-N response based on RC. Covariates were 78% PS=0, 89% T2, 84% male, median age 65, 51% randomized to ddMVAC, 49% GC with 33% pT0 and 52% downstaging. Although the TCGA 3 group classifier (Basal-Squamous (BS)/Neuronal, Luminal, Luminal infiltrated) and GC Coxen score yielded the largest AUCs (0.607, 0.610) for pT0 response, neither reached statistical significance (p=0.20, p=0.22). For downstaging (<pT2), the 3 category Consensus classifier (BS/NE-like, Luminal, Stroma-rich) significantly increased the AUC from 0.568 (strat factors alone) to 0.620 (p=0.044). The MDA classifier AUC was 0.640 and the GC Coxen score AUC was 0.626, but neither were significant (p=0.076, p=0.14. The MVAC Coxen score did not improve the AUC beyond the stratification factors. Conclusions: The Consensus classifier, which is based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging when added to clinical stage and PS. With additional followup, we will assess the association of COXEN scores and subtypes with overall survival. Clinical trial information: NCT02177695 .
Pathological response rates and quality of life outcomes of neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle-invasive transitional cell carcinoma of the urinary bladder.
Authors: Challapalli Amarnath , Masson Susan , White Paul , Dailami Narges , Pearson Sylvia , Rowe Edward , Koupparis Anthony , Oxley Jon , Ash-Miles Janice , Bravo Alicia , Foulstone Emily , Persad Raj , Bahl Amit
Published: May 2020

5030

Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy, safety and tolerability of cisplatin cabazitaxel combination in this patient group. Methods: A phase 2 single arm trial (Simon 2 stage), to recruit at least 26 evaluable patients was designed with 80% power to detect the primary endpoint, objective response rate (ORR) of > 35%. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging), measured by pathologic staging (T2 or greater at diagnosis, to T1 or less at radical cystectomy). Treatment was with Cisplatin 70mg/m2 and Cabazitaxel 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. Quality of Life (QoL) data were collected at baseline, prior to each cycle of chemotherapy and at 3-5 weeks after 4th cycle of chemotherapy using EQ-5D and EORTC QLQ-C30, BLM30 questionnaires. Results: Objective response was seen in 15 out of 26 evaluable patients, 57.7% and over a third of patients achieved pCR (9/26; 34.6%). 78% (21/27) of patients completed all cycles of treatment, with only 6.7% of the reported adverse events (AEs) being graded 3 or 4. There were 6 treatment related SAEs reported but no SUSARs. In patients who achieved objective response the median progression free (PFS) and overall survival (OS) were not reached (median follow up: 41.5m). In contrast, median PFS (7.2m) and OS (16.9m) were significantly worse (p = 0.001) in patients who did not respond. Response rates for EORTC QLQ-C30, BLM 30 and EQ5D questionnaires was 70.4, 70.4 & 63% respectively, at end of treatment. There was no significant difference in EORTC QLQ C30 summary, global health scores and EQ5D score with treatment. There was a significant decline in mean QLQ C30 domain scores after 1st cycle compared to baseline, but no further deterioration with subsequent cycles of chemotherapy. Conclusions: Cabazitaxel with cisplatin as NAC of MIBC can be considered a safe, well-tolerated and effective regimen with higher pCR rate of 34.6%. This compares favorably to that with Cisplatin/Gemcitabine (23-26%). Minimal changes in Global Health & EQ5D observed during NAC further demonstrates the excellent tolerability of this regimen and to our knowledge are the first data regarding QoL in NAC in MIBC. These results warrant further evaluation in a larger phase 3 study. Clinical trial information: 2011 004090 82 .
Comparative effectiveness of second-line (2L) single-agent atezolizumab (A), nivolumab (N), and pembrolizumab (P) in patients (Pts) with locally advanced or metastatic urothelial cancer (aUC) who progressed on platinum-based systemic chemotherapy (plat-chemo): Results from a real-world dataset.
Authors: Swami Umang , Haaland Ben , Maughan Benjamin Louis , Nussenzveig Roberto , Esther John , Kessel Adam , Pal Sumanta K. , Grivas Petros , Agarwal Neeraj
Published: May 2020

5032

Background: Five PD-1/L1 inhibitors (PDi) are approved for 2L therapy (Rx) for aUC after progression on plat-chemo, but none compared with each other in randomized trials. Here, we assessed comparative effectiveness of 2L PDi in real-world setting. Methods: Pt level data of Pts with aUC were extracted from Flatiron Health EHR-derived de-identified database. Inclusion criteria: 1L Rx with plat-chemo; receipt of single agent PDi in 2L; initiation of 2L PDi 6 mos before data-cut off. Exclusion criteria: >90 days from diagnosis to date of next visit to ensure active engagement of Pts with data providing site; initiation of 2L after 7/31/2016 to ensure uptake of PDi for aUC. OS was compared from the date of initiation of 2L Rx. Comparative effectiveness was examined by Cox proportional hazards model, stratified by treatment propensity score. Each Pts’ propensity of receiving each 2L PDi was modeled via a random forest based on Pt and disease characteristics potentially driving Rx selection for a PDi (gender, smoking status, race/ethnicity, relapsed vs de novo disease, time between 1L & 2L Rx, cis vs carboplatin in 1L; year of Rx with PDi & following characteristics before 2L Rx: ECOG, Hb, age, ICD codes for liver or CNS mets, albumin & PD-L1 status when available). Results: 703 Pts with aUC who initiated 2L Rx between 8/1/2016 to 10/31/2019 were eligible. 2L Rx were A (n=322), N (n=127) & P (n=254). Durvalumab & avelumab were excluded due to low utilization in this dataset. Median follow up from 2L initiation was 4.8 mos. Median OS (mos; 95% CI) with A (6.4 mos; 5-8.7), N (8 mos; 6.3-11.3) and P (8.5 mos; 6.1-11.6) were similar (propensity stratified log rank p=0.19; simple log-rank p=0.34). Over time proportion of Pts receiving 2L A decreased, P increased & N increased then decreased (p<0.001). Propensity stratified comparative effectiveness estimates are below. Conclusions: In this real-world cohort of Pts with aUC, OS with 2L Rx with A, N, & P were similar on both univariate and propensity stratified analyses. These results agree with prior trial level meta-analysis (PMID 31200951). Strength of this analysis includes large Pt level data from a real world cohort. Limitations include retrospective nature of this study. [Table: see text]
Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Results of an open-label phase II clinical study Polaris-03.
Authors: Sheng Xinan , Chen Haige , Hu Bin , Yao Xudong , Liu Ziling , Yao Xin , Guo Hongqian , Hu Yi , Ji Zhigang , Luo Hong , Shi Benkang , Liu Jiyan , WU Jin , Zhou Fangjian , He Zhisong , Fan Jinhai , Huang Yiran , Guo Jun
Published: May 2020

5040

Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I study of toripalimab in subjects with heavily pretreated metastatic UC had demonstrated an acceptable safety profile and promising clinical activity. Here we report the safety and efficacy result of toripalimab in a phase II clinical study (POLARIS-03) in Chinese patients with metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients receive toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response is assessed every 8 weeks. Tumor PD-L1 expression and other biomarkers will be evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and the study enrollment was completed with 151 patients enrolled from 15 participating centers. The median age was 62 years and 66% were male. 87% patients had visceral metastasis. By the cut-off date of Jan 6, 2020, 92.1% (139/151) patients experienced treatment related adverse event (TRAE) and grade 3 and above TRAE occurred in 35.8% (54/151) patients. Most common TRAE included anemia, triglycerides increased, proteinuria, fatigue, and hyperglycemia. Treatment discontinuation due to a TRAE occurred in 6 (4.0%) patients, while dose delay due to a TRAE occurred in 23 (15.2%) patients. Three patients with major protocol deviations were excluded from efficacy analysis. Among 148 patients assessed by IRC per RECISTv1.1, 2 CR, 36 PR, and 30 SD were observed for an ORR of 25.7% and a DCR of 45.9%. The median DOR was 15.7 months. The median PFS was 1.9 months, and the median OS was estimated 20.8 months. PD-L1 expression results were obtained from 141 patients. PD-L1+ patients (n=46) had significant better ORR than PD-L1- patients (n=95), 41.3% versus 16.8% ( p<0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients with a manageable safety profile. Patients will be continuously monitored for safety and overall survival. Clinical trial information: NCT03113266 .
Dissecting outcomes of patients (pts) with <ypT2N0 disease after neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC): Results from a large, international, multicenter collaboration.
Authors: Ravi Praful , Pond Gregory Russell , Diamantopoulos Leonidas Nikolaos , Jain Rohit K. , Skelton William Paul , Gupta Sumati , Tward Jonathan David , Olson Kathleen , Singh Parminder , Grunewald Camilla Marisa , Niegisch Guenter , Lee Jae-Lyun , Gallina Andrea , Bandini Marco , Necchi Andrea , Mossanen Matthew , McGregor Bradley Alexander , Curran Catherine , Grivas Petros , Sonpavde Guru
Published: May 2020

5043

Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.
Analysis of chemotherapy-related modulation of the immune microenvironment in muscle invasive bladder cancer.
Authors: Hasanov Elshad , Tabayoyong William , Chen Jianfeng , Yang Guoliang , Nie Fengqi , Meng Jieru , Hoang Anh , Zhu Yueting , Efstathiou Eleni , Bondaruk Jolan , Wang Wei-Lien , Guo Charles , Zhang Miao , Czerniak Bogdan , Logothetis Christopher , Kamat Ashish M. , Gao Jianjun
Published: May 2020

5049

Background: Novel immune checkpoint inhibitors provide significant clinical benefits for patients with metastatic bladder cancer. It is known that chemotherapy administered to muscle invasive patients prior to radical cystectomy (neoadjuvant chemotherapy) improves survival. However, it is unknown whether immune checkpoint inhibitor therapy in combination with chemotherapy can provide further clinical benefits as neoadjuvant therapy. Here, we test the hypothesis that treatment of bladder cancer with certain chemotherapy agents can modulate bladder tumor immune microenvironment (TIME) for optimal combination with immune checkpoint therapy. Methods: Time course and dose response experiments were performed using eight human bladder cancer cell lines (UMUC3, RT4, 253J, RT112, J82, HT1376, T24, and HT1197) and two murine bladder cancer cell lines (MB49, MBT2). Conventional chemotherapy agents and combinations (MVAC, GemCis, PemVin) were used to treat bladder cancer cell lines. Flow cytometry analysis was used to measure immune cell subsets and PD-L1 expression. For in vivo studies, the subcutaneous MB49 murine bladder cancer model was used to evaluate responses to chemotherapy and anti-PD-L1 combinations. Pre- and post-treatment bladder tumors from patients who received neoadjuvant MVAC and GemCis are selected to evaluate changes in TIME. Results: Our data demonstrate that chemotherapy agents varies in their ability to up-regulate PD-L1 expression on bladder cancer cell lines. Vinblastine, gemcitabine, and pemetrexed treatment each resulted in significant upregulation of PD-L1 expression. Combination regimens with GemCis or PemVin demonstrated induction of PD-L1 across different cell lines. In in-vivo studies, GemCis + anti-PD-L1 had a synergistic activity in causing tumor regression. We also found that sequential versus concurrent treatment with chemotherapy and anti-PD-L1 had a similar outcome. Tissue analyses show that combination chemotherapies increased CD4 Th cell infiltration while decreasing Treg cells in TIME. Consistent with the in vitro data, PD-L1 expression was also up-regulated with combination treatment. The evaluation of TIME modulation in human bladder tumors treated with neoadjuvant MVAC or GemCis is ongoing. Conclusions: Our data suggest that chemotherapy could favorably modulate TIME and thus, may be combined with immune checkpoint inhibitor to improve anti-tumor responses in the neoadjuvant setting for patients with muscle invasive bladder cancer.