bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and preliminary efficacy of rogaratinib in combination with atezolizumab in a phase Ib/II study (FORT-2) of first-line treatment in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression.
Authors: Rosenberg Jonathan E. , Gajate Pablo , Morales-Barrera Rafael , Lee Jae-Lyun , Necchi Andrea , Penel Nicolas , Zagonel Vittorina , Sierecki Mitchell Robert , Piciu Ana-Maria , Ellinghaus Peter , Sweis Randy F. 
Published: May 2020

5014 Background: Programmed cell-death ligand 1 (PD-L1) overexpression is a mechanism for immune escape in UC. Rogaratinib, an oral pan-FGFR1-4 inhibitor, showed promising efficacy in a Phase I study in pts with solid tumors, including UC, with FGFR1-3 mRNA overexpression (Schuler et al. Lancet Oncol 2019). This Phase Ib/II study is evaluating rogaratinib in combination with atezolizumab, a PD-L1 inhibitor, in pts with FGFR-positive, locally advanced or metastatic UC (NCT03473756). We report results from the Phase Ib study. Methods: Cisplatin-ineligible pts with untreated metastatic UC were eligible if high FGFR1 or 3 mRNA was detected by RNA in situ hybridization of archival tissue (RNAscope). Pts were treated at a starting dose of rogaratinib 800 mg p.o. BID and atezolizumab 1200 mg i.v. on day 1 (21-day cycle). Primary objectives were safety, tolerability, and determination of the recommended Phase II dose. Results: 27 pts were treated (rogaratinib 800 mg + atezolizumab, n = 11; rogaratinib 600 mg + atezolizumab, n = 16); 85% were male, median age was 72 years (range 47-83), 37% had an ECOG PS of 1, and 96% had negative/low PD-L1 expression. Most common treatment-emergent adverse events (TEAEs) were diarrhea (63%), hyperphosphatemia (44%), and urinary tract infection (37%). Dose interruption/reduction due to AEs occurred in 67%/37% of pts; TEAEs lead to discontinuation in 45.5% (800 mg) and 12.5% (600 mg). Most common grade 3/4 TEAEs were increased lipase without pancreatitis (11%), rash, and increased alanine aminotransferase (7% each). Rogaratinib-related unique TEAEs were hyperphosphatemia (44%) and retinal pigment epithelium detachment (4%). The maximum tolerated dose (MTD) was rogaratinib 600 mg BID based on lower overall frequency of AEs. Of 23 evaluable pts (600 mg, n = 13; 800 mg, n = 10), overall 9 (39%) pts had an objective response (RECIST v1.1); 3 (13%) pts had a complete response (600 mg: 2/13 pts), 6 (26%) pts had a partial response (600 mg: 5/13 pts), and 6 (26%) pts had stable disease (600 mg: 4/13 pts). Conclusions: Rogaratinib with atezolizumab showed promising efficacy and safety in cisplatin-ineligible pts with tumor FGFR1 or 3 mRNA-positive UC, with nearly all pts demonstrating low or negative PD-L1 expression. Pts are being enrolled at the MTD of rogaratinib 600 mg BID plus atezolizumab. Clinical trial information: NCT03473756 .
Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiung-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Von Minckwitz Gunter , Geyer Charles E. , Boulet Thomas , Song Chunyan , Lewis Phillips Gail , Nowicka Malgorzata , de Haas Sanne , Basik Mark 
Published: May 2020

502 Background: The phase 3 KATHERINE study (NCT01772472) compared adjuvant T-DM1 versus H in patients with residual invasive breast cancer after neoadjuvant chemotherapy plus HER2-targeted therapy. Here we report exploratory analyses of the relationship between invasive disease-free survival (IDFS) and biomarkers potentially related to response. Methods: Formalin fixed paraffin-embedded tissue samples were collected before neoadjuvant treatment and/or at surgery. Surgical samples were used for analyses, except when only pre-treatment samples were available (~20% of cases). DNA was derived to identify PIK3CA hotspot mutations and gene expression (RNA) analysis was used to detect HER2, PD-L1, CD8 and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitor signatures. RNA analysis was adjusted for tumor content and expression levels were dichotomized at the median into low (≤) and high (>) groups. The effect of treatment and biomarkers on IDFS was assessed. Results: PIK3CA mutation (mut) status was available from 1363 (91.7%) patients. T-DM1 IDFS benefit was independent of PIK3CA mut status (mut: HR 0.54; 95%CI 0.23–0.90; non-mut: HR 0.48; 95%CI 0.35–0.65) and no impact of PIK3CA mut was observed within either treatment arm. Gene expression data were available from 1059 (71.3%) patients. Similar gene expression levels were observed between treatment arms, but, unlike the surgical samples (n = 815), the pre-treatment samples (n = 244) were not representative of the ITT population. Thus, subsequent analyses were based on surgical samples (H n = 398; T-DM1 n = 417). Consistent treatment benefit with T-DM1 vs H was observed across the single-gene and immune gene-signature subgroups as in the ITT population. High vs low HER2 expression was associated with worse outcome (HR 2.02; 95% CI 1.32–3.11) within the H arm, but not within the T-DM1 arm (HR 1.01; 95% CI 0.56–1.83). High vs low PD-L1 expression was associated with better outcome within the H arm (HR 0.66; 95% CI 0.44–1.00) but not within the T-DM1 arm (HR 1.05; 95% CI 0.59–1.87). Similar trends were observed in the checkpoint inhibitor subgroups. Conclusions: These exploratory analyses provide the first data on the relationship between biomarker expression in residual disease after HER2-targeted therapy and outcomes. PIK3CA mut status did not influence outcomes with H or T-DM1. T-DM1 benefit appeared to be independent of all biomarkers assessed. Clinical trial information: NCT01772472 .
Biomarker analysis and updated clinical follow-up of preoperative ipilimumab (ipi) plus nivolumab (nivo) in stage III urothelial cancer (NABUCCO).
Authors: Van Dijk Nick , Gil Jimenez Alberto , Silina Karina , Hendricksen Kees , Smit Laura , De Feijter Jeantine , van Montfoort Maurits L , Broeks Annegien , Lubeck Yoni , Sikorska Karolina , Boellaard Thierry N. , Kvistborg Pia , Vis Daniel J , Hooijberg Erik , Schumacher Ton , van den Broek Maries , Wessels Lodewyk FA , Blank Christian U. , van Rhijn Bas W.G. , Van Der Heijden Michiel Simon 
Published: May 2020

5020 Background: Encouraging pathological complete response (pCR) rates were observed in trials testing neoadjuvant pembrolizumab or atezolizumab in urothelial cancer (UC). In cT3-4N0 tumors, pCR to atezolizumab was only 17% and restricted to tumors showing characteristics of preexisting T cell immunity. In NABUCCO, we aimed to increase response to pre-operative checkpoint blockade, particularly in high risk patients (pts), by combining ipi plus nivo in stage III UC. We previously reported pCR in 46% and downstaging to no remaining invasive disease in 58% (ESMO2019). Here, we present biomarker analyses and updated clinical follow-up (FU) data. Methods: Twenty four stage III (cT3-4aN0 or cT2-4aN1-3) UC pts who were unfit to receive cisplatin-based chemotherapy or refused, were treated with ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. The primary endpoint was feasibility (resection < 12 weeks). Efficacy (pCR), safety and biomarker analysis were secondary endpoints. Whole-exome sequencing (WES) was done on baseline tumor samples and local lymph node (LN) metastases showing no response. RNA-seq and multiplex immunofluorescence (mIF) for immune cell markers were done pre- and post-therapy. Results: After a median FU of 15.6 months, 2 pts relapsed (both non-pCR); 1 of these 2 pts died of metastatic disease. Tumors showing complete response (CR, for biomarker analysis defined as pCR, CIS or pTa) had a significantly higher tumor mutational burden than non-CR tumors. CR to ipi+nivo was independent of baseline CD8 T-cell presence. There was no difference between CR and non-CR tumors in baseline immune gene signatures, such as interferon gamma and T-effector signatures. Surprisingly, exploratory gene expression analysis revealed that non-CR was associated with a baseline B cell immune signature, particularly immunoglobulins and genes involved in B cell receptor signaling. CD20 positive cells (by mIF) and presence of tertiary lymphoid structures (TLS) at baseline were also associated with non-CR. Upon treatment with ipi+nivo, early and mature TLS increased significantly in responding tumors. A subset of pts showed CR in the bladder, but non-CR in a local LN tumor focus. WES revealed that these LN metastases were genetically different from the primary tumor bulk. Conclusions: At 15.6 months follow-up, recurrence after pre-operative ipi+nivo was low. Pathological complete response was not restricted to tumors exhibiting preexisting T cell immunity. Clinical trial information: NCT03387761 .
Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial.
Authors: Ficial Miriam , Jegede Opeyemi , Sant'Angelo Miriam , Moreno Sonia , Braun David A. , Wind-Rotolo Megan , Pignon Jean-Christophe , Catalano Paul J. , Sun Maxine , Van Allen Eliezer Mendel , Freeman Gordon J. , Sharpe Arlene , Hodi F. Stephen , Motzer Robert J. , Wu Catherine J. , Atkins Michael B. , McDermott David F. , Shukla Sachet A. , Choueiri Toni K. , Signoretti Sabina 
Published: May 2020

5023 Background: We previously showed that levels of CD8+ tumor infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+TIM3−LAG3−) were associated with response to nivolumab (nivo) in pretreated mccRCC pts (Pignon et al, 2019). Here, we sought to validate these findings in a randomized Phase III trial of nivo versus everolimus (evero) (CM-025) and explore the association of the biomarker with transcriptomic profiles. Methods: Tumor tissues from the CM-025 trial were analyzed (nivo arm: n = 116, evero arm: n = 107). Density/percentage of CD8+ PD1+TIM3−LAG3− TIC was evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by IHC. Linear association with outcomes was assessed using binary logistic (ORR, clinical benefit (CB) defined as CR/PR and PFS≥12 months) and Cox PH (PFS, OS) regression models (1-sided p-values shown). Bulk RNA-seq was performed in a subset of samples (n = 71) and data analyzed using ssGSEA and Gene Signature Scores (GSS). Results: In the nivo arm, density of CD8+ PD1+TIM3−LAG3− TIC (IF biomarker) was associated with ORR (OR = 1.43, p = 0.03) and CB (OR = 1.54, p = 0.02) while a trend was observed with PFS (HR = 0.87, p = 0.06). At an optimized cutoff, nivo treated pts with high IF biomarker (24/116, 20.7%) had higher ORR (45.8% vs 19.6%, p = 0.01) and CB (33.3% vs 14.1%, p = 0.03) and longer median PFS (9.6 vs 3.7 months, p = 0.03) than pts with low IF biomarker. A significant interaction between the IF biomarker and treatment was seen for both PFS and OS (2-sided p = 0.02 and 2-sided p = 0.08, respectively; significance determined as p < 0.15). By bulk RNA-seq, several inflammatory pathways (FDR q < 0.1) and inflammatory GSS (FDR q < 0.05) were enriched in the high IF biomarker group. When combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated clinical outcomes (ORR, CB and PFS) in the nivo arm. In the evero arm, the IF biomarker was neither prognostic nor predictive of any clinical outcome. Conclusions: High levels of CD8+ PD1+TIM3−LAG3− TIC predicted response to nivo (but not to control evero) in mccRCC pts and were associated with activation of inflammatory response. Combination with TC PD-L1 further improved its predictive value, confirming our previous findings (Pignon et al, 2019). Further validation in the setting of first-line anti-PD-1 therapy is ongoing.
Outcomes and the impact of genomic characteristics on patients with metastatic urothelial carcinoma enrolled in early phase trials.
Authors: Alhalabi Omar , Hahn Andrew W , Meric-Bernstam Funda , Naing Aung , Piha-Paul Sarina Anne , Janku Filip , Pant Shubham , Yap Timothy A , Hong David S. , Fu Siqing , Campbell Erick , Le Hung , Shah Amishi Yogesh , Campbell Matthew T , Tannir Nizar M. , Siefker-Radtke Arlene O. , Gao Jianjun , Roszik Jason , Subbiah Vivek 
Published: May 2020

5029 Background: With the recent approvals of checkpoint inhibitors (CPIs), a fibroblast growth factor receptor (FGFR) inhibitor, and an antibody-drug conjugate, patients with platinum-refractory metastatic urothelial carcinoma (mUC) have several treatment options available. However, many patients with platinum-refractory mUC need novel therapies after progressing on current therapies. We assessed the role of early phase trials in treatment of mUC and the impact of genomic alterations on their outcomes. Methods: We retrospectively analyzed medical records of patients with mUC who received an investigational therapy at the phase 1 clinic and had CLIA-certified clinical next generation sequencing. Clinical parameters and mutations were abstracted. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Among the 57 pts enrolled in 41 unique phase 1 trials between 2015 and 2019, 16% (9/57) had variant histology: neuroendocrine carcinoma (n = 3) and urachal carcinoma (n = 6). Median age was 64. Majority were males (72%). 97% received prior platinum therapy and 60% had received prior CPI therapy. Across the pure urothelial carcinoma cohort (n = 48), median PFS was 4.2 months (m), median OS was 9.8 m, and the overall response rate (ORR) was 19%. TP53, FGFR, TERT, and ARID1A alterations (alt) were detected in 54%, 41%, 21% and 17% of UC patients, respectively. Patients harboring a TP53 alt, compared to no alt, had a shorter median PFS of 3.2m vs 9.6 m (HR = 2.738 [1.247 - 6.011], p = 0.0121). On the contrary, median PFS was longer in FGFR alt, compared to no alt, 6.3m vs 3.2m (HR = 0.4662 [0.224 - 0.971], p = 0.0415). Of note, 64% of FGFR alt patients were treated under an early phase FGFR targeting trial. Median OS was numerically longer in FGFR alt and shorter in TP53 alt but did not reach statistical significance (table). Conclusions: Patients with mUC may derive clinical benefit from enrollment in phase I clinical trials. Patients with TP53 alterations had numerically worse outcomes. Patients with mUC should be considered for an FGFR targeting therapy in the setting of an FGFR alteration. [Table: see text]
Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings.
Authors: Lyou Yung , Grivas Petros , Rosenberg Jonathan E. , Hoffman-Censits Jean H. , Quinn David I. , Petrylak Daniel Peter , Galsky Matt D. , Vaishampayan Ulka N. , De Giorgi Ugo , Gupta Sumati , Burris III Howard A. , Rearden Jessica , Andresen Corina , Wang Hao , Daneshmand Siamak , Bajorin Dean F. , Pal Sumanta K. 
Published: May 2020

5038 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), previously reported to be effective and well tolerated in patients with locally advanced/unresectable or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al. Cancer Discovery 2018]. However, this previous study did not examine differences in infigratinib activity based on number of prior lines of treatment (LOT). TKIs studied in other indications (e.g. VEGFRis in renal cell carcinoma) have shown consistent activity in both the first and later LOT. Given the effect seen with other TKIs, we sought to determine if infigratinib showed consistent treatment responses in patients with mUC according to LOT. Methods: Eligible patients had mUC and prior platinum-based chemotherapy unless contraindicated and activating FGFR3 mutations/fusions. Infigratinib was dosed at 125 mg orally daily (3 weeks on/1 week off). The primary endpoint of objective response rate (ORR: partial response [PR] and complete response [CR]) was assessed, as well as disease control rate (DCR: CR + PR + stable disease [SD]). After classification of LOT for each patient, subgroup analysis of response by LOT was performed. Results: 67 patients were enrolled; 81% received ≥1 prior LOT for mUC. 13 patients (19.4%) received infigratinib as 1st LOT for mUC due to ineligibility to receive platinum-based chemotherapy. ORR for the 67 patients was 25% (95% CI 15.5–37.5) and DCR was 64% (95% CI 51.5–75.5). The ORR with 1st-line infigratinib was 31% (95% CI 9.1–61.4) compared with 24% (95% CI 13.5–37.6) for 2nd and later (salvage) LOT. DCR was 46% (95% CI 19.2–74.9) for 1st-line and 69% (95% CI 54.4–80.5) for ≥2 LOT. 13 of the 59 patients with urothelial bladder carcinoma (UBC) received 1st-line treatment with an ORR of 31% (95% CI 9.1–61.4) and 46 patients in ≥2 LOT had an ORR of 20% (95% CI 9.4–33.9). All 8 patients with upper tract urothelial carcinoma (UTUC) received salvage therapy, with an ORR of 50% and a DCR of 100%. An analysis of other outcome measures (e.g. PFS, OS) will be presented. Conclusions: These results indicate that infigratinib has activity in patients with mUC regardless of LOT. Additionally, patients with UTUC showed a trend for better ORR and DCR. Taken together, these results support the ongoing adjuvant PROOF 302 study comparing infigratinib with placebo in patients with resected disease, assessing infigratinib in an even earlier setting in a UTUC-enriched population (NCT04197986). Clinical trial information: NCT01004224 .
Outcomes of patients (pts) with metastatic urothelial carcinoma (mUC) following discontinuation of enfortumab-vedotin (EV): Emergence of a new unmet need.
Authors: Curran Catherine , Pond Gregory Russell , Kazakova Vera , Grivas Petros , Diamantopoulos Leonidas Nikolaos , Alva Ajjai Shivaram , Su Christopher , Jain Rohit K. , Tandon Ankita , Zhang Jingsong , Necchi Andrea , Marandino Laura , Merchan Jaime R. , Plastini Trisha M. , Sonpavde Guru 
Published: May 2020

5048 Background: Enfortumab vedotin (EV) is an antibody drug conjugate recently approved to treat mUC following prior platinum and PD1/L1 inhibitors. The outcomes and patterns of therapy of pts following discontinuation of EV has yet to be studied. We investigated outcomes of pts who completed EV treatment for mUC at multiple institutions in order to identify benchmarks for evaluation of new agents following EV. Methods: Clinical data were obtained from mUC patients who had completed EV treatment from collaborating academic institutions. Descriptive stats were performed to describe the overall dataset and compare patient characteristics and outcomes of those who went on to receive further treatment post-EV and those who did not. Results: Data were available for 63 patients from 6 collaborating institutions: DFCI, University of Michigan, University of Washington, Moffitt Cancer Center, INT Milan and University of Miami. 17 (27%) were female and 46(73%) were male. The median age was 68 (range 43-83. The primary site of malignancy included bladder, upper tract, and other in 43 (68%), 19 (30%), and 1pt (.02%), respectively. The histologies included pure UC and mixed predominant UC in 49 (78%), and 14 pts (22%), respectively. 32 pts (51%) received further therapy after EV and 31pts (49%) did not. Longer duration of prior EV therapy was associated with receipt of post-EV therapy (p=0.0437). Treatments received post-EV were: trial therapy (n=14), PD1/L1 inhibitor (n=7), pemetrexed (n=4), taxane (n=3), carboplatin (n=2) and unknown in 2 pts. Objective response was observed in 3 of 32 pts (9.4%) who received therapy post-EV. The median duration of time from end of EV to death was 24 weeks. The median overall survival (OS) of those who received post-EV therapy and did not receive post-EV therapy was 37.5 weeks and 12 weeks, respectively. Conclusions: Outcomes of mUC following discontinuation of EV are dismal with only 51% receiving subsequent therapy. This study identifies an unmet need setting and establishes benchmarks for the interpretation of activity of new agents evaluated following EV.
Maintenance oral etoposide (VP-16) after high-dose chemotherapy (HDCT) for patients with relapsed metastatic germ-cell tumors (mGCT).
Authors: Anouti Bilal , Akel Reem , Althouse Sandra K. , Abonour Rafat , Abu Zaid Mohammad Issam , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: May 2020

5051 Background: HDCT and peripheral-blood stem-cell transplant (PBSCT) can cure up to 60% of patients with relapsed mGCT. Maintenance daily oral VP-16 after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the role of maintenance VP-16 post HDCT+PBSCT compared to observation. Methods: The prospectively maintained Indiana University testicular cancer database was interrogated. Patients with relapsed non-seminoma who completed HDCT+PBSCT and achieved serologic remission and hematologic recovery were evaluated. Outcomes of patients who received maintenance VP16 (N = 141) were compared to patients who were observed (N = 252). In this retrospective study, Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariable and multivariable cox regression models were used to determine variables associated with PFS. Results: 2-year PFS in the maintenance VP-16 versus observation group was 55% vs. 44% (p = 0.008). 2-year OS was 61% vs. 52% (p = 0.01). A multivariable analysis was performed including the factors: primary tumor site (testis vs. mediastinum), IGCCCG risk, platinum refractory, HDCT line of therapy (2nd vs. ≥3rd), tumor marker amplitude at HDCT initiation, and receipt of maintenance VP-16 post HDCT vs. observation. Maintenance VP-16 was confirmed as an independent predictor of improved PFS with HR 0.48 [95% CI, 0.35-0.66] (p < 0.001). Conclusions: Maintenance oral VP-16 post HDCT+PBSCT improved PFS and OS. In a multivariable model including known adverse prognostic factors, maintenance VP-16 was an independent predictor of improved PFS. [Table: see text]