bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of nivolumab in patients with advanced refractory biliary tract cancers (BTC).
Authors: Kim Richard D. , Kim Dae Won , Alese Olatunji B. , Li Daneng , Shah Neal , Schell Michael J. , Zhou Jun Min , Chung Vincent
Published: May 2019

4097

Background: Biliary tract cancers (BTC) are often typically diagnosed at an advanced stage. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. The phase II study evaluated safety and efficacy of nivolumab, anti PD-1 antibody in refractory BTC patients. Methods: Pts with histologically proven BTC who progressed on at least one line but no more than three lines of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by RECIST 1.1 every 8 weeks. The Simon two staged design was used to assess ORR.18 patients were accrued and if one response was seen, the plan was to accrue additional 34 patients. Secondary endpoints were PFS, OS and safety profile. Results: At data cutoff (Jan 14, 2018), 54 patients with BTC (female: 50%, Median age: 65 years) were enrolled. The primary sites of tumor were intrahepatic cholangiocarcinoma (63%) extrahepatic (11%), and gallbladder (26%). 30 pts (56%) failed 1 line of therapy and 24 (44%) failed more than one line of therapy. 45 pts (1 pt withdrew consent, 1pt just enrolled prior to data cutoff and 7 pts came off the study due to clinical progression) were evaluable for response rate. Out of 45 pts, 10 pts (22%) achieved PR (1 unconfirmed PR) and 17 pts (37.8%) achieved SD. DCR was 60%. All patients who responded were microsatellite stable. For evaluable 45 pts with median follow up of 13.34 months, median PFS was 3.98 months (95% CI: 2.33-5.98) and the median OS was 14.22 months (95% CI: 6.64-NA). 6 and 12month OS was 71.4 and 52.3% and 6 and 12 month PFS was 35.2% and 24.1% respectively. Most common treatment related AEs (TRAE) was alkaline phosphatase increased (24.5%). Grade III/IV TRAEs were seen in 11 pts (20.4%); most common were hyponatremia (3 pts) and elevated alkaline phosphatase (2 pts). No treatment related AEs led to discontinuation of the study drug. Tissue samples were collected in all pts with planned correlative studies underway including the PDL 1 status. Conclusions: Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting 2 years. Further randomized trial is warranted in refractory BTC. Clinical trial information: NCT02829918.
Predictors of poor outcome for transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).
Authors: Prins Petra , Singh Bhavana P , Armstrong Samantha Ann , He Aiwu Ruth
Published: May 2019

4100

Background: The use of TACE in select patients with BCLC stage B HCC has been shown to improve survival. Despite this, it remains unclear which patients will benefit from repeated TACE versus switching to systemic therapy upon disease progression. The purpose of this study is to identify prognostic factors that predict poor outcomes in patients who receive TACE. Methods: In this single-institutional retrospective analysis, patients with unresectable HCC were treated with TACE between 2007-2016. Relevant factors such as staging by BCLC stage B, Child-Pugh score, vascular invasion (VI), tumor thrombus (TT), AFP levels, and number of TACE treatments within six months from the initiation of TACE were analyzed using either Pearson’s chi-square test or the student's t-test. The Kaplan-Meier method was used for survival analysis. Results: Patients (n = 176) underwent TACE; 45% had stage I-II disease, 42% were BCLC stage B prior to TACE, 71% were Child-Pugh A, 21% had extrahepatic spread, 34.7% had VI, and 26% had TT. The median number of TACE treatments was 2 (range, 1- 6). The median overall survival (mOS) was 43 months (m) (95% CI 31.3-54.7) and mOS from start of TACE was 34m (95% CI 26.2-41.8). Elevated AFP (>400) correlated with decreased mOS (25m vs. 35m, p=0.041). Similarly, the presence of TT correlated with poor outcomes (25m vs. 37m, p=0.015). The mOS was also negatively impacted by having 3 or more TACE treatments within a 6 m period (25m vs. 38m, p = 0.09). AFP >400, TT, and interval between TACE were all independent factors in this multivariate analysis, resulting in a shorter mOS of approx. 2 years compared to 3 years in patients without these negative prognostic factors. There was a strong association with both elevated AFP and TT (Chi square p=0.009). Conclusions: Elevated AFP (>400), the presence of TT, and a need for 3 or more TACE treatments within 6 months appear to be independent predictors for shorter mOS in patients receiving TACE. Patients with these poor prognostic factors tend to have more aggressive HCC, and earlier initiation of systemic therapy might provide benefit to these patients. A larger study is needed for confirmation of these findings.
The SUNEVO (GETNE-1408) trial to evaluate the activity and safety of thecombination of sunitinib with evofosfamide (TH-302) in patients with G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve forsystemic treatment: A phase II study of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumors (GETNE).
Authors: Grande Enrique , Lopez Carlos , Alonso-Gordoa Teresa , Benavent Marta , Capdevila Jaume , Teule Alex , Custodio Ana , Sevilla Isabel , Gajate Pablo , Molina-Cerrillo Javier , Hernando-Cubero Jorge , Garcia-Carbonero Rocio
Published: May 2019

4105

Background: Angiogenesis plays an important role in tumorigenesis and progression of pNETs. Evofosfamide (EVO) is a DNA alkylator prodrug that selectively activates under hypoxia. Sunitinib as monotherapy shows a wide range of responses (9-24%) in similar populations. We hypothesized that sunitinib-induced hypoxia might increase the cytotoxic activity of EVO in patients with metastatic pNETS and naïve for systemic treatment other than somatostatin analogues (SSA). Methods: This is a phase-II, single-arm, and multicenter trial of EVO (340mg/m2 on days 8, 15 and 22 every 4 weeks) and sunitinib (37.5mg/day continuously). Primary endpoint was Objective Response Rate (ORR) by RECIST v1.1 assessed every 8 weeks. A Simon two-stage optimal design was used, considering a minimum of 3 responses in the first 18 pts in order to start with the second stage (power = 0.80, alpha = 0.05). Results: Between May/2015 and May/2018, 17 pts were included (median age was 62.4 y.o). Prior SSA was reported in 7 (41.2%) pts and 8 (47.1%) had a Ki-67 > 10%. There were 2 responders (11.8%; n = 1 complete and n = 1 partial response); stable disease was observed in 76.5%. Median (range) PFS and duration of response were 10.4 months (m) (2.9-17.9m) and, respectively 24.4m (13.7-35.2m), respectively. Grade 3 or 4 adverse events occurred in 11 (64.7%) pts, being neutropenia (33.3%), fatigue (16.7%), thrombocytopenia (11.1%), hand-foot syndrome (5.6%), and pancreatitis (5.6%) the most frequent. Toxicity led to treatment discontinuation in 5 (38.5%) pts. Dose reductions were reported in 20% (sunitinib) and 100 % (EVO) of pts. Conclusions: Combination of sunitinib and EVO failed to demonstrate activity in terms of tumor shrinkage as only two patients achieved response, therefore, second stage was not proceeded. While cross trial comparisons are difficult, response rate of 12% with the combination was disappointing. Concerns over toxicity arose; translational analysis are undergoing. Clinical trial information: NCT02402062.
Efficacy and safety of pembrolizumab in patients with advanced adrenocortical carcinoma.
Authors: Raj Nitya Prabhakar , Zheng Youyun , Kelly Virginia , Katz Seth , Chou Joanne F , Do Richard K. G. , Capanu Marinela , Zamarin Dmitriy , Ariyan Charlotte Eielson , Untch Brian R. , O'Reilly Eileen Mary , Gopalan Anuradha , Berger Michael F. , Olino Kelly , Segal Neil Howard , Reidy Diane Lauren
Published: May 2019

4112

Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.
Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
Authors: Park Joon Oh , Feng Yin-Hsun , Chen Yen-Yang , Su Wu-Chou , Oh Do-Youn , Shen Lin , Kim Kyu-Pyo , Liu Xiufeng , Bai Yuxian , Liao Huimin , Nie Jing , Qing Min , Ji Qinmei , Li Jiongyan , Zhao Mianzhi , De Porre Peter , Monga Manish
Published: May 2019

4117

Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.
H3B-6527 clinical biomarker assay development and characterization of HCC patient samples.
Authors: Kumar Pavan , Rimkunas Vicki , Yu Kun , Zhang Zhaojie , MacKenzie Crystal , Schindler Joanne , Smith Peter , Zhu Ping , Selvaraj Anand , Yu Lihua , Das Subhasree , Joshi Jaya Julie
Published: May 2019

4121

Background: FGFR4/FGF19 signaling axis is a novel therapeutic target in HCC. Multiple covalent FGFR4 inhibitors, including H3B-6527, are under clinical development. Preclinical efficacy studies in mice (including PDX) have shown that FGF19 expression (FGF19+) is a predictive biomarker for FGFR4 inhibitor response. The mechanisms driving FGF19 expression in HCC is largely unknown however, in some cases, focal amplification of ch11q13.3 containing FGF19 gene is thought to drive the FGF19 expression. Consistent with the preclinical observations, clinical studies have also shown that FGF19+is a predictive biomarker for FGFR4 inhibitor response. However, these trials have also reported a large number of FGF19+patients failing to respond to FGFR4 inhibitors necessitating refinement of patient selection strategies. In an attempt to obtain deeper insights into the role of FGF19+as a predictive biomarker and potentially uncover additional biomarkers that will enable improvement in patient selection strategies, we have characterized a set of 258 HCC patient samples Methods: Samples were acquired from biobanks and utilized to qualify clinical assays including FGF19 copy number (FISH), mRNA expression (qRT-PCR), FGF19 protein (IHC), and a focused NGS panel for assessing both mutations and copy number. A multiplexed protein and mRNA platform enabled assessment of p-ERK and Ki67 (protein) and Cyp7A1 (mRNA) amongst other exploratory PD biomarkers from two FFPE slides. Results: FGF19 positivity rates for IHC and qRT-PCR were 18% (41/225) and 42% (87/209), respectively. The overall correlation was 60%, with 63% (22/235) IHC positive cases also being positive by qRT-PCR. For IHC+/qRT-PCR (-) cases, RNA quality may have impacted assay sensitivity. 4% (9/244) of samples were positive for FGF19 copy number. Among samples with FGF19 copy number gains, 22% (2/9) did not show positive FGF19 expression. Conclusions: Based on our data, FGF19 mRNA is a more inclusive selection strategy and offers an approach to further refine thresholds for efficacy as determined in the clinic. Multiplexed protein-mRNA assays were also validated and implemented to enable a more comprehensive clinical biomarker program.
Metformin use and pancreatic cancer survival in U.S. veterans with diabetes mellitus: Are there racial differences?
Authors: Toriola Adetunji T. , Luo Suhong , Thomas Theodore Seth , Drake Bettina F. , Chang Su-Hsin , Sanfilippo Kristen Marie , Carson Kenneth Robert
Published: May 2019

4129

Background: Experimental and observational studies suggest that metformin holds promise in improving survival among pancreatic cancer patients. However, findings from prior observational studies have been questioned because most did not control for immortal time bias, which can overestimate the survival benefit of a drug. In addition, previous studies did not present data on African American patients. Thus, it is unknown if any survival advantage from metformin extends to African Americans. To address these limitations, we analyzed data from the U.S. Veterans Health Administration (VHA). Methods: A population-based retrospective cohort study of 3,811 (N = 773 are African Americans) pancreatic cancer patients with pre-existing diabetes mellitus diagnosed within the VHA between October 1, 1998 and December 30, 2010, and followed until December 2014. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using both the time-varying Cox proportional hazards regression model, which controls for immortal time bias, and conventional Cox model. Analyses were adjusted for confounders. We also stratified analyses by race. Further, we performed analyses among patients who were metformin naïve (N = 1158) at the time of pancreatic cancer diagnosis (most representative of patients enrolled in clinical trials). Results: Median survival was 4.5 months among metformin users versus 3.7 months among non-users. Metformin use was not associated with pancreatic cancer survival in analysis using the time-varying Cox model: HR = 1.05 (95% CI 0.92-1.14, P-value = 0.28). Results were identical among non-Hispanic Whites and African Americans. In analysis using conventional Cox model, metformin use was associated with an artificial survival benefit: HR = 0.89 (95% CI 0.83-0.98, P-value = 0.01). Among patients who were metformin naïve at the time of pancreatic cancer diagnosis, metformin use was associated with improved survival in analysis using the time-varying Cox model: HR = 0.77 (95% CI 0.61-0.98, P-value = 0.03). The HRs were 0.78 (95% CI 0.61-0.99, P-value = 0.04) among non-Hispanic Whites and 1.20 (95% CI 0.75-1.93, P-value = 0.45) among African American patients. Conclusions: We observed no associations between metformin use and pancreatic cancer survival. Nevertheless, we noted improved survival (limited to non-Hispanic White patients) among patients who were metformin naïve at the time of pancreatic cancer diagnosis, which requires conformation in other studies.
SWOG S1505: Initial findings on eligibility and neoadjuvant chemotherapy experience with mFOLFIRINOX versus gemcitabine/nab-paclitaxel for resectable pancreatic adenocarcinoma.
Authors: Sohal Davendra , Lew Danika L. , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Wade James Lloyd , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S.
Published: May 2019

4137

Background: Clinical outcomes after curative therapy of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. For early control of systemic disease with aggressive perioperative chemotherapy (CTx), we conducted a prospective trial in the National Clinical Trials Network (NCTN) setting. Methods: S1505 was a randomized phase II trial of periop (12 weeks pre-, 12 weeks post-op) CTx with either mFOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin – without bolus 5-FU and leucovorin; Arm 1), or gemcitabine/nab-paclitaxel (Arm 2). Eligibility required adult patients with ECOG PS 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease: no involvement of the celiac, common hepatic, or superior mesenteric arteries (and, if present, variants); < 180° interface between tumor and vessel wall, of the portal or superior mesenteric veins; patent portal vein/splenic vein confluence; no metastases. Primary outcome is 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients, accrual up to 150 patients was planned, to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 74 to Arm 1; 73 to Arm 2. At central radiology review, 42/147 (29%) were ineligible; of these, 15 (36%) had venous involvement ≥180°, 22 (52%) had arterial involvement, 28 (67%) had distant disease. One patient had distal cholangiocarcinoma (ineligible); one withdrew consent after randomization. Eligible patients (n = 103) had median age 64 years; males 58%; whites 89%; PS 0 64%. Of 103, 99 (96%) started and 86 (83%) completed preop CTx. There was one death due to sepsis and 61 additional patients experienced grade 3/4 toxicities. To date, 76 of 99 (77%) patients went to surgery and 72 (73%) underwent resection. Conclusions: This is the first-ever NCTN study of periop CTx for resectable PDA. Accrual was brisk, establishing feasibility. Ineligible cases after central radiology review highlight quality control and physician education imperatives for neoadjuvant PDA trials. Preop CTx safety and resection rates are encouraging. Follow up for OS is ongoing. Clinical trial information: NCT02562716.
BIONADEGE: Genomic profiling of small bowel adenocarcinoma from the NADEGE prospective cohort.
Authors: Aparicio Thomas , Svrcek Magali , Henriques Julie , Afchain Pauline , Lièvre Astrid , Tougeron David , Gagniere Johan , Terrebonne Eric , Piessen Guillaume , Legoux Jean-Louis , Lecaille Cedric , Pocard Marc , Gornet Jean-Marc , Zaanan Aziz , Lavau-Denès Sandrine , Lecomte Thierry , Benallaoua Mourad , Helfen Sabine , Vernerey Dewi , Laurent-Puig Pierre
Published: May 2019

4140

Background: Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. Methods: BIONADEGE is an ancillary study of the NADEGE cohort that enrolled 347 patients (pts) with SBA from 2009 to 2012. Next generation sequencing investigates the presence of 740 hot spot somatic mutations in 46 genes involved in carcinogenesis. The MSI (MicroSatellite Instable) status was assessed using 5 microsatellites. The MMR (MisMatch Repair) status was assessed by immunochemistry (4 antibodies). Results: A total of 196 tumour samples were collected and 125 pts had conclusive results for mutation analysis. The clinical and tumours characteristics were comparable in the NADEGE and BIONADEGE cohort except for metastatic stage at diagnostic underrepresented in the BIONADEGE cohort (17.7%) due to missing tumour sample. A predisposing disease was reported in 25 (20.0%) cases (among them 14 Lynch syndromes and 7 Crohn diseases). The number of mutation observed was 0 in 9.6% pts, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. The most frequent genomic alteration were KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%). Altogether, a genomic alteration was observed in 90.3% of tumour. KRAS mutation were more frequent in synchronous metastatic tumour than in localized tumour (72.7% vs 38.2%, p = 0.003). There was no significant difference of mutation rate according to primary location for the most frequently altered gene. With caution to small sample, IDH1 mutation is more frequent and APC mutation never seen in Crohn disease. The rate of dMMR tumor was 38.6% in localized tumour and 0% in synchronous metastatic tumour. After a median follow-up of 55 months (95%CI [44-63]), M0 stage, pN0, pT1-2 were associate with better survival in univariate analysis. No significant prognostic value of genomic alteration was associated with OS. dMMR status was associate with a better prognosis for OS in pts with MMR status determined by immunohistochemistry (HR = 0.55 [0.29-1.01], p = 0.055). Conclusions: A high frequency of targetable alteration is observed in SBA. There is several specificities according to predisposing disease. No association between genomic alteration and prognostic was observed except a trend for a better prognosis associate with dMMR.
Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: A trial of the ECOG-ACRIN cancer research group (E2810).
Authors: Appleman Leonard Joseph , Puligandla Maneka , Pal Sumanta K. , Harris Wayne , Agarwal Neeraj , Costello Brian Addis , Ryan Christopher W. , Pins Michael , Kolesar Jill , Vaena Daniel A. , Parikh Rahul Atul , Hashmi Mehmood , Dutcher Janice P. , DiPaola Robert S. , Haas Naomi B. , Carducci Michael Anthony
Published: May 2019

4502

Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.
CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Ballman Karla V. , Halabi Susan , Watt Colleen , Hahn Olwen Mary , Steen Preston D. , Dreicer Robert , Flaig Thomas W. , Stadler Walter Michael , Sweeney Christopher , Mortazavi Amir , Morris Michael J.
Published: May 2019

4503

Background: The combination of gemcitabine (G) and cisplatin (C) is a standard therapy for metastatic urothelial carcinoma (mUC). Based on data that angiogenesis plays a role in UC growth and progression, a randomized placebo-controlled trial was performed. Methods: Patients mUC, no prior chemotherapy for metastatic disease and >12 months from prior (neo)adjuvant chemotherapy and ECOG PS 0-1 were randomized 1:1 to G 1000 mg/m2 IV days 1 and 8 and C IV 70 mg/m2 day 1 with bevacizumab (GCB) 15 mg/kg IV or placebo (GCP) day 1 every 21 days. Randomization was stratified by the presence of visceral metastases and prior chemotherapy. The primary endpoint was overall survival (OS) defined as the time from randomization to death or last follow-up (FU). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and ≥ grade 3 toxicity. With 445 deaths, the log-rank test had an 87% power to detect a hazard ratio (HR) of 0.74 with a 2-sided α=0.05. The primary analysis was based on the stratified log-rank test adjusting on stratification factors. Alliance Data Safety and Monitoring Board approved the final OS analysis be performed at 420 events due to lower than expected event rates. Results: 506 patients were randomly assigned (252 GCB, 254 GCP) stratified by the presence of visceral disease and prior chemotherapy for UC. The median FU for patients still alive was 46.2 months. Median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP with a HR of 0.87 (95%CI 0.72-1.06; 2-sided Wald p=0.17). The HR for PFS was 0.77 (95%CI 0.63-0.93) in favor of GCB (p=0.0074). Grade 3 or greater adverse event rate was 83.5% with GCB compared to 80.7% with GCP. Conclusions: The addition of bevacizumab to GC chemotherapy did not result in improved OS (primary endpoint) in patients with mUC but there was a PFS improvement. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180853, U10CA180888, Genentech https://acknowledgments.alliancefound.org. Clinical trial information: NCT00942331.
Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182.
Authors: Galsky Matt D. , Pal Sumanta K. , Mortazavi Amir , Milowsky Matthew I. , George Saby , Gupta Sumati , Fleming Mark T. , Dang Long H. , Geynisman Daniel M. , Walling Radhika , Alter Robert S. , Robin Erwin L. , Wang Jue , Gupta Shilpa , Chism David D. , Picus Joel , Philips George , Quinn David I. , Hahn Noah M. , Yu Menggang
Published: May 2019

4504

Background: Platinum-based chemotherapy for 1st-line treatment of pts with metastatic urothelial cancer (mUC) is typically administered for a fixed duration followed by observation until recurrence. PD-1 blockade with pembro improves survival of pts with mUC progressing despite platinum-based chemotherapy. We explored the potential benefit of earlier use of PD-1 blockade using a "switch maintenance" approach. Methods: Pts with mUC achieving at least stable disease after up to 8 cycles of 1st-line platinum-based chemotherapy were enrolled. Pts were randomized 1:1 to pembro 200 mg IV q3 weeks versus placebo for up to 24 months; pts progressing on placebo could cross over to pembro. Randomization was stratified based on pre-chemotherapy visceral metastases (Y/N) and response to 1st-line chemotherapy (CR/PR vs. SD). The primary objective was to determine the progression-free survival (PFS) as per irRECIST among pts treated with pembro versus placebo. Results: Between 12/2015 and 11/2018, 107 pts were randomized to placebo (n=52) versus pembro (n=55). The baseline pt characteristics are shown in the Table. Pts randomized to placebo and pembro received a median of 6 and 8 cycles, respectively. Excluding patients with baseline CRs, the objective response rate was 12% (5/42) on placebo and 22% (10/46) on pembro. Grade 3-4 treatment emergent adverse events occurred in 48% of pts on placebo and 56% on pembro. At a median follow-up of 14.7 months, 41 pts have died and 26/52 pts randomized to placebo have crossed over to pembro. PFS was significantly longer in patients randomized to pembro vs. placebo (Maximum Efficiency Robust Test p=0.036; log-rank p = 0.038). The 18-month restricted mean progression-free survival time was 5.6 months with placebo and 8.2 months with pembro (p=0.023). Conclusions: Switch maintenance pembro may “deepen” responses achieved with 1st-line chemotherapy. Switch maintenance pembro prolongs PFS in pts with mUC completing 1st-line platinum-based chemotherapy. Clinical trial information: NCT02500121. [Table: see text]
Infigratinib in upper tract urothelial carcinoma vs urothelial carcinoma of the bladder and association with comprehensive genomic profiling/cell-free DNA results.
Authors: Dizman Nazli , 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 Howard A. , Soifer Harris S. , Li Gary , Dambkowski Carl L. , Moran Susan , Ye Yining , Daneshmand Siamak , Bajorin Dean F. , Pal Sumanta K.
Published: May 2019

4510

Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant activity in patients (pts) with advanced or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al 2018]. Given the distinct biologic characteristics of upper tract UC (UTUC) and urothelial carcinoma of the bladder (UCB), we sought to determine if infigratinib had varying activity in these settings. Methods: Eligible pts had mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy, unless contraindicated. Pts received infigratinib 125 mg orally daily (3 wks on/1 wk off). Overall response rate (ORR: CR+PR) and disease control rate (DCR; CR+PR+SD) were characterized in UCB and UTUC pts. Comprehensive genomic profiling was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA). Blood was collected for cell-free (cf)DNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer. Results: 67 pts were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. ORR was 25.4% and DCR was 64.2%. In the 8 pts with UTUC, 1 CR and 3 PRs were observed (ORR 50%); the remainder had a best response of SD (DCR 100%). UTUC pts were predominantly 2nd line (62.5%), with only 2 (25%) showing response to previous treatment. In pts with UCB, 13 PRs were observed (ORR 22%), and 22 pts had a best response of SD (DCR 59.3%). Notable differences in genomic alterations between cohorts included a higher frequency of FGFR3-TACC3 fusions (12.5% vs 5.8%) and FGFR3 R248C mutations (50% vs 11.5%), and a lower frequency of FGFR3 S249C mutations (25% vs 59.6%) in UTUC vs UCB. Consistent with previous reports [Sfakianos et al 2016], UTUC pts had a differential frequency of alterations in HRAS, CDKN2B and ARID1A. Sufficient cfDNA yield was obtained in UTUC and UCB pts and a comprehensive comparison of these data will be presented. Conclusions: Differences in cumulative genomic profile were observed between UCB and UTUC in this FGFR3-restricted experience, underscoring the distinct biology of these diseases. Results with infigratinib in UTUC support a planned phase III adjuvant study predominantly in this population. Clinical trial information: NCT01004224.
Atezolizumab (atezo) + bevacizumab (bev) versus sunitinib (sun) in pts with untreated metastatic renal cell carcinoma (mRCC) and sarcomatoid (sarc) histology: IMmotion151 subgroup analysis.
Authors: Rini Brian I. , Motzer Robert J. , Powles Thomas , McDermott David F. , Escudier Bernard , Donskov Frede , Hawkins Robert E. , Bracarda Sergio , Bedke Jens , De Giorgi Ugo , Porta Camillo , Ravaud Alain , Parnis Francis , Grande Enrique , Zhang Wei , Huseni Mahrukh A. , Carroll Susheela , Sufan Roxana Ioana , Schiff Christina , Atkins Michael B.
Published: May 2019

4512

Background: In the Phase 3 IMmotion151 trial, atezo + bev showed improved PFS vs sun in untreated mRCC pts expressing PD-L1. Here we report results of a prespecified subgroup analysis in pts whose tumors have sarc histology, an independent predictor of poor survival. Methods: Pts were randomized to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sun 50 mg po qd for 4w on, 2w off. Coprimary endpoints were reported previously (Motzer ASCO GU 2018). Secondary endpoints included INV-PFS and OS in sarc pts and are shown here with INV-ORR, safety, PRO and biomarker data. Results: 142 randomized pts (16%) from IMmotion151 had tumors with any component of sarc histology; mPFS was 8.3 vs 5.3 mo with atezo + bev vs sun and mOS was NR vs 15.0 mo, respectively (see Table for PD-L1+). ORR was 49% vs 14% and CR rate was 10% vs 3% in the atezo + bev vs sun arms. Grade 3-4 AEs occurred in 27 pts (40%) with atezo + bev and 34 (49%) with sun. Using the MDASI scale, sarc pts reported longer median time to deterioration (TTD) of symptom interference with daily activities with atezo + bev vs sun (11.3 vs 4.9 mo). Prevalence of AngiogenesisHigh gene expression (GE) signature subset was lower (34% vs 65%) and T-effectorHigh GE subset was higher (54% vs 40%) in sarc vs non-sarc tumors. PD-L1+ disease was more common in sarc vs non-sarc tumors (63% vs 39%). Conclusions: mRCC pts with sarc histology had longer OS and PFS and a higher ORR/CR rate when treated with atezo + bev vs sun, regardless of PD-L1 status. Biomarker data support a biological correlate for the increased responsiveness to atezo + bev in sarc pts. Clinical trial information: NCT02420821. [Table: see text]
CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features.
Authors: McDermott David F. , Choueiri Toni K. , Motzer Robert J. , Aren Osvaldo Rudy , George Saby , Powles Thomas , Donskov Frede , Harrison Michael Roger , Rodriguez Cid Jeronimo Rafael Rafael , Ishii Yuko , McHenry M. Brent , Mekan Sabeen Fatima , Rini Brian I. , Tannir Nizar M.
Published: May 2019

4513

Background: Patients (pts) with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognosis and suboptimal outcomes with anti-VEGF targeted therapy. Nivolumab plus ipilimumab (N+I) demonstrated superior objective response rate (ORR) and overall survival (OS) vs sunitinib (S) in previously untreated pts with International Metastatic RCC Database Consortium (IMDC) intermediate/poor (I/P)-risk, clear-cell, advanced RCC in the phase 3 CheckMate 214 trial. Methods: We performed a post-hoc exploratory analysis of N+I vs S in CheckMate 214 sRCC pts. The presence of sarcomatoid features was assessed by keyword search for “sarcomatoid” in pts with available local pathology reports accompanying pretreatment tumor samples. Results: 842 (77%) of 1096 intention-to-treat pts had local pathology reports available, including 112 randomized pts with I/P-risk sRCC (N+I, n = 60; S, n = 52). Baseline characteristics of sRCC pts were balanced between arms. Notably, 47% vs 53% of I/P-risk sRCC pts in the N+I and S arms had tumor PD-L1 expression ≥1% at baseline, which was higher than in all I/P-risk pts (N+I, 26% vs S, 29%). In descriptive analyses performed at a minimum follow-up of 30 months, confirmed ORR and complete response rate per investigator (RECIST v1.1), OS, and progression-free survival (PFS) per investigator were improved with N+I vs S in I/P-risk pts with sRCC (Table). No new safety signals were seen in sRCC pts. Conclusions: In this post-hoc descriptive subgroup analysis of CheckMate 214, N+I demonstrated promising efficacy and prolonged survival vs S, with consistent safety, in previously untreated, I/P-risk, advanced clear-cell RCC with sarcomatoid features. Prospective studies of N+I that include pts with sRCC are ongoing. Clinical trial information: NCT02231749. [Table: see text]
Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920.
Authors: Emamekhoo Hamid , Olsen Mark , Carthon Bradley Curtis , Drakaki Alexandra , Percent Ivor John , Molina Ana M. , Cho Daniel C. , Bendell Johanna C. , Gordan Lucio N. , Rezazadeh Kalebasty Arash , George Daniel J. , Hutson Thomas E. , Lee Richard J. , Young Tina C. , Johansen Jennifer , Tykodi Scott S.
Published: May 2019

4517

Background: Previous clinical trials of patients (pts) with aRCC, including CheckMate 214, have mostly excluded pts with brain metastases. However, antitumor activity in pts with brain metastases has been observed in pts with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and pts with non-small cell lung cancer treated with NIVO 240 mg + IPI 1mg/kg. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO + IPI treatment in pts with aRCC with a high unmet medical need. Here, we present the safety and efficacy interim results for the cohort of pts with brain metastases. Methods: Pts with previously untreated aRCC of any histology, with asymptomatic brain metastases (not on corticosteroids or receiving radiation), and Karnofsky performance status ≥70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses, followed by NIVO 480 mg every 4 weeks. Pts were treated until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was the incidence of high-grade immune-mediated adverse events (IMAEs). Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 per investigator. Exploratory endpoints included additional safety analyses and overall survival (OS). Results: Overall, 28 patients were enrolled in the brain metastases cohort. With a minimum follow-up of 6.47 months, grade 3-4 IMAEs within 100 days of last dose were reported in 6 cases. The grade 3-4 IMAEs observed in ≥ 1 patient were diarrhea, colitis, diabetic ketoacidosis, immune-mediated hepatitis, hypophysitis, and rash of any type (n = 1 each). No treatment-related grade 5 IMAEs were reported. ORR by RECIST v1.1 per investigator in all treated subjects was 28.6% (95% CI 13.2–48.7). Median PFS in all treated subjects was 9.0 months (95% CI 2.9–not estimable [NE]). Median OS has not been reached (95% CI 13.1–NE). Conclusions: In pts with aRCC and brain metastases who are often excluded from clinical trials, NIVO + IPI treatment showed a safety profile consistent with previous reports of this dosing regimen, with encouraging antitumor activity. Clinical trial information: NCT02982954.
Correlation of methylthioadenosine phosphorylase (MTAP) loss with response to anti-folate therapy in urothelial bladder carcinoma (UBC).
Authors: Alhalabi Omar , Chen Jianfeng , Campbell Matthew T , Slack Tidwell Rebecca , Han Guangchun , Wang Wei-Lien , Song Jian H. , Ramachandran Sumankalai , Lopez Lidia , Hoang Anh , Siefker-Radtke Arlene O. , Titus Mark Anton , Guo Charles , Gallick Gary , Msaouel Pavlos , Efstathiou Eleni , Logothetis Christopher , Ho Thai Huu , Wang Linghua , Gao Jianjun
Published: May 2019

4521

Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.
Outcomes of patients (pts) with metastatic urothelial cancer (mUC) and poor performance status (PS) receiving anti-PD(L)1 agents.
Authors: Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Li Ang , Devitt Michael Edward , Drakaki Alexandra , Shreck Evan , Joshi Monika , Velho Pedro Isaacsson , Alonso Lucia , Nelson Ariel Ann , Liu Sandy , Moses Marcus W. , Barata Pedro C. , Hoimes Christopher J. , Galsky Matt D. , Sonpavde Guru , Yu Evan Y. , Shankaran Veena , Lyman Gary H. , Grivas Petros
Published: May 2019

4525

Background: Anti-PD(L)1 immune checkpoint inhibitors (ICI) prolong overall survival (OS) after platinum chemotherapy in mUC. However, clinical outcomes in pts with poor PS at time of ICI initiation are unknown. We hypothesized that ICI initiation in pts with ECOG PS 2-3 would be associated with worse outcomes vs. pts with ECOG PS < 2, and impact death location. Methods: A retrospective cohort study in 8 institutions identified pts with mUC who received ICI. Demographic, clinicopathologic, treatment (tx) patterns, tx response, and outcomes were collected. Primary endpoint: overall response rate (ORR). Secondary endpoints: median (m) OS in pts receiving ICI as 1st and 2nd line (1L, 2L); odds of dying in hospital (vs elsewhere) for pts receiving ICI (vs no tx) within 30 days of death; and estimated drug cost for pts with ICI within 30 days of death based on average wholesale price. Unadjusted logistic regression was used to assess association between ORR and ECOG PS (2-3 vs < 2) and wald test was used to compare mOS between ECOG PS (2-3 vs < 2). Results: 194 consecutive pts (30% women, 41% never smokers, median age at diagnosis 69) treated with ICI for mUC were identified. Median number of total tx lines was 2; all pts received ≥1 ICI line (6 pts received 2 ICI lines); 97, 79, 17 and 7 pts received ICI in 1L, 2L, 3L and 4L, respectively; 26% pts with ICI in 1L and 2L had ECOG PS 2-3. ORR and mOS are shown in table. Among 106 pts who died, 96 had available death location; of those, 8% received ICI within 30 days of death. Starting ICI within 30 days of death (vs no tx) was associated with higher odds of hospital death (OR 6.05, 95%CI 1.3-27.6). Estimated average ICI cost/pt within 30 days of death was $1400.58. Conclusions: Pts with ECOG PS 2-3 at time of ICI initiation had similar ORR vs ECOG PS < 2 but worse mOS. ICI initiation within 30 days from death was associated with higher likelihood of hospital death. ICI may not circumvent the negative prognostic role of poor PS, so biomarker-based pt selection is critical. Limitations include lack of adjustment for selection bias and other confounders at time of ICI initiation; data validation is ongoing. [Table: see text]