bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor efficacy of concurrent everolimus with hepatic transarterial bland embolization (evero-embo) in patients with metastatic well differentiated neuroendocrine tumor (NET).
Authors: Anthony Lowell Brian , Chauhan Aman , Wu Jianrong , Krohmer Steven J , Gabriel Gaby , Adams Val R. , Evers Mark , Arnold Susanne M. , Khouli Riham
Published: May 2019

4115

Background: Hepatic transarterial embolization (HAE) is an effective loco-regional therapy for neuroendocrine tumor (NET) management. Systemic targeted therapies, such as everolimus and sunitinib, are typically held 2-4 weeks prior to and after procedures. The safety of concurrent use of everolimus with HAE has been previously reported (GI-ASCO). HAE induces anoxic injury while everolimus effects cell growth, proliferation and survival. Combining these two modalities may result in clinical synthetic lethality effectively debulking significant hepatic disease and/or delay progression. Historically bland HAE has a median hepatic PFS of ~9 months. In this study, the clinical efficacy of evero-embo is examined. Methods: A review of clinical and radiographic data was conducted for all sequential patients who underwent evero-embo between September 2016 and April 2018 at the University of Kentucky Markey Cancer Center. An independent radiologist performed RECIST measurements. Patients were required to have had systemic everolimus for ≥ 1 month prior to embolization in order to be included in this study and be on everolimus immediately post procedure. Patients with at least 12 months post procedure follow up were included for efficacy review. Results: A total of 51 HAEs with concurrent systemic everolimus were performed in 34 NET patients. Twenty one of 24 patients were noted to have a partial response. Rest had stable disease. Hepatic progression was not observed. Twenty-one of the 34 patients have had 12 or more months of follow up post procedure (median of 17 months). None of these 21 patients have had hepatic progression. Conclusions: Evero-embo results in a partial response rate of 62% and may have significant antitumor activity when compared to bland hepatic artery embolization in NET patients. With a median follow-up of 17 mos, hepatic progression has not occurred in any patient. Additional follow up is necessary to compare the median hepatic PFS of evero-embo to the historical drug-eluting bead HAE PFS.
Paclitaxel/carboplatin with or without cetuximab for treatment of carcinoma with unknown primary (PACET-CUP): Results of a multi-center randomized phase II AIO trial.
Authors: Krämer Alwin , Stein Alexander , Huebner Gerdt , Stahl Michael , Kasper Stefan , Kretzschmar Albrecht , Kohne Claus-Henning , Grünwald Viktor , Hofheinz Ralf , Schütte Katharina , Löffler Harald , Bokemeyer Carsten , Folprecht Gunnar ,   Arbeitsgemeinschaft Internistische Onkologie (AIO) - CUP group
Published: May 2019

4120

Background: Paclitaxel/carboplatin is one of the standard regimens for empiric treatment of patients (pts) with carcinoma with unknown primary (CUP) when a specific therapy is not available. The EGFR antibody cetuximab demonstrated efficacy in several cancer types. Methods: Pts with newly diagnosed non-resectable, undifferentiated or adeno-CUP were randomized to 6 cycles paclitaxel 175 mg/m² and carboplatin AUC 5 every three weeks (arm A) or the same chemotherapy plus cetuximab (400 mg/m², then 250 mg/m² weekly; arm B) at 13 German centres. CUP pts belonging to favorable prognosis groups [i.e. women with isolated peritoneal carcinomatosis or axillary lymph node metastases, men with retroperitoneal lymph nodes, pts with specific tumor entities according to histology / immunohistochemistry] were excluded from the trial. The primary endpoint was progression-free survival (PFS), secondary endpoints were response rate (RR) and overall survival (OS). Results: Between 03/2010 and 03/2017, 72 pts were randomized to arm A and 78 pts to arm B. The median age was 61 years, 84 pts were male (40 and 44 pts in arm A and B). 58 pts had a performance status (PS) of 0 (24 and 34 pts), 89 pts a PS of 1 (47 and 42 pts in arm A and B), and one patient in arm A had a PS of 2. PFS and OS did not differ between arms. The median PFS was 3.7 [95%CI: 3.0 - 4.4] and 4.6 [95%CI: 2.9 - 6.2] months in arms A and B (HR 0.98 [95%CI: 0.70-1.37]), the median OS 8.1 [95%CI: 6.5 - 9.8] and 7.4 [95%CI: 5.1 - 9.6] months in arms A and B, respectively (HR 1.10 [95%CI: 0.77 - 1.56]). There was a statistically non-significant trend towards a higher RR with cetuximab: 11 pts had a partial response in arm A (15% [95%CI: 7.9 - 26%]), and 17 pts in arm B (22% [95%CI: 13%-33%], p = 0.30). Twenty-five pts in each arm had stable disease, and 36 pts in each arm had progressive disease or were not evaluable for response. Conclusions: This study represents one of the largest trials in pts with CUP and demonstrates that randomized trials are feasible in this disorder with high medical need. The outcome of CUP pts in the unfavorable prognosis group was not improved by adding cetuximab to empiric therapy paclitaxel/carboplatin. Clinical trial information: NCT00894569.
PanCO: An open-label, single-arm pilot study of phosphorus-32 (P-32; Oncosil) microparticles in patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) in combination with FOLFIRINOX or gemcitabine + nab-paclitaxel (GNP) chemotherapies.
Authors: Ross Paul J. , Croagh Daniel , Aghmesheh Morteza , Nagrial Adnan , Nguyen Nam , Nikfarjam Mehrdad , Wasan Harpreet Singh , Ajithkumar Thankamma V. , Iwuji Chinenye , Hendlisz Alain , Maher Thomas , Kraszewski Anna , Harris Marion
Published: May 2019

4125

Background: LAPC is associated with a poor prognosis. Current standard treatment is limited to chemotherapy or chemo-radiotherapy. P-32 Microparticles is a brachytherapy device that implants a predetermined dose of P-32 into pancreatic tumours via endoscopic ultrasound (EUS) guidance. This reports the initial results of a pilot study in combination with chemotherapy. Methods: Eligible patients were permitted to receive either GNP or FOLFIRINOX. P-32 was implanted at week 4 or 5. The dose of P-32 was calculated from tumour volume to deliver an absorbed dose of 100 Gy. Diffusion pattern of the P-32 suspension was assessed by EUS and bremsstrahlung SPECT/CT imaging. Safety data was graded using CTCAE v4.0 criteria. Response was assessed according to RECIST 1.1 with CT scans every 8 weeks and FDG-PET scans at baseline and week 12. Results: 50 patients were enrolled (Intent-to-Treat population (ITT)) of which 42 were implanted with the device (Per Protocol population (PP)). 10 received FOLFIRINOX and 40 GNP. Median age was 65, 28 were male and all had a PS 0/1. 1070 adverse events (ITT) were reported; 153 (80% of patients) were ≥ Grade 3. The most common AEs of ≥ Grade 3 were haematological (39, 46%) and gastrointestinal disorders (30, 34%). No serious device- or radiation-related toxicities have been reported. PP Local Disease Control Rate at Week 16 was 90%; 95% CI: 77-97% and at Week 24 was 71%; 95% CI: 55-84%. Overall Response Rate (ORR) was 31%; 95% CI: 18-47%. Median change in tumour volume from Baseline to Week 16 and to Week 24 was -38% (range +89% to -90%) and -27.5% (range +139% to -79%). Ten (24%) patients underwent surgical resection following repeat staging. Eight patients had R0 margin. Conclusions: The use of EUS-guided implantation of P-32 is feasible, with an acceptable safety profile in combination with first-line chemotherapy for LAPC patients. Encouraging OR and DCR are observed. Further follow-up to inform results of local progression free survival and progression free survival is warranted. Acknowledgement: Nab-paclitaxel was supported by Specialised Therapeutics Australia Pty Ltd. Clinical trial information: NCT03003078.
Final results of JASPAC05: Phase II trial of neoadjuvant S-1 and concurrent radiotherapy followed by surgery in borderline resectable pancreatic cancer.
Authors: Takahashi Shinichiro , Ohno Izumi , Ikeda Masafumi , Konishi Masaru , Kobayashi Tatsushi , Akimoto Tetsuo , Kojima Motohiro , Morinaga Soichiro , Toyama Hirochika , Shimizu Yasuhiro , Miyamoto Atsushi , Hishinuma Shoichi , Takakura Norihisa , Takayama Wataru , Hirano Satoshi , Otsubo Takehito , Nagino Masato , Kimura Wataru , Sugimachi Keishi , Uesaka Katsuhiko ,   JASPAC Group
Published: May 2019

4127

Background: Borderline resectable pancreatic cancer (BRPC) is frequently associated with positive surgical margins and a poor prognosis when treated with upfront surgery. This study was designed to assess whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate. Methods: This was a multicenter, single-arm, phase II study. Patients with BRPC received S-1 (40 mg/m2 bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of the superior mesenteric vein or portal vein; and (2) tumor contact ≤180° with the superior mesenteric artery, common hepatic artery, or celiac axis. The primary endpoint was the R0 resection rate in BRPC confirmed by central review. Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (RECISTv1.1), pathological response rate, surgical morbidity (Clavien–Dindo classification), and toxicity (CTCAEv4.0). At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and threshold value for the primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible, of whom 41 had BRPC by central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% (95% CI, 37.6%–66.0%) in 52 eligible patients and 63% (95% CI, 46.9%–77.9%) in 41 patients with BRPC. The radiological response rate was 5.8%, while destruction of > 50% of tumor cells was shown microscopically in 32% of patients. Postoperative grade III/IV adverse events were observed in 7.5% of operated patients. Among the 52 eligible patients, the 2-year OS rate, median OS, and median PFS were 51%, 25.8 mo, and 6.7 mo. Of the 41 patients with BRPC, the 2-year OS rate, median OS, and median PFS were 58%, 30.8 mo, and 10.4 mo. Conclusions: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate with encouraging survival rates in BRPC. A phase II/III trial evaluating this treatment is ongoing. Clinical trial information: NCT02459652.
Relacorilant (RELA) with nab-paclitaxel (NP): Safety and activity in patients with pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA).
Authors: Munster Pamela N. , Sachdev Jasgit C. , Fleming Gini F. , Borazanci Erkut Hasan , Grabowsky Jennifer A. , Sharma Manish , Custodio Joseph , Greenstein Andrew , Lu Lawrence , Nguyen Dat , Shepherd Stacie Peacock
Published: May 2019

4130

Background: Glucocorticoid receptor (GR) pathway activation has been linked with chemotherapy resistance (CTR). RELA (formerly CORT125134, Corcept Therapeutics), a potent selective GR modulator, in combination with paclitaxel reduced CTR and enhanced activity against tumor growth in preclinical models of solid tumors. Methods: Patients (pts) with advanced solid tumors, ≤3 prior lines of cytotoxic therapy, ECOG status 0-1, and adequate marrow function received RELA (100, 150, or 200mg) + NP (60, 80, or 100mg/m2). Once daily RELA was given either continuously (CON) or intermittently (INT) (day before, of, and after NP). NP was dosed weekly for 3 of 4 weeks (wks) of a 28-day cycle. Prior NP therapy was allowed. Results: 72 pts have been enrolled [mean age 60 (range 18-81), mean number of prior therapies 3, prior taxane (TXN) treatment 54/72 (75%)]. 61 pts received ≥1 dose of RELA. Grade ≥3 AE ≥10% for CON: neutropenia (6/43, 14%); INT: neutropenia (6/18, 33%), anemia (2/18, 11%), and mucosal inflammation (2/18, 11%). Prophylactic G-CSF became mandatory in later cohorts. Recommended Phase 2 Dose: RELA 100mg-CON/150mg-INT + NP 80mg/m2 (exposures similar to NP 100mg/m2 due to CYP3A4 inhibition by RELA). Disease control (DC) > 24 wks was noted in 5/27 (19%) PDAC pts: 3 PR, 2 SD (27-50 wks). 3 pts achieved benefit despite progression on prior TXN with time to progression (TTP) 1.9-3.6x longer than prior TXN. 4/13 (31%) OvCA pts had DC > 24 wks: 1 CR, 1 PR, 2 SD (33-54+ wks). 1 pt had TTP 4.4x longer than prior TXN. 3 additional PRs were observed: acinar pancreatic cancer, TTP 31 wks (4.4x prior TXN); vulvar SCC HPV+, TTP 55 wks (3.9x prior TXN); cholangiocarcinoma, DC 29+ wks. Expression of GR-regulated genes involved in inflammation, apoptosis, and CTR distinguished pts with DC from pts without DC, providing proof of mechanism. Conclusions: RELA+NP resulted in durable disease control in pts with metastatic PDAC, OvCA, and other solid tumors, including those that have progressed on prior TXN. TTP was often several-fold longer than previously achieved on TXN therapy. Toxicities are manageable with prophylaxis for neutropenia. Further evaluation in OvCA NCT03776812, PDAC, and others are planned. Clinical trial information: NCT02762981.
Methylated circulating tumor DNA (Met-DNA) as an independent prognostic factor in metastatic pancreatic adenocarcinoma (mPAC) patients.
Authors: Pietrasz Daniel , Wang-Renault Shufang , Dahan Laetitia , Taieb Julien , Le Malicot Karine , Rinaldi Yves , Doat Solene , Phelip Jean-Marc , Taly Valerie , Bachet Jean-Baptiste , Laurent-Puig Pierre
Published: May 2019

4136

Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.
SWOG S1314: A randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer.
Authors: Flaig Thomas W. , Tangen Catherine M. , Daneshmand Siamak , Alva Ajjai Shivaram , Lerner Seth P. , Lucia M. Scott , McConkey David James , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Bangs Richard Carlton , MacVicar Gary R. , Bastos Bruno R. , Gustafson Daniel , Plets Melissa , Thompson Ian Murchie
Published: May 2019

4506

Background: Both dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). We investigated COXEN, a gene expression model, as a predictive biomarker. Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective was to assess whether the pre-specified dichotomous treatment-specific COXEN gene expression profile is prognostic of pT0 rate or ≤ pT1 at surgery, and to assess whether COXEN score is a predictive factor between regimens and response. Logistic regression was used to model response, adjusting for stratification factors. Results: 167 patients were included; the ddMVAC/GC arms had a median age of 65/64, PS = 0 in 80%/75%, Male proportion of 88%/79% and T2 stage of 87%/92%. All had at least 3 cycles of chemo and surgery/progression within 100 days of last chemo. There were favorable COXEN ddMVAC scores in 32% and GC score in 26%. The pT0 rates for ddMVAC and GC were 32% and 35%; the rates of ≤ pT1 were 55% and 49%, respectively. Conclusion: The COXEN scores were not significantly prognostic for response in their individual arms; The COXEN GC score was significant predictor for downstaging in pooled arms. There was no evidence of an interaction between COXEN score and regimen in predicting response. The prospective data and samples from this study will allow for further development of COXEN and other predictive biomarkers. Clinical trial information: NCT02177695. [Table: see text]
Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Zaghloul Tarek , Smith Andrew , Abdalla Ahmed , William Hany , Hwang Wei-Ting , Baumann Brian Christopher
Published: May 2019

4507

Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemotherapy or decline it, even though such treatment may be warranted. There is no clear alternative adjuvant therapy for these patients, who are usually observed. In this study, we compare post-op radiotherapy (PORT) vs. adjuvant chemotherapy in a randomized clinical trial. We hypothesized that PORT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. In 2007, a third arm comparing adjuvant chemo was added. Herein, we report the results of PORT vs. adjuvant chemo. Patients ≤70 y/o with ≥1 of the following factors (≥pT3b/T4a, grade 3, or positive nodes) with negative margins after RC + pelvic node dissection were eligible. Routine follow-up & pelvic CT q6 months were performed. PORT included 3D conformal pelvic RT (45Gy/1.5Gy BID). Chemo included gemcitabine/cisplatin x 4. Post-hoc non-inferiority exploratory analysis was performed. Results: The PORT arm accrued 78; the chemo arm accrued 45. 51% had urothelial carcinoma; 49% had squamous cell carcinoma/other. The two arms were well-balanced except for gender (p = 0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for PORT vs. chemo alone were 54% vs. 47% (HR 0.65(95%CI 0.35-1.19, p = 0.16) for DFS; 92% vs. 69% (HR 0.28(95%CI 0.10-0.82), p = 0.02 for LRFS; 75% vs. 79% (HR 2.39(95%CI 0.94-6.09), p = 0.07) for DMFS; 61% vs. 60% (HR 0.94(95%CI 0.52-1.69), p = 0.83) for OS. Late grade ≥3 GI toxicity was observed in 6 PORT patients (8%) & 1 chemo patient (2%). Based on our data, there is a greater than 90% probability that the true difference in 2 yr DFS is less than 10%, the pre-specified non-inferiority margin. Conclusions: This randomized study demonstrates superior local control with PORT vs. adjuvant chemo with no significant differences in DFS, DMFS or OS. Results suggest that PORT could be an option for patients with LABC after RC who are medically unfit for adjuvant chemo or who decline it. Clinical trial information: NCT01734798.
FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis.
Authors: Siefker-Radtke Arlene O. , Currie Graeme , Abella Esteban , Vaena Daniel A. , Rezazadeh Kalebasty Arash , Curigliano Giuseppe , Tupikowski Krzysztof , Andric Zoran Gojko , Lugowska Iwona , Kelly William Kevin
Published: May 2019

4511

Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. Reported response rates to immune checkpoint inhibitors (ICI) are approximately 20%. 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), which may result in lower sensitivity to ICI. V (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of both the wildtype and genetically activated receptor. This is a Phase 1b/2 study designed to evaluate V monotherapy window followed in combination of V with P(VP) (NCT03123055). Methods: This trial enrolled mUC pts with failure to ≥ 1 prior line of chemotherapy or recurrence ≤ 12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG <2. Treatment consisted of v at 25 mg/kg alone for 2 week monotherapy window followed by combination with P 200 mg q3w.during the V window paired tumor biopsy were obtained. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity [ORR]). Results: 35 pts have received treatment (Ph1b:8, WT:20, M/F+: 7). WT patients were unselected for PD-1 status, predominately male (55%) white (95%), all had received at least 1 line of prior chemo and 60% had Bellmunt scores of > 1. The safety profile is consistent with previously reported data for P. TEAE occurring in >20% of patients were nausea, anemia, diarrhea and fatigue. Six WT patients (30%) had responses (4 confirmed responses, 1 unconfirmed), and an additional patient with an iRECIST response. Responses occurred at a median of 3.5 months. At 4+ months of follow up, 13(65%) remain on treatment @ a median of 8 cycles (range: 1-13). At 5+ months the median PFS has not been reached. Conclusions: VP combination therapy is well tolerated with an encouraging ORR and prolonged PFS in the WT cohort; greater than one would anticipate from P alone based upon historical data. We will be reporting 9+ month preliminary PFS/OS and updated OOR/DOR data. Clinical trial information: NCT03123055.
Efficacy of immune checkpoint inhibitors (ICI) and genomic characterization of sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC).
Authors: Bakouny Ziad , Vokes Natalie , Gao Xin , Nassar Amin , Abou Alaiwi Sarah , Flippot Ronan , Bouchard Gabrielle , Steinharter John A. , Nuzzo Pier , Pan Wenting , Flaifel Abdallah , Lee Gwo-Shu Mary , Braun David A. , Wei Xiao X. , Signoretti Sabina , McGregor Bradley Alexander , Harshman Lauren Christine , Van Allen Eliezer Mendel , Choueiri Toni K.
Published: May 2019

4514

Background: S/R mRCC are poorly characterized rapidly progressing tumors associated with poor prognosis. Although conventional therapies are less effective for these tumors, emerging data suggests that ICIs may be especially effective. Our aim was to characterize the genomic alterations (GA) in S/R mRCC tumors and evaluate their response to ICIs. Methods: We retrospectively compared the activity of first-line ICIs to non-ICI-based therapies for S/R mRCC patients (pts) treated at DFCI and analyzed sequencing data from an NGS panel (275-447 genes) on a subset of these patients (matched by histology to non-S/R mRCC). For S/R mRCC pts treated with ICI vs non-ICI therapies, overall survival (OS) and time to treatment failure (TTF) were compared by Cox regression and objective response rate (ORR) by logistic regression. GA frequencies were compared by Fisher’s test and tumor mutational burden (TMB) by Mann Whitney U between S/R and non-S/R mRCC. Results were considered statistically significant if p < 0.05 or q < 0.10. Results: 125 S/R mRCC pts were included (88 S, 23 R, 14 S&R) among which 103 were clear cell and 48 had sequencing data. GA in BAP1 were significantly more frequent in S/R vs non-S/R (25% vs 4.3%; q = 0.096) while other GA had similar frequencies and TMB (median [IQR]) was similar (7.2 [5.2-8.4] vs 6.8 [5.3-9.1] mut/Mb; p = 0.98). Median follow-up was 35.4 (95% CI = 24.9 – 46.0) months (m). On multivariable analysis, S/R mRCC pts treated with ICI had significantly better clinical outcomes (Table). Conclusions: Pts with S/R mRCC have a higher frequency of BAP1 GA and better outcomes on ICIs compared to non-ICI-based therapies. Future studies should determine the molecular mechanisms underlying the improved response to ICIs in S/R mRCC. [Table: see text]
Patient-reported outcomes (PROs) in IMmotion150: Atezolizumab (atezo) alone or with bevacizumab (bev) versus sunitinib (sun) in first-line metastatic renal cell carcinoma (mRCC).
Authors: Pal Sumanta K. , McDermott David F. , Atkins Michael B. , Escudier Bernard , Rini Brian I. , Motzer Robert J. , Fong Lawrence , Joseph Richard Wayne , Oudard Stephane , Ravaud Alain , Bracarda Sergio , Suarez Rodriguez Cristina , Lam Elaine Tat , Choueiri Toni K. , Ding Beiying , Quach Caroleen , Hashimoto Kenji , Schiff Christina , Piault Elisabeth , Powles Thomas
Published: May 2019

4515

Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were > 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]
Phase II study of nivolumab and ipilimumab for advanced bladder cancer of variant histologies (BCVH).
Authors: McGregor Bradley Alexander , Campbell Matthew T , Xie Wanling , Siefker-Radtke Arlene O. , Shah Amishi Yogesh , Venkatesan Aradhana M. , Kilbridge Kerry L. , Sonpavde Guru , Bubley Glenn , McKay Rana R. , Choueiri Toni K.
Published: May 2019

4518

Background: Patients with BCVH have poor outcomes and data regarding the management of this heterogeneous group of patients is limited. Nivolumab and ipilimumab has demonstrated safety and efficacy in urothelial carcinoma and other malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluate the efficacy of nivolumab and ipilimumab in patients with BCVH and other advanced rare genitourinary cancers (NCT 03333616). Herein, we report the preliminary results of the fully accrued BCVH cohort. Methods: Eligible patients had metastatic BCVH, ECOG performance status of 0-2 and were either untreated or had received any number of lines of prior therapy excluding prior immunotherapy. Patients underwent a baseline biopsy and blood collection for correlative studies and received treatment with nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 19 BCVH patients were enrolled at 4 institutions between 4/2018 and 1/2019: squamous cell (n = 6), small cell (n = 3), adenocarcinoma (n = 3), urachal (n = 5), plasmacytoid (n = 1), and spindle cell (n = 1). 13 (68%) patients had received prior systemic therapy including platinum-based chemotherapy in 92% patients. Median number of cycles of ipilimumab plus nivolumab received was 3 (range 1-8) and median follow-up was 3.6 (0.3-8.8) months. 13 patients had undergone at least one scan; ORR was 31% (4/13, 80%CI: 14-52%), with partial responses seen in small cell carcinoma (n = 2), urachal (n = 1) and a complete response in 1 patient with plasmacytoid carcinoma. 3 patients (16%) developed treatment-related grade 3 toxicities with 1 (5%) grade 4 toxicity. Conclusions: Nivolumab and ipilmumab resulted in objective responses in a subset of patients with BCVH with manageable toxicities. Updated clinical and correlative data will be presented. This combination may warrant further investigation in patients with BCVH, which has substantial unmet needs. Clinical trial information: NCT 03333616.
Defects in DNA repair genes and long-term survival in cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC).
Authors: Miron Benjamin , Ross Eric A. , Anari Fern , O'Neill John , Hoffman-Censits Jean H. , Zibelman Matthew R. , Kutikov Alexander , Viterbo Rosalia , Greenberg Richard E. , Chen David , Lallas Costas D. , Trabulsi Edouard John , Alpaugh R. Katherine , Dulaimi Essel , Golemis Erica , Uzzo Robert , Plimack Elizabeth R.
Published: May 2019

4536

Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]
Proximity to oil refineries and risk of bladder cancer: A population-based analysis.
Authors: Dafashy Tamer , Phillips Daniel , Ray-Zack Mohamed Danny , Kerr Preston , Shan Yong , Baillargeon Jacques G. , Kuo Yong-Fang , Mehta Hemalkumar B , Williams Stephen Bentley
Published: May 2019

4538

Background: Exposure to aromatic amines is a risk factor for bladder cancer. Incidence rates according to proximity to oil refineries are largely unknown. We sought to determine proximity of oil refineries and bladder cancer incidence in the State of Texas which is home to the largest number of oil refineries in the United States. Methods: We used the Texas Cancer Registry database to identify patients diagnosed with bladder cancer from January 1, 2001 to December 31, 2014. The U.S. census data from 2010 was used to ascertain overall population size, age and sex distributions. Heat maps of the 28 active oil refineries in Texas were developed. Incidence of bladder cancer were compared according to proximity ( < 10 vs. ≥ 10 miles) to an oil refinery. Risk ratios were adjusted using a Poisson regression model. Results: A total of 45,517 incident bladder cancer cases were identified of which 5,501 cases were within 10 miles of an oil refinery. In adjusted analyses, bladder cancer risk was significantly greater among males vs. females (Relative Risk (RR) 3.41, 95% Confidence Interval (CI), 3.33-3.50), and greater among people living within 10 miles from an oil refinery than those living outside a 10-mile radius from an oil refinery (RR 1.19, 95% CI, 1.08-1.31). Conclusions: People living within 10 miles from oil refineries were at greater risk for bladder cancer. Further research into exposure to oil refineries and bladder cancer incidence is warranted.
Analysis of EGFR mutant urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Madison Russell , Gupta Sumati , Ross Jeffrey S. , Pal Sumanta K. , Schrock Alexa Betzig , Miller Vincent A. , Heymach John , Necchi Andrea , Juckett Luke , Ali Siraj Mahamed , Chung Jon , Reddy Venkataprasanth P.
Published: May 2019

4545

Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFR alt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 71%) and TP53 (59% v 74%) were the most frequently mutated genes in EGFR alt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 61%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFR alt in UTUC than BUC (7/17, 41% v 13/93, 14%; p = 0.01). Compared to other EGFR alt , EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (UTUC EGFRexon20 v EGFR alt other: 0% v 100%, p = 5.1E-5; BUC EGFRexon20 v EGFR alt other: 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.
KEYNOTE-052: Phase 2 study evaluating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC)— Updated response and survival results.
Authors: O'Donnell Peter H. , Balar Arjun Vasant , Vuky Jacqueline , Castellano Daniel E. , Bellmunt Joaquim , Powles Thomas , Bajorin Dean F. , Grivas Petros , Hahn Noah M. , Plimack Elizabeth R. , Savage Mary J. , Fang Xiao , Godwin James Luke , Frenkl Tara L. , De Wit Ronald
Published: May 2019

4546

Background: Initial results of the phase 2 KEYNOTE-052 (NCT02335424) study led to approval of pembro for cisplatin-ineligible patients (pts) with advanced UC. Updated results representing follow-up of over 2 y since last pt enrolled are presented. Methods: Pts had confirmed advanced UC, were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to ˂60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class III heart failure), and received no prior chemotherapy for metastatic disease. Pts received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. Primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points: duration of response (DOR), overall survival (OS), and safety. Data cutoff was September 26, 2018. Results: Among pts assessed (N = 370), median age was 74 y, 85% had visceral disease, and 30% were PD-L1 positive (combined positive score [CPS] ≥10). Median follow-up was 11.4 mo (range, 0.1-41.2) for all pts and 29.3 mo (range 7-41.2) for responders. Confirmed ORR was 29% (95% CI, 24-34): complete response, 9% (n = 33); partial response, 20% (n = 73). Median DOR was 30.1 mo (95% CI, 18.1-not reached [NR]); 67% and 52% of pts had DOR ≥12 and ≥24 mo, respectively. Median OS was 11.3 mo (range 9.7-13.1); 12- and 24-mo OS rates were 47% and 31%, respectively. In pts with CPS ˂10 (n = 251) and ≥10 (n = 110), respectively, confirmed ORR was 20% (95%CI, 16-26) and 47% (95% CI, 38-57). Median DOR for pts with CPS < 10 and ≥10 was 18.2 mo (95% CI, 9.7-NR) and NR (95% CI, 18.1-NR); DOR ≥24 mo was 45% and 57%, respectively. Median OS for pts with CPS < 10 and ≥10 was 9.7 mo (95% CI, 7.6-11.5) and 18.5 mo (95% CI, 12.2-28.5); 24-mo OS rates were 24% and 47% respectively. Treatment-related adverse events (AEs) occurred in 67% of pts. Most common were fatigue and pruritus (18% each); 21% were grade ≥3, including 1 death (myositis). Conclusions: With extended follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible pts with advanced UC and was more pronounced in those with PD-L1 expression CPS ≥10. Pembro safety profile was as expected. Clinical trial information: NCT02335424.
Interim analysis of the fierce-21 phase 2 (P2) study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).
Authors: Mellado Begona , Castellano Daniel E. , Pang S , Urun Yuksul , Park Se Hoon , Vaishampayan Ulka N. , Pal Sumanta K. , Currie Graeme , Abella Esteban , Vogl Florian D. , Necchi Andrea
Published: May 2019

4547

Background: Patients (pts) with mUC with FGFR3 mutations who have failed platinum-based chemotherapy have a poor prognosis. Their response to immune checkpoint inhibitors appears diminished 10% or less compared to WT pts. 20% of mUC pts harbor FGFR3 mutations or fusions (M/F). Vofatamab is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VFM) or in combination with docetaxel (VFD). Methods: The P2 expansion enrolled mUC pts with FGFR3 M/F+ tumor (identified with FoundationONE CDx™), who failed ≥ 1 prior line of chemotherapy (including prior taxane for pts receiving VFM) or recurred ≤ 12 months of (neo)adjuvant chemotherapy. Pts had measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone and in combination with docetaxel at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and objective response-rate (ORR). Results: In the P2, 21 pts each received VFM and VFD. 57% of VFD pts had received at least 2, and 71% of VFM at least 3 prior lines of therapy. Best response to prior therapy was PD for 67% of VFD and 38% of VFM. The safety profile is consistent with previously reported data. TEAEs occurring in > 20% of pts were decreased appetite, diarrhea, pyrexia, asthenia, anemia, dyspnea, and fatigue. Most common vofatamab-related TEAEs in > 10% of pts were asthenia, diarrhea, decreased appetite and rash; all were Grade 1 or 2. In VFM, only 1 pt had a grade 3 TEAE and no pt discontinued treatment due to an AE. There were no cases of hyperphosphatemia, ocular or nail toxicity; 1 pt reported grade 2 skin toxicity. For pts receiving VM, median age was 70 yrs, ECOG 1 = 67%, Hgb < 10 g/dL 5%, liver metastases 19%. Responses have been seen in 7 pts to date including those receiving both VFM and VFD. Conclusions: Vofatamab both alone and combined with D in a q3w schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VFM and VFD have demonstrated efficacy in terms of ORR. PFS/OS and DOR data will be presented at 7+ months for VFD and 9+ months for VFM. Clinical trial information: NCT02401542.
Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Preliminary results of an open-label phase II clinical study.
Authors: Sheng Xinan , Chen Haige , Yao Xin , Hu Yi , Yao Xudong , Liu Ziling , Zhou Fangjian , Huang Yiran , Guo Jun ,   Shanghai Junshi Biosciences Co., Ltd.
Published: May 2019

4554

Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I studies of toripalimab in subjects with heavily pretreated metastatic UC have demonstrated an acceptable safety profile and promising clinical activity. Here we report the preliminary safety and efficacy result of toripalimab in a phase II clinical study in Chinese patients with refractory/metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients will receive toripalimab, also known as JS001, 3 mg/kg Q2W until disease progression or unacceptable toxicity. All patients with measurable disease will be assessed for clinical response every 8 weeks according to RECISTv1.1. Tumor PD-L1 expression and tumor mutational burden will be measured for correlation with clinical response. Results: From May 2017 to February 10, 2019, 79 patients were enrolled from 7 participating centers. The median age was 61 years with 57.5% male. By the cut-off date of Jan 20, 2019, common treatment related AEs were mostly grade 1 or 2, including anemia, hyperglycemia, ALT increased, AST increased and hypothyroidism. Among 65 evaluable patients, 2 complete responses, 18 partial responses, and 13 stable diseases were observed, for an objective response rate (ORR) of 30.8% and a disease control rate of 50.8%. 70% (14/20) responses were ongoing by the cut-off date. PD-L1 expression results were obtained from 56 subjects. PD-L1+ patients (n=16, 28.6%) had significant better ORR than PD-L1- patients (n=40), 62.5% versus 15.0% ( p<0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients and a manageable safety profile. Toripalimab elicited a favorable 62.5% ORR in PD-L1 positive patients, while PD-L1 negative patients also achieved a 15% ORR, including one complete response. Patients will be continuously monitored for additional safety and efficacy readouts (DOR, PFS and OS). Clinical trial information: NCT03113266.
Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).
Authors: Apolo Andrea B. , Mortazavi Amir , Hu Zishuo Ian , Schonhoft Joseph , Chu Lincy , Anderson Amanda K. L. , Wang Yipeng , Dittamore Ryan , Pal Sumanta K. , Lara Primo , Stein Mark N. , Steinberg Seth M. , Mayfield Christian , Cordes Lisa M. , Mallek Marissa , Costello Rene , Diaz Carlos , Trepel Jane B , Bottaro Donald P.
Published: May 2019

4555

Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, CTC heterogeneity, CTC morphologic subtypes, and progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 123 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) drawn at Baseline, Cycle (C) 2 Day (D) 1, and C3D1 were processed using the Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was also assessed. Results: From 07/20/2016-09/01/2018, 52 pts [urothelial carcinoma (UC) N = 33; plasmacytoid N = 1; Clear cell renal cell carcinoma N = 4; bladder adenocarcinoma N = 8; bladder squamous cell carcinoma N = 2; bladder small cell N = 2; renal medullary N = 2] were treated. Median age was 61.5 years (range 20-82); 35 (67%) were male. N = 37 (71%) had visceral involvement, N = 15 (29%) with liver involvement, N = 11 (21%) with bone involvement. CTCs were found in the peripheral blood of 26/40 (65%) pts at baseline. 1/40 pts (bladder adenocarcinoma) had PDL1+ CTCs at Baseline. Median CTC/mL at Baseline, C2D1, C3D1, were not significantly different. CTC counts of > 2 and > 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Unsupervised clustering of CTC images identified 5 main CTC subtypes, of which the presence of one was significantly associated with shorter OS (p = 0.0014, not adjusted for multiple testing). Additionally, we observed a trend towards patients with higher CTC heterogeneity at C2D1 having longer OS, when adjusting for the risk associated with CTC enumeration (p = 0.084). Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were somewhat but not statistically lower in responders vs. non-responders. On treatment lower CTCs and the absence of aggressive CTC subtypes were associated with better clinical outcomes. Ongoing analyses include single cell genomics, and analysis of T-cell populations. Clinical trial information: NCT02496208.