Prevalence of PD-L1 expression in first-line (1L) locally advanced/unresectable or metastatic urothelial carcinoma (UC).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS67-TPS67
Author(s):  
Petros Grivas ◽  
Alicia K. Morgans ◽  
Yair Lotan ◽  
Jeffrey P. Gregg ◽  
Daniel M. Geynisman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Tissue ◽  
Performance Status ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Mutational Burden ◽  
Platinum Based Chemotherapy ◽  
Tumor Mutational Burden ◽  
Pre Treatment ◽  
And Performance

TPS67 Background: Treatments for 1L advanced/metastatic UC include platinum-based chemotherapy, an immune checkpoint inhibitor (ICI) or clinical trial enrollment. Not all patients benefit from, or are eligible for, specific therapies due to comorbidities and performance status. There is an urgent need for biomarker-directed strategies to enable patient selection and improve outcomes. Currently the only clinically used molecular biomarker is PD-L1 protein expression in tumor tissue. Although inconsistent and variable among assays, higher PD-L1 expression generally correlates with increased ICI response rate. Improved understanding of the prevalence and potential prognostic and/or predictive role of PD-L1 can further enhance its clinical utility and guide novel clinical trial designs. Methods: This observational study will enroll 250 patients with advanced UC prior to starting or during 1L therapy, as initiated at the discretion of participating clinicians, from 60 US community sites. The primary endpoint is prevalence of PD-L1 expression by VENTANA SP263 Assay (exact [Clopper-Pearson] 95% CI) on pre-treatment tumor tissue. Secondary endpoints include the association of pre-treatment PD-L1 expression with pre-treatment tumor tissue mutational burden (tTMB), descriptions of treatment response and outcomes (ORR based on RECIST 1.1, PFS, OS) and assessment of their correlations with PD-L1 expression. Exploratory endpoints include the association of pre-treatment tumor tissue PD-L1 with pre-treatment blood-based tumor mutational burden (bTMB), changes in circulating tumor DNA (ctDNA) levels at various timepoints, the correlation between tTMB and bTMB values, and the association of those biomarkers for outcomes of PFS and OS. Enrollment will take place over 24 months with follow-up to 30 months from study enrollment. With 250 patients, the 95% CI for 30%, 45%, and 60% observed prevalence of PD-L1 high are (24.4%, 36.1%), (38.9%, 51.2%), and (53.6%, 66.1%), respectively; the various secondary and exploratory analyses will be descriptive.

Causes of patient ineligibility in clinical trials of metastatic urothelial cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4556-4556
Author(s):  
Gwynn Ison ◽  
Virginia Ellen Maher ◽  
Chana Weinstock ◽  
Sundeep Agrawal ◽  
Michael Holman Brave ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Urothelial Cancer ◽  
Tumor Tissue ◽  
Performance Status ◽  
Locally Advanced ◽  
Underlying Disease ◽  
Inhibitor Therapy ◽  
Eligibility Criteria ◽  
Metastatic Urothelial Cancer ◽  
Morbid Conditions

4556 Background: Registrational trials of PD-1/PD-L1 inhibitor therapy help inform clinicians and patients about the expected outcomes of patients receiving these drugs. However, the clinical trial population does not reflect all patients with the underlying disease. There have been ongoing efforts to expand eligibility criteria for clinical trial enrollment that are expected to mitigate some of these factors. We reviewed four registrational trials of PD-1/PD-L1 inhibitor therapy to better understand why patients were deemed ineligible for trial enrollment and whether expanded eligibility criteria may have addressed the reasons for ineligibility. Methods: We reviewed four trials that led to approval of PD-1/PD-L1 inhibitor therapy. These trials screened 1931 and enrolled 1253 patients with metastatic or locally advanced urothelial cancer who had previously received platinum-based therapy. We examined the datasets to determine patient demographics and reasons for trial ineligibility. Results: There were no differences in the demographics characteristics of patients who were eligible or ineligible for study treatment. However, when compared to the SEER database the screened population was younger, and minorities were under-represented. Causes of patient ineligibility included: 1) Lack of Tumor Tissue/PD-L1 Low Tumor Staining (23%), 2) Underlying Disease characteristics were not met (19%), 3) Laboratory Abnormalities (18%), 4) Excluded Co-morbid Conditions (16%), 5) Poor Performance Status (15%), 6) Refused Consent (10%), 7) Other (7%), and 8) Incorrect Prior Therapy (5%). Conclusions: Clinical trial accrual should be representative of all patients with the underlying disease. Changes in trial eligibility criteria such as less stringent requirements concerning tumor tissue (when possible), co-morbid conditions, laboratory abnormalities, and performance status may improve patient accrual. These, when added together, formed the majority of the reasons for clinical trial ineligibility.

Capecitabine (C), oxaliplatin (OXP), and radiation (RT) in resectable esophagus cancer (EC): A phase II trial with gene expression profiling (GEP)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15543-e15543
Author(s):  
N. I. Khushalani ◽  
J. Miecznikowski ◽  
D. Wang ◽  
N. Nowak ◽  
H. Nava ◽  
...  
Keyword(s):  
Phase Ii ◽  
Tumor Tissue ◽  
Clinical Stage ◽  
Performance Status ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Distinct Pattern ◽  
Dose Finding ◽  
Pre Treatment ◽  
And Performance

e15543 Background: Novel chemotherapy regimens in combination with RT aim to improve the pathologic complete response (pCR) in EC. Following our dose-finding phase I study, the present phase II neo-adjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, with secondary end-points of evaluating toxicity, quality of life, and GEP of tumor tissue for correlation to therapeutic response. Methods: EC patients (PTS) with stages II-IVa, adequate organ function and performance status (ECOG 0–1) were eligible. Treatment consisted of OXP, 85mg/m2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m2 bid on days of RT, and 50.4 Gy RT (3-D conformal) in 28 fractions, followed by an esophagectomy (E) 4–6 weeks later. 2 cycles of OXP + C were administered post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-treatment (Rx), day (D) 17 and at E; > 50% viable tumor cells were required. Results: 20 PTS have been enrolled (17 male, 3 female); median age 59.5 yrs; 17 adenocarcinomas & 3 squamous-cell cancers. Clinical stage: II (3), III (13) and IVa (4). 18 PTS have completed NA therapy; Grade 4 toxicity includes anemia (1), lymphopenia (2); grade 3 toxicity includes esophagitis (1), pneumonia (1), wound infection (1), anastomotic leak (2), esophageal fistula (1), bowel obstruction (1), fatigue (1), hyperbilirubinemia (1), elevated ALT, AST (1 & 2, respectively), hypoalbuminemia (3), OXP hypersensitivity (2) & leucopenia (1). One PT died > 60d post- operatively secondary to infection. 15 PTS have undergone an E with 3 pCR (20%). Analysis on pre-Rx GEP on 17 PTS revealed a distinct pattern for pCR PTS with 325 over-expressed and 79 under-expressed genes. Ongoing functional analysis will characterize GEP changes in 1) pCR PTS pre-Rx & at D17, 2) pCR & non-pCR PTS pre-Rx, and 3) by histology. Validation will be performed via RT-PCR. Accrual to the trial continues. Conclusions: C, OXP & RT appears to be a tolerable and efficacious NA regimen for EC. The exploratory GEP analysis may provide insight on predicting response to NA therapy. Acknowledgement: The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc. [Table: see text]

scholarly journals Safety and Activity of Metronomic Temozolomide in Second-Line Treatment of Advanced Neuroendocrine Neoplasms

2019 ◽  
Vol 8 (8) ◽  
pp. 1224 ◽  
Author(s):  
Salvatore Tafuto ◽  
Claudia von Arx ◽  
Monica Capozzi ◽  
Fabiana Tatangelo ◽  
Manuela Mura ◽  
...  
Keyword(s):  
Performance Status ◽  
Complete Response ◽  
Neuroendocrine Neoplasms ◽  
Line Treatment ◽  
Second Line ◽  
Clinical Experiences ◽  
Significant Treatment ◽  
Platinum Based Chemotherapy ◽  
Suitable Treatment ◽  
And Performance

Background. Platinum-based chemotherapy is the mainstay of front-line treatment of patients affected by pluri-metastatic intermediate/high grade NeuroEndocrine Neoplasms (NENs). However, there are no standard second-line treatments at disease progression. Previous clinical experiences have evidenced that temozolomide (TMZ), an oral analog of dacarbazine, is active against NENs at standard doses of 150 to 200 mg/mq per day on days 1 to 5 of a 28-day cycle, even if a significant treatment-related toxicity is reported. Methods. Metastatic NENs patients were treated at the ENETS (European NeuroEndocrine Tumor Society) center of excellence of Naples (Italy), from 2014 to 2017 with a second-line alternative metronomic schedule of TMZ, 75 mg/m2 per os “one week on/one week off”. Toxicity was graded with NCI-CTC criteria v4.0; objective responses with RECIST v1.1 and performance status (PS) according to ECOG. Results. Twenty-six consecutive patients were treated. Median age was 65.5 years. The predominant primary organs were pancreas and lung. Grading was G2 in 11 patients, G3 in 15. More than half of patients had a PS 2 (15 vs. 11 with PS 1). The median time-on-temozolomide therapy was 12.2 months (95% CI: 11.4–19.6). No G3/G4 toxicities were registered. Complete response was obtained in 1 patient, partial response in 4, stable disease in 19 (disease control rate: 92.3%), and progressive disease in 2. The median overall survival from TMZ start was 28.3 months. PS improved in 73% of patients. Conclusions. Metronomic TMZ is a suitable treatment for G2 and G3 NENs particularly in PS 2 patients. Prospective and larger trials are needed to confirm these results.

scholarly journals Methods of measurement for tumor mutational burden in tumor tissue

2018 ◽  
Vol 7 (5) ◽  
pp. 661-667 ◽  
Author(s):  
Bárbara Meléndez ◽  
Claude Van Campenhout ◽  
Sandrine Rorive ◽  
Myriam Remmelink ◽  
Isabelle Salmon ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Methods Of Measurement

Induction chemotherapy with S-1 plus cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15501-15501
Author(s):  
J. Chung ◽  
Y. Choi ◽  
H. Shin ◽  
G. Choi ◽  
W. Lee ◽  
...  
Keyword(s):  
Performance Status ◽  
Locally Advanced ◽  
Local Treatment ◽  
Complete Response ◽  
Hematological Toxicity ◽  
Common Grade ◽  
Adequate Organ Function ◽  
Grade 3 ◽  
And Performance ◽  
Mild Toxicity

15501 Background: This study was to assess the efficacy and safety profiles of the combination treatment with S-1 and Cisplatin in patients with locally advanced SCCHN. Methods: Eligible patients were defined as histologically confirmed SCCHN, stage III or IV with no evidence of distant metastasis, evaluable lesions, adequate organ function, age of 20–80 years, and performance status 0,1 or 2. Cisplatin was infused over 1 hour on day 1 (75 mg/m2) and S-1 was administered orally for 14 consecutive days (day 2–15). The dosages of S-1 were assigned according to the patients’ body surface area (BSA): 50 mg twice a day (BSA < 1.5m2), 60 mg twice a day (BSA > 1.5m2). Each course was repeated every 3 weeks. After 2 course, tumor response were evaluated by CT scan and laryngoscopy. If the patients achieved a response (complete response: CR, or partial response: PR), they received one more course of chemotherapy before undergoing the radiotherapy or operation as a definitive local treatment. Results: All 22 patients were assessable for response and toxicity. The overall response was 80.9% (CR: 3, PR: 14). The adverse reactions occurred 120 times in 54 courses of 22 cases. The most common grade 3/4 adverse events were neutropenia, which occurred in 8 patients. Non-hematological toxicity of grade 3 and 4 included nausea and vomiting in 4 patients, fever in one patient and, fatigue in one patient. Since the observation period is short, the analysis about survival rate is not obtained so far. Conclusions: S-1 plus Cisplatin combination chemotherapy is effective against locally advanced SCCHN with mild toxicity. No significant financial relationships to disclose.

Impact of socioeconomic status on treatment outcome in patients with advanced esophagogastric cancer in Northern Ireland

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20531-e20531
Author(s):  
Y. Manikyam ◽  
G. G. Hanna ◽  
R. J. Harte ◽  
P. G. Henry ◽  
R. F. Houston ◽  
...  
Keyword(s):  
Socioeconomic Status ◽  
Northern Ireland ◽  
Median Survival ◽  
Performance Status ◽  
Locally Advanced ◽  
Ecog Performance Status ◽  
Disease Extent ◽  
Esophagogastric Cancer ◽  
And Performance ◽  
The Impact

e20531 Background: The survival advantage for combination chemotherapy in advanced gastroesophageal adenocarcinoma is well documented. Epirubicin and cisplatin in combination with either 5FU (ECF) or capecitabine (ECX) result in response rates of 35–46% and a median survival of around 9 months in RCT. We report the impact of socioeconomic status on the outcome of ECF and ECX treatment in advanced gastroesophageal cancer patients in Northern Ireland between 2000 and 2007. Methods: All patients with advanced esophageal (O), gastric (G), or esophagogastric junction (OGJ) adenocarcinoma, receiving palliative chemotherapy from January 2000 to August 2007, were identified from our institutional database. Baseline demographics, clinical characteristics, treatment details, and clinical outcomes were recorded. Patients receiving chemotherapy in a clinical trial were excluded. Survival was estimated using the Kaplan-Meier method. Deprivation was assessed using the patient's home address deprivation index (DPI) (Northern Ireland Multiple Deprivation Measure 2005; May 2005. Northern Ireland Statistics and Research Agency. www.nisra.gov.uk ). Results: 274 eligible patients (m=200, f=74, O=114, OGJ=19, G=141) were identified. Median age was 62 years (range 22–83). 172 (62.8%) had ECOG performance status 0 or 1. 231 patients (84.3%) had metastatic disease, 43 (15.7%) had locally advanced disease. 216 (78.8%) patients received ECF and 58 (21.2%) patients received ECX. Overall median survival was 7.3 months. Treatment response and performance status were strong predictors of survival, however disease extent did not influence survival. Median survival was significantly longer in those with DPIs in the upper two quintiles than the lower 3 quintiles (9.5 months vs. 6.8 months, p=0.032). Conclusions: Outcomes achieved with palliative ECF/ECX treatment are similar to the reference clinical trials. Socioeconomic deprivation is significantly associated with reduced survival in this group of patients and is unrelated to disease extent at presentation; however it may be related to nutritional status and comorbidity and requires further investigation. No significant financial relationships to disclose.

Phase II trial of combination therapy with intravenous carboplatin (C) and oral everolimus (EVE) and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trial Consortium study.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 156-156
Author(s):  
Muthu Kumaran Veeraputhiran ◽  
Daniel H. Shevrin ◽  
Lance K. Heilbrun ◽  
Daryn Smith ◽  
Jing Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Mtor Inhibition ◽  
Measurable Disease ◽  
Grade 3 ◽  
And Performance ◽  
Castrate Resistant

156 Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. Methods: Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or > 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). Results: 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was > 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. Clinical trial information: NCT01051570.

Genotyping of circulating tumor DNA in biliary tract cancer to reveal diagnostic and prognostic information.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 291-291 ◽  
Author(s):  
Andreas Wolfgang Berger ◽  
Thomas Jens Ettrich ◽  
Daniel Schwerdel ◽  
Anna Dolnik ◽  
Florian Beuter ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Palliative Treatment ◽  
Tumor Tissue ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Imaging Data ◽  
Tract Cancer ◽  
Pretreated Patients ◽  
Tumor Dna

291 Background: Biliary tract cancer (BTC) shows increasing incidence and is associated with a high mortality. Diagnosis is difficult due to the frequently occurring inaccessibility of the tumor for biopsy. Noninvasive approaches for (i) assessing and (ii) monitoring the tumor-specific molecular setup are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: Blood and tumor tissue samples from patients with locally advanced or metastatic BTC prior to and during palliative treatment were collected. Tumor tissue and corresponding ctDNA samples underwent targeted genotyping of the 15 most frequently mutated genes in BTC. Findings were correlated with clinical and imaging data. Results: 24 therapy naive patients with histologically confirmed BTC were included for analyses. The overall mutational concordance (blood/tissue) was 74% and 92% for intrahepatic tumors. The mean variant allele frequency (VAF) in tumor tissue of therapy naïve patients was significantly higher compared to the respective ctDNA (p = 0.0291). In turn, the sequencing depth for ctDNA was significantly deeper (p = 0.0001), enabling us to detect also rare variants. Mean ctDNA VAF at baseline significantly correlated with tumor load (Spearman, r = 0.4073, p = 0.0433) and, exclusively for intrahepatic tumors, also with progression-free survival (Spearman, r = -0.5878, p = 0.0386). During 1st line palliative treatment, we detected a change in the mutational landscape in 36% of cases, Moreover, we had access to ctDNA samples of 5 pretreated patients. While ctDNA samples of therapy naïve patients (n = 23) showed a mean of 0.78 mutations per patient, ctDNA samples of pretreated patients (n = 5) exhibited a mean of 0.4 mutations (p = 0.5519). Conclusions: The molecular landscape of BTC is depicted in ctDNA which may enable to adapt diagnostic and therapeutic strategies to the specific molecular setup present at a certain time. In contrast, the use of targeted resequencing is likely to be insufficient for a comprehensive assessment of treatment induced BTC evolution. For this purpose, we suggest a more extensive analysis of ctDNA by broader sequencing applications and the incorporation of epigenetics.

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