tbuckley/cabot-search huggingface dataset:
Randomized open-label study of M7824 versus pembrolizumab as first-line (1L) treatment in patients with PD-L1 expressing advanced non-small cell lung cancer (NSCLC).
Authors: Myung-Ju Ahn, Fabrice Barlesi, Enriqueta Felip, Edward B. Garon, Claudio Marcelo Martin, Tony S. K. Mok, Everett E. Vokes, Laureen S. Ojalvo, Andre Koenig, Isabelle Dussault, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2019)

TPS9114 Background: Transforming growth factor β (TGF- β) promotes tumor progression via immune- and non–immune-related processes. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the NCT02517398 study of patients with advanced NSCLC (n = 80) treated with M7824 in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that M7824 may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate M7824 treatment in patients with advanced NSCLC in the 1L setting. Methods: Here we present a global, randomized trial comparing M7824 vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either ≥80% by the Dako 73-10 pharmDx kit or ≥50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression-free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT03631706.
Systematic assessment of LCMV based vaccine vectors expressing melanocyte differentiation antigens in human in vitro assays and in mouse melanoma models.
Authors: Lukas Flatz, Jovana Cupovic, Sarah Schmidt, Lucas Onder, Marie Therese Abdou, Anna Katharina Fritsche, Weldy Bonilla, Oltin Tiberiu Pop, Thomas Tüting, Andreas Bergthaler, Klaus Orlinger, Tobias Bald, Burkhard Ludewig, Sandra Ring
Journal: Journal of Clinical Oncology (2019)

e14299 Background: Antibodies blocking the immune checkpoint pathways represent an important milestone in the treatment of patients with metastatic melanoma. However, individuals presenting cold tumors do usually not show a clinical benefit. New cancer vaccine approaches are needed to cover this gap. Methods: A novel replication attenuated vaccine vector based on lymphocytic choriomeningitis virus expressing full length melanocyte differentiation antigens is evaluated in mouse melanoma models and in PBMCs and T cell cultures from melanoma patients. Results: Here, we demonstrate that intratumoral but not intravenous injection of a recombinant propagating LCMV vector expressing the melanoma-associated antigen TRP2 leads to T cell-dependent eradication of established s.c. melanoma. Importantly, intratumoral vaccination shows an abscopal effect on distant lung metastasis and protects from a rechallenge with melanoma. Confocal microscopy and flow cytometry reveal that intratumoral injection of rLCMV vectors reprograms the tumor microenvironment resulting in sustained T cell fitness. In addition, we demonstrate that rLCMV vectors can efficiently transduce human antigen presenting cells. Moreover, in vitro data confirm that rLCMV efficiently induces T cells against various melanoma-associated antigens in PBMCs from melanoma patients. Conclusions: Preclinical assessment of propagating rLCMV vectors shows unique features of this cancer vaccine resulting in a profound and multistep activation of the cancer immunity cycle resulting in eradication of established melanomas in the B16F10 mouse model after one single immunization. Positive proof of principle experiments using PBMCs from melanoma patients suggest a rapid evaluation in clinical trials.
Landscape of lung cancer molecular biology in a NON-selected population.
Authors: Rosa Ana Marcos, Jaime Ceballos, Elena Filipovich, Jose Maria Mazarico, Raquel Tur, Maria Rocio Martin, Jose Ales-Martinez
Journal: Journal of Clinical Oncology (2019)

e20648 Background: The molecular study of non-small cell lung cancer (NSCLC) allows for targeted treatment. EGFR and ALK alterations have been observed in 14% and 5% of Caucasian patients (p) respectively. These alterations are mainly detected in women with adenocarcinoma (ADC) and non-smokers. In a non-selected (all comers) NSCLC population from Ávila (Spain) we found a different profile. Methods: We collected data from 185 consecutive p the Pathology Department database of Hospital Nuestra Señora de Sonsoles from 2012 to 2017. All p were tested for EGFR and ALK. Analyses were done with Cobas or Therascreen tests. Results: EGFR mutations were found in 11 p out of 185 (6.7%). Histology was ADC in 8 p (72.7%) and squamous cell carcinoma (SC) in 3 p (27.3%). Male (m) &amp; smokers: 4/11 (36,4%). The type of mutation was: Exon 20: 3 p (27.3%). 2 m and 1 female (f). 2 smokers and 1 former smoker. 2 ADC and 1 SC; Del 19: 4 p (36.4%). 1 m and 3 f. 1 non-smoker, 2 former smokers and 1 smoker. 3 ADC and 1 SC; Exon 21: 4 p (36,4%). 2 m and 2 f. 3 non-smokers and 1 smoker. 3 ADC and 1 SC. All p. received treatment with 1st generation anti-EGFR drugs for a median 6.4 months (m). Progression Free Survival was 6.39 m (exon 20: 5.1 m; Del 19: 6.5 m; exon 21: 7.2 m). Overall survival was 18.0 m (exon 20: 26.1 m; Del 19: 18.2 m; exon 21: 11.8 m). ALK translocation was found in 5 p out of 158 (3.2%). Histology was ADC in 3 p (60%) (all f, 2 non-smokers and 1 former smoker) and SC in 2 p (40%) (2 smoker m.) Conclusions: Although the small sample size prevents definitive conclusions, EGFR mutations in exon 20 are more frequent in smokers and mutations in exon 21 in non-smoking patients with ADC. ALK translocation was observed independent of sex, tobacco or histologic type. For EGFR and ALK alterations, screening based on sex or pathology would have missed findings with therapeutic implications. We conclude it is important to extend the analysis of molecular alterations to all patients with NSCLC since more of them could benefit from targeted drugs.[Table: see text]
Impact of cancer in pulmonary embolism presentation and outcomes: A large academic center study.
Authors: Cherry Au, Ena Gupta, Phue Khaing, Joseph DiBello, Tayoot Chengsupanimit, Edith P. Mitchell, Frances West, Michael Baram, Bharat K. Awsare, Gregory C. Kane
Journal: Journal of Clinical Oncology (2019)

6613 Background: The risk of venous thromboembolism is increased 4- to 7-fold in patients with malignancy, emphasizing the need to identify and treat these patients early to improve outcomes. We aimed to study the clinical presentation and outcomes of pulmonary embolism (PE) in patients with and without cancer. Methods: We performed a retrospective analysis of consecutive patients diagnosed with PE via CT scan from 2014-2016 at Jefferson Hospital. We compared patient characteristics, presentation, PE characteristics and mortality of patients with and without cancer. Cox proportional regression hazards model was used for survival-time analysis. Results: Our study included 581 patients, of which 187 (32.1%) had active cancer. Cancer patients were less likely to have chest pain (18.2% vs 37.4% p &lt; 0.01), syncope (2.7% vs 6.6% p = 0.05), bilateral PEs (50% vs 60% p = 0.025), and right heart strain (RHS) (48% vs 58% p = 0.024). Indwelling catheters (IC) were present in 41.2% (n = 77) of cancer patients. However, presence of IC was not associated finding of incidental PEs (26% vs 18.2% p = 0.201). There was no difference in hospital length of stay (8.9 vs 9.4 days p = 0.61) or intensive care unit admission (31.9% vs 33.3% p = 0.75). There were fewer massive PE (3.2% vs 7.1% p = 0.06) in patients with cancer, but this difference was not statistically significant. Cancer patients elected comfort care at higher rates (15.2% vs 5.4% p = 0.01). Cancer patients had higher 1-year mortality as compared to non-cancer (adj HR 6.9, 95% CI 3.3- 14.7, p &lt; 0.01). Among cancer patients, 52.7% had metastasis with a higher 1-year mortality (adj HR 2.5, 95% CI 1.8- 4.9, p &lt; 0.1) and 35.8% were on active chemotherapy with no difference in 1-year survival (adj HR 1.1, 95% CI 0.6-1.8, p = 0.79). The most represented cancers were genitourinary, lung and head and neck (35.3%, 23.0%, 13.4%, respectively). Conclusions: Cancer patients presented with less severe pulmonary emboli which may be due to increased health care contact and pre-clinical suspicion. The presence of IC did not affect the size, location of PE or incidental PEs among cancer patients. Although cancer patients have higher 1-year mortality, PE may not be as large as a contributor as previously perceived.
Use of a theoretical framework to examine declines in clinical trial enrollment.
Authors: Christine B. Mackay, Kerry Hepler, Christine Makosky Daley, Joanna Veazey Brooks
Journal: Journal of Clinical Oncology (2019)

e18037 Background: Clinical trial enrollment at a group of community oncology sites dropped significantly surrounding acquisition by an academic medical center. While previous research used empirical data to identify enrollment barriers, this study used a theoretical framework to investigate research site personnel behavior associated with enrollment, and to further explore clinical trial enrollment barriers. Methods: Data from focus groups and interviews were analyzed using the integrated TDF and COM-B theoretical framework [1] . [1] Theoretical Domains Framework with Capability, Opportunity, Motivation Behavior Wheel. Results: Fifty-six community personnel [2] participated in focus groups and interviews about enrollment experiences before and after the acquisition. Participants described how changes in the workplace and resources affected their Opportunity to enroll: "It's kind of hard to put somebody on a study when you don't have one available." -cs "You can't grow a research department by cutting staff. What message does it send to the organization as far as the importance of research? …it makes you wonder whether the organization truly backs the research effort." -m Physician participants specifically shared that the lack of time and staff devoted to research hampered enrollment efforts, consequently affecting their Motivation: “Current road block is that doc doesn't have time to go through the patient records, so if [the study coordinator] could determine eligibility before the patient visit, that would be helpful.” -p Participants expressed frustration in not knowing the processes for opening trials, therefore their Capability was affected. “I think [in the past], we knew more about what was out there, where I don't see as much of that here now. I don't know if it's because we don't have a research nurse or we are not getting a list [of trials] anymore or what is going on." -cs [2] Quotes from personnel cs = clinic staff, m = manager, p = provider. Conclusions: Participants perceived many barriers to clinical trial enrollment after the acquisition. To optimally continue providing services as expected, support systems need to be maintained. This study provided evidence of using the TDF for exploring enrollment barriers.
Clinical outcomes and genomic analysis in patients with very high-risk clinically localized prostate cancer treated by radical prostatectomy.
Authors: Pedro Isaacsson Velho, David Lim, Hao Wang, Harsimar B Kaur, Mark Christopher Markowski, Michael Anthony Carducci, Emmanuel S. Antonarakis, Colin C. Pritchard, Tamara L. Lotan, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2019)

5067 Background: Very high risk prostate cancer is associated with poor response to local and systemic treatments, however few cases have been molecularly profiled. We studied patients with primary Gleason pattern 5 disease (PG5; Gleason scores 5+5 or 5+4) after undergoing radical prostatectomy (RP). Methods: Consecutive PG5 cases were retrospectively studied. Clinical-pathologic features, tumor somatic sequencing (UW Oncoplex), germline sequencing and PTEN, TP53 and ERG status by immunohistochemistry were correlated with biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Kaplan–Meier curves were used in time-to-event data. Univariate and multivariable (MVA) Cox proportional-hazards models (95% confidence intervals (CI Clinical-pathological variables were selected for the multivariate analysis using stepwise method and were used to adjust the effect of each mutation. Results: Of 60 patients with available tissue and follow-up, 90% had non-organ confined disease, 58% had seminal vesicle invasion (SVI), 27% had lymph node involvement, and 15% had ductal or intraductal histologic features. Overall, 43% developed metastasis with a TCR of 12 months. On multivariable analysis of clinical-pathologic variables, only ductal/intraductal histology (HR = 4.43; 95% CI: 1.76-11.15; p = 0.002) and SVI (HR = 5.14; 95% CI: 1.83-14.47 p = 0.002) were associated with metastasis. Of patients with somatic sequencing data, 22% (11/49) had homologous recombination (HR) and 12% (6/49) had mismatch repair (MMR) gene alterations. In addition, 33% (16/49) had TP53 mutation and 51% (29/57) had PTEN loss. Only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis and no genomic alterations remained significant in multivariable analyses. Conclusions: Patients with PG5 have poor outcomes and more than one third have mutations in DNA repair genes. The unusually high incidence of actionable HR and MMR alterations provides the rationale for the design of adjuvant clinical trials in this population. [Table: see text]
Characterizing biomarker testing over time in lung cancer patients using oncology electronic medical records (EMR).
Authors: Jennifer Christian, Joe Wagner, Gregory Mastrogiovanni, Andrew David Norden, Ian Kurashige
Journal: Journal of Clinical Oncology (2019)

e20056 Background: This study characterizes biomarker testing over time in Non-Small Cell Lung Cancer (NSCLC) patients treated within a clinical setting. There have been tremendous advances in treatments for NSCLC that target specific biomarkers such as epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and the Programmed cell death-ligand 1 (PD-L1) pathway. As we consider using oncology EMR records for future studies, it is critical to understand the extent to which biomarker testing is conducted in routine care, the extent to which testing has increased, and the types of patients for which it is done. Methods: This is a retrospective observational analysis derived from the COTA Oncology EHR database from January 1, 2015 through December 31, 2017. The data sets generated for the study included all relevant, retrospective patient-level, de-identified data available for patients with lung cancer, including EGFR, ALK, and PD-L1 testing regardless of age, gender, and stage at diagnosis. We examined characteristics associated with each type of test received as well as by those who had received all 3 biomarker tests, 1-2 of the tests, or no biomarker testing. Analyses were conducted using SAS V. 9.1 and stratified by data source. Results: There were 1,891 patients in the COTA database. Among newly diagnosed NSCLC patients, EGFR testing has been consistently conducted in patients during the study period (76 – 86%), while ALK testing [44% in 2015Q1 to 74% in 2017Q4] and PD-L1 testing [12% in 2015Q1 to 77% in 2017Q4] have steadily increased each quarter. Overall, testing was more likely to be conducted in non-squamous cell lung cancer patients, Stage IV lung cancer, and those without a history of smoking. For EGFR, testing was more prevalent among women and young age groups ( &lt; 64 years vs. 65 and older). Conclusions: Biomarker testing has rapidly increased for ALK and PD-L1, which correlates with the uptake of new targeted therapies. Further research could be conducted to understand clinical outcomes associated with this increase in testing as well as the impact on healthcare resource utilization.
CCTG CO.26: Updated analysis and impact of plasma-detected microsatellite stability (MSS) and tumor mutation burden (TMB) in a phase II trial of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with refractory metastatic colorectal carcinoma (rmCRC).
Authors: Eric Xueyu Chen, Derek J. Jonker, Jonathan M. Loree, Hagen F. Kennecke, Scott R. Berry, Felix Couture, Chaudhary E. Ahmad, John R. Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl L. Koski, Alice Chia-chi Wei, Dongsheng Tu, Christopher J. O'Callaghan
Journal: Journal of Clinical Oncology (2019)

3512 Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p &lt; 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values &gt; 0.7). Using a minimum p-value approach, pts with TMB &gt;28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.
Role of chemotherapy (CT) in performance status 3 and 4 small cell lung cancer (SCLC) patients
Authors: E. Cronenberger, A. Rodrigues, I. Small, P. De Biase, M. Zamboni, M. Zukin, C. Ferreira
Journal: Journal of Clinical Oncology (2006)

17026 Background: SCLC is an aggressive malignancy, but has shown high response rate to CT. Performance status (PS) has been recognized as one of the main prognostic factors in SCLC. Sudden and toxic deaths after CT were found to correlate with poor PS. There are few data about risk-benefit ratio of CT in PS 3 and 4 patients, although it has been often used. This study was performed to assess the clinical and laboratorial factors and the outcome of poor PS SCLC patients that received CT in our institution. Methods: A retrospective review was performed at INCA’s tumor registry for SCLC cases diagnosed between January 2001 and December 2004. Patients with pre-treatment ECOG PS 3 and 4 that received CT were selected for analysis. Results: Thirty of 107 SCLC patients (28%) were eligible (73.3% PS 3/ 26.7% PS 4). The median patient age was 64 years and 73.3% were male. Extensive- disease was observed in 83% of these patients. At the first cycle, 21 patients (70%) had to be hospitalized to receive CT and 5 of them (24%) required respiratory support. There were 10 deaths (33.3%) after the first cycle of CT. The median response rate was 77.8% and median overall survival was 2.8 months (138 days for PS 3 and 5 days for PS 4). In this series, there was a statistically significant correlation of PS 4, high serum LDH, hospitalization to start treatment and respiratory support with worse survival. Conclusions: Despite good response rate, poor PS patients, especially PS 4, had high risk of early CT related mortality and had dismal survival. Further studies are required to determine how to best treat these high-risk patients, in particular PS 4 patients, to minimize the early treatment related mortality and to give them the best form of palliation and prolongation of life. No significant financial relationships to disclose.
Mucosal melanoma staging and classification: Firstly established.
Authors: BIN LIAN, Chuanliang Cui, Xin Song, Xiaoshi Zhang, Di Wu, Lu Si, Zhihong Chi, Xinan Sheng, Li Zhou, Lili Mao, Bixia Tang, Xuan Wang, Si Ming Li, Xieqiao Yan, Charles M. Balch, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e21008 Background: Mucosal melanomas (MM) have a significantly worse survival outcome than cutaneous melanoma. The current staging rules for cutaneous melanoma do not apply to mucosal melanoma. Our previous studies have demonstrated mucosal melanomas arising from different anatomic sites can be staged and treated as a single disease entity. We are recommending a new evidence-based staging system for mucosal melanoma. Methods: The mucosal melanoma staging recommendations were made on the basis of a multivariate analysis of 543 patients with stages I, II, and III melanoma and 547 patients with stage IV melanoma to clarify TNM classifications and stage grouping criteria. Results: New staging definitions include the following: (1) in patients with localized melanoma, the depth of tumor invasion of the primary melanomas is the most dominant prognostic factor: T1 for tumor invading mucosa or submucosa; T2 for tumor invading the muscularis propria; T3 for tumor invading adventitia; T4 for tumor invading adjacent structures; (2) The dominant prognostic factor for regional nodal metastases is the number of metastatic nodes: N1 for 1 regional metastatic node; N2 for 2 or more regional metastatic nodes; (3) On the basis of a multivariate analysis of patients with distant metastases, the dominant component in defining the M category is the site of distant metastases (M1:lung only vs. M2:liver only vs. M3:brain only vs. M4:all other visceral metastatic sites). An elevated serum lactate dehydrogenase level would be designated in parenthesis. The staging grouping of mucosal melanoma can be defined as follow: (1) stage I: T1N0M0; (2) Stage II:T2-4N0M0; (3) Stage IIIA: T1-4N1M0, Stage IIIB: T1-4N2M0; (4) Stage IV: anyTanyNM1-4. Conclusions: Using an evidence-based approach, the proposed staging system of mucosal melanoma is the first to be established that reflects our improved understanding of this disease.