tbuckley/cabot-search huggingface dataset:
Comparable survival of African-Americans and Caucasian patients with multiple myeloma: A hospital-based study including 117,926 patients.
Authors: Ehsan Malek, Kamal Chamoun, Paolo Fabrizio Caimi, Stanton L. Gerson, Ben Kent Tomlinson, Seema Patel, Marcos J.G. De Lima, Pingfu Fu
Journal: Journal of Clinical Oncology (2019)

e18170 Background: Multiple Myeloma (MM) counts the most common hematologic malignance among African-Americans with twice the incidence of whites. The outcomes have greatly improved during the last 15 years, however with changing demographics there is an increasing focus on how various subgroups, based on race and ethnicity may be benefiting from survival improvement in MM. Previous studies showed that if access to care is assured, racial disparity-driven differences in outcome may be mitigated. Here, we conducted a study using the National Cancer Data Base (NCDB), which covers more than 70% of cancer pts in the USA, to evaluate survival patterns by race. Methods: MM patients (pts) diagnosed between years 2005 and 2014 and reported to the NCDB were analyzed (n = 117926). Pts were divided in three groups based on the year (y) of diagnosis (2005-07, 2008-10 and 2011-14). Kaplan-Meier method and log-rank test were used for overall survival analysis (OS). The effect size, hazard ratio (HR), of race on OS was estimated by Cox model adjusted by confounders. Results: Median age at diagnosis was 67 y (19 - 90); 55% were males. Median follow up was 30 months (m) (0 - 145). Median OS for white and black pts was 46 m (95% CI: 45.4 - 46.6) and 50.6 m (95% CI: 49.1 - 52.3), respectively (p &lt; 0.0001). Black had longer OS compared to white pts by univariable analysis in all three study periods, noticeably with a trend toward higher survival benefit in most recent years. After adjusting for a variety of factors there was no statistically significant difference between the two racial groups (Table). Conclusions: This large study confirmed that after adjusting for confounding factors survival is similar for white and black MM pts. [Table: see text]
A revised Children's Oncology Group (COG) neuroblastoma risk classification system: Report from the COG biology study ANBL00B1.
Authors: Meredith Irwin, Arlene Naranjo, Susan Lerner Cohn, Wendy B London, Julie M Gastier-Foster, John M. Maris, Rochelle Bagatell, Julie R. Park, Michael D. Hogarty
Journal: Journal of Clinical Oncology (2019)

10012 Background: The COG risk classification system previously used the International Neuroblastoma Staging System (INSS). The pre-treatment INRG staging system (INRGSS) has been adopted internationally, requiring integration of INRGSS with known prognostic biological and clinical characteristics to evaluate outcomes and assess whether this incorporation will require revision to the established COG risk classifier. Methods: 4,037 newly diagnosed neuroblastoma patients were enrolled on COG ANBL00B1 between 2006-2014. Staging per the INSS and INRGSS was determined. Tumor biological and histologic features, including MYCN status [amplified (A) versus not amplified (NA)], ploidy, histology, and segmental chromosome aberrations (SCA) including 1p and 11q LOH, were assessed centrally. Survival analyses were performed to identify independent prognostic factors and to calculate event-free and overall survival (EFS, OS) for combinations of variables used to determine risk group assignments according to COG and INRG classification templates. Results: Using the original COG risk classifier 1,309 low (LR), 992 intermediate (IR) and 1,736 high-risk (HR) patients were identified with 5-year EFS of 91.4±2.1%, 84.3±2.9%, 45.2±3.1%, and OS of 98.1±1.0%, 94.0±1.9%, 54.1±3.0%, respectively. Outcomes based on combinations of clinical and biological prognostic factors were determined and compared for subsets of patients according to the COG (version1) and INRG risk classification systems to develop a revised COG risk classifier that incorporates the INRGSS (version 2, subset shown in table). Conclusions: Use of INRGSS requires a revision to the COG risk classifier. By combining INRGSS and presence of SCA together with age, MYCN status, ploidy, and histology to determine outcome of patients treated with modern era therapies, we developed a revised risk classification system to inform therapy and COG clinical trial eligibility. Clinical trial information: NCT00904241. [Table: see text]
Real-world clinical experience of the Galician Lung Cancer Group: Afatinib in patients with EGFR positive mutation.
Authors: Sara Agraso Busto, Vanesa Varela, Natalia Fernández Núñez, Jose-luis Firvida, Lucía Santomé, Francisco Javier Afonso, Cristina Azpitarte, Noemi De Dios Alvarez, Jorge Garcia, Begoña Campos Balea, Maria Carmen Areses Manrique, Diego Pereiro Corbacho, Gerardo Huidobro, Martin Lazaro Quintela, Joaquín Casal Rubio
Journal: Journal of Clinical Oncology (2019)

e20654 Background: Treatment with tyrosine kinasa inhibitors has been a revolution for the patients with non-small cell lung cancer and EGFR positive mutation, especially in patients with exon 19 deletions. Afatinib seems one of the best options of treatment. Methods: Retrospective study on patients from differents hospitals in Galicia (Spain) diagnosed of metastasic lung adenocarcinoma with EGFR positive mutation who have received first line treatment with afatinib between July 2015 and September 2018 were included. The main objective was to compare our clinical experience concerning response rate, progression free survival and toxicity with published data. Results: 45 caucasians patients were included in our analysis (33 women, 12 men). Median age was 71.2 years (range 39-91 years) and 29 patients had never smoked. Exon 19 deletion was the most common mutation (41 patients, 91.1%). The objective overall response was 68.9% (95% CI: 82.4-55.3), complete responses were observed in 6 patients (13.3%) and partial responses were found in 25 patients (55.6%). Stable disease was observed in 8 patients (17.8%) and disease progression in 1 patient (2.2%), 5 patients have not been re-evaluated (11.1%). Median progression free survival (PFS) was 27 months (95% CI: 14.8-39.1) and overall survival was not reached. Common adverse events grade 3/4 were mucositis and skin toxicity in 11 patients (24.4%) and diarrhea in 6 patients (13.3%), respectively. The dose was reduced in 28 patients (62.2%) and treatment was discontinued in 8 patients (17.8%) owing to adverse events. Conclusions: Median PFS in our patients is 15 months longer than the information retrieved from differents studies with similar response rates and toxicity. This might be due to a majority of population with exon 19 deletion which, according to published data, seems to benefit more from afatinib than from other EGFR mutations.
Dora: A randomized phase II multicenter maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum responsive advanced triple-negative breast cancer (aTNBC).
Authors: Sarah Sammons, Tira Jing Ying Tan, Tiffany A. Traina, Sung-Bae Kim, Young-Hyuck Im, Carol Bachelder, Paul Kelly Marcom, Rebecca Alexandra Dent
Journal: Journal of Clinical Oncology (2019)

TPS1113 Background: PARP inhibition (PARPi) with olaparib is approved in HER2-negative germline BRCA mutant (g BRCAm) metastatic breast cancer. Maintenance PARPi in relapsed platinum-sensitive ovarian cancer improves median PFS regardless of gBRCA mutation status. Preclinical work has shown that platinum response strongly correlates with olaparib response in breast cancer models; hence, maintenance therapy trials are underway in aTNBC. PARPi modulates immune responses and enhances immunogenicity in many preclinical models. We hypothesize that olaparib either alone or in combination with the PD-L1 inhibitor durvalumab will have clinical efficacy as maintenance therapy in aTNBC subjects who have responded to platinum-based chemotherapy. Methods: DORA is a randomized, international, multicenter, phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab as maintenance therapy in platinum-sensitive aTNBC. 60 subjects will be enrolled following a minimum of 3 cycles of treatment with platinum-based (cisplatin or carboplatin) chemotherapy as a single agent or combination therapy in the first or second-line setting. Subjects deriving clinical benefit (CR / PR / SD) from platinum-based therapy will be eligible and randomized in a 1:1 ratio. Patients in arm 1 will receive olaparib orally 300mg BID continuously and in arm 2 will receive olaparib orally 300mg BID continuously in combination with durvalumab 1500mg IV every 4 weeks. Assessment of tumor response will be done every 8 weeks. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, clinical benefit rate, safety. Correlative analyses: pre-treatment archival/fresh biopsy samples are mandated. Post-treatment tissue biopsy is requested. Serial ctDNA will be collected at baseline, staging, and progression to correlate with response and track emerging genomic alterations in a platinum sensitive cohort under the pressure of PARP inhibition. Whole exome DNA sequencing, IHC for PDL-1 and TILs will be performed on tissue samples. ClincalTrials.gov Identifier: NCT03167619. (Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR). Clinical trial information: NCT03167619.
A phase I study of convection-enhanced delivery of <sup>124</sup>I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.
Authors: Mark M. Souweidane, Kim Kramer, Neeta Pandit-Taskar, Zhiping Zhou, Pat Zanzonico, Maria Donzelli, Serge K. Lyashchenko, Sofia Haque, Sunitha B Thakur, Nai-Kong V. Cheung, Steven M. Larson, Ira J. Dunkel
Journal: Journal of Clinical Oncology (2019)

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124 I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm 3 , and for dose level 7, 10.5 - 19.0 cm 3 . The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.
Overall survival in PEMVITASTART randomized trial comparing immediate vs. conventional strategies of vitamin supplementation in NSCLC patients on 1<sup>st</sup> line pemetrexed-platinum chemotherapy.
Authors: Navneet Singh, Valliappan Muthu, Kuruswamy Thurai Prasad, Milind Baldi
Journal: Journal of Clinical Oncology (2019)

e20538 Background: PEMVITASTART ( NCT02679443 ) was an open label phase II randomized trial [Singh N, et al. Cancer (DOI: 10.1002/cncr.32028)] involving locally advanced/metastatic non-squamous NSCLC patients treated with 1 st line pemetrexed-platinum chemotherapy (CTx). The trial assessed the hematological toxicity profile in Delayed Arm (DA; conventional strategy) in whom CTx was initiated after 5-7 days of vitamin B12/folate supplementation (B12-FAS) vs. Immediate Arm (IA) in whom patients received B12-FAS simultaneously (≤24 hours) with CTx initiation. All outcomes were reported in modified ITT population (patients who received ≥1 cycle). A non-significant trend towards better radiological responses was observed in IA (PR 33% vs. 18%; p = 0.06). Herein, we report exploratory post-hoc analysis of overall survival (OS) for the mITT population (n = 150; 77 IA, 73 DA) of PEMVITASTART. Methods: OS was calculated from date of enrolment to date of death/last follow up. Survival cutoff date was 28 months after last patient enrolment. Median OS was calculated by Kaplan-Meier method and group differences analyzed by log-rank test. Factors affecting OS were assessed by Cox proportional hazards (CPH) analysis and hazard ratios [HRs] with 95% confidence intervals (CIs) calculated (from univariate and stepwise multivariate models). Results: Median OS was 12.7 m (95% CI 8.0–17.4) and did not differ between IA [15.0 m (10.5-19.4)] and DA [11.7 m (4.1-19.3)]. 1 yr and 2 yr survival rates were similar (IA 42% and 21% vs. DA 44% and 23%). On univariate CPH analysis, factors associated with better OS were female gender, ECOG PS 0, absence of metastatic disease and receipt of maintenance pemetrexed CTx (mPEM) while current/ex-smoker status, disease progression (as best response) and age ≥70 years were a/w worse OS. Baseline Hb and homocysteine (both assessed as continuous variables) and receipt of packed RBC transfusions/ESAs for anemia correction did not influence OS. On multivariate CPH analysis, current/ex-smokers HR 2.2 (95% CI 1.3-3.7; p &lt; 0.01) and mPEM HR 0.5 (95% CI 0.3-0.9; p = 0.01) were both significant. Median OS for current/ex-smokers was 7.4m (95% CI 5.4-9.4) vs. 25.6m (95% CI 16.2-35.0) for non-smokers (log rank p &lt; 0.001) while for patients receiving mPEM, it was 22.7m (95% CI 9.9-35.4) vs. 9.7m (95% CI 4.9-14.5) for those not receiving mPEM (log rank p = 0.02). Conclusions: Smoking status and mPEM were strong and independent prognostic factors for OS in the PEMVITASTART trial. Clinical trial information: NCT02679443.
A phase II clinical trial of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor-positive triple-negative breast cancer.
Authors: Jin Sun Lee-Bitar, Paul Henry Frankel, Susan Elaine Yost, Timothy W. Synold, Norma Martinez, Aileen Tang, Dan Schmolze, Sophia Apple, Arti Hurria, James Ross Waisman, George Somlo, Niki Tank Patel, Mina S. Sedrak, Joanne E. Mortimer, Yuan Yuan
Journal: Journal of Clinical Oncology (2019)

1069 Background: Androgen receptor (AR) targeting therapy has shown single agent activity in triple negative breast cancer (TNBC). GTx-024, a nonsteroidal selective androgen receptor modulator (SARM), demonstrated preclinical and clinical activity in AR + breast cancer. The current study is designed to test the safety and efficacy of GTx-024 and pembrolizumab in patients with AR + metastatic TNBC (mTNBC). Methods: This is an open-label phase 2 study for AR + mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Key eligibility criteria include patients with AR + ( &gt; 10%, 1+ by IHC); mTNBC; ECOG 0-1; measurable disease per RECIST 1.1. Patients are excluded if they had prior checkpoint inhibitors or AR targeted agents. The primary objective is to evaluate the tolerability of GTx-024 and pembrolizumab, and determine the response rate. Results: Seventeen patients were enrolled in the study. One patient was ineligible due to previously undiagnosed brain metastases. Ten of 16 patients had visceral metastasis (lung or liver), and 15% of patients had received ≥ 3 previous lines of therapy for mTNBC. Among 16 patients evaluable for response, 2 patients achieved a best response of partial response (PR), 2 patient had stable disease (SD, 18 and 19 weeks ), 11 patients had progressive disease (PD), and 1 patient is too early for restaging imaging. Durable response was found in 1 patient. Grade 3 toxicities include 1 diarrhea and 1 dry skin. Grade 2 adverse events include 3 elevated liver function, 1 adrenal insufficiency, 1 hyperthyroidism, 1 palpitation, 1 diarrhea, 1 hyperhydrosis, 1 hot flashes and 1 headache. Three patients had dose delay and two patients had dose reduction. Conclusions: AR targeted therapy GTx-024 combined with pembrolizumab is well tolerated with clinical activity. Clinical trial information: NCT02971761.
Genomic profiling of pulmonary lymphoepithelioma-like carcinoma (PLELC).
Authors: Chengzhi Zhou, Zhanhong Xie, Yinyin Qin, Laiyu Liu, Hua Zhang, Weineng Feng, Xiaohong Xie, Xinqing Lin, Jiexia Zhang, Ming Ouyang, Yingying Gu, Bing Li, Han Han-Zhang, Jing Liu, Suiyi Mai, Shuyin Chen, Lu Zhang
Journal: Journal of Clinical Oncology (2019)

1572 Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p &lt; 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p &lt; 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.
Correlation of immune-related adverse events with peripheral baseline immune markers and overall survival in patients with metastatic melanoma on ipilimumab and chemotherapy.
Authors: Khashayar Esfahani, Pamela Thebault, Rejean Lapointe, Rahima Jamal, Wilson H. Miller
Journal: Journal of Clinical Oncology (2019)

9561 Background: Very few predictive markers have been validated for immune-related adverse events (irAE), which are the number one reason for cessation of treatment and treatment-related deaths on checkpoint inhibitors. In a phase II trial of combined ipilimumab (ipi) with carboplatin/paclitaxel (C/P) (NCT01676649), we sought to determine baseline peripheral blood markers predictive of irAEs and to correlate these adverse with subsequent survival. Methods: Thirty patients with untreated unresectable/metastatic melanoma were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and Ipi (3mg/kg) every 3 weeks x 4. irAEs were graded according to the CTCAE v5.0. Median follow-up was 60 months. Baseline blood markers was assessed by a 37 multiplex cytokine-chemokine platform (Meso Scale Discovery) and multiparameter flow cytometry. Results: Grade 2 or higher irAE occurred in 11/30 of patients (4 colitis, 2 hepatitis, 2 hypophysitis, 3 rash). Median survival was 43.8 months in patients with irAE and 14.5 months for those without irAE (p = 0.001). Pts with irAE had lower baseline circulating levels of IL-6 (3.6 vs. 19.8 pg/mL, p = 0.049), TNF alpha (7.6 vs. 11.6 pg/mL, p = 0.003), CXCL9 (83.4 vs. 116.8 pg/mL, p = 0.042) and CCL3 (52.3 vs. 76.4 pg/mL, p = 0.012), but higher baseline circulating dendritic cells (DC) (4.9 vs. 2.9 % of total PBMC, p = 0.002) and a lower level of myeloid-derived suppressor cells (MDSC) (0.8 vs. 1.7 %, p = 0.049). There was no correlation between baseline B cell circulating numbers or differentiation and irAEs. Conclusions: Although results from previous studies of ipi monotherapy vary, our small study shows a highly significant correlation between irAEs and improved long term outcome for patients treated with ipi/C/P. Our exploratory analysis also identifies putative predictive immune and cytokine-chemokine markers of irAEs, which are associated with: 1) Antigen presentation dysregulation (high DC cells) and lack of adequate auto-immune suppression (low MDSC), as also seen in classic autoimmune diseases; and 2) A low inflammatory baseline signature (low TNF, IL-6, CCL3, CXCL9) consistent with possible immune exhaustion and reduced lymphocytic homeostatic fitness. Our combined markers depict a dysregulated immune landscape favorable to the expansion of self-reactive immune cells under CTLA-4 blockade. Our results are hypothesis generating and require further evaluation in a larger group of patients, including PD-1 treated cohorts. Clinical trial information: NCT01676649.