tbuckley/cabot-search huggingface dataset:
Association of low neutrophil-to-lymphocyte ratios (NLR) and high lymphocyte-to-monocyte ratios (LMR) with overall survival and response to induction chemotherapy (IC) when used to select patients (pts) with locally advanced squamous cell of the larynx (LSCC) for combined chemoradiation (CRT).
Authors: Zachary Risch, Emily Bellile, Ryan Townsend, Paul Swiecicki, Keith Casper, Kelly M Malloy, Norman D Hogikyan, Matthew E Spector, Andrew Shuman, Chaz Stucken, Steven Bennett Chinn, Douglas Brian Chepeha, Shruti Jolly, Michelle Lynn Mierzwa, Carol Rossier Bradford, Avraham Eisbruch, Thomas E. Carey, Mark E Prince, Gregory T. Wolf, Francis P. Worden
Journal: Journal of Clinical Oncology (2019)

e17539 Background: University of Michigan Cancer Center (UMCC) protocol 9520 treated pts with stage III/IV LSCC with 1 cycle of cisplatin &amp; 5-FU (PF) to select pts for definitive therapy. Pts whose tumors attained a ≥ 50% response after 1 cycle of PF underwent CRT. Those who had a &lt; 50% response to IC were treated with total laryngectomy + RT. Correlative science from UMCC 9520 demonstrated that an increased percentage of CD4+ cells predicted response to PF &amp; suggested improved survival. Published retrospective data also has demonstrated that lower NLR &amp; higher LMR are associated with improved prognosis in p16- SCC of the oropharynx &amp; pyriform sinus, while cancers with higher NLR &amp; lower LMR have a worse prognosis. Similar to our previous correlative analysis, this study is also a secondary analysis of the predictive value of NLR &amp; LMR in a prospective trial of bio-selective IC. Methods: NLR &amp; LMR were calculated from pre-treatment CBC for all pts (N = 87) enrolled onto UMCC 9520. Results: All 87 pts received IC with PF. 65/87 (75%) responded to IC &amp; received CRT. Results of response to IC compared the NLR &amp; LMR ratios by logistic regression analysis &amp; was used to create NLR &amp; LMR cut points. Among pts with LMR ≥ 3, the response rate (RR) was 89% while the RR was 64% with LMR &lt; 3 (p = 0.008). Among pts with NLR &lt; 4.7, the RR was 79% while the RR of pts with &gt; 4.7 was 58% (p = 0.06). Overall &amp; disease specific survivals were greater in pts with LMR ≥ 3, (log rank p = 0.04, p = 0.03, respectively). Conclusions: Higher LMR &amp; lower NLR are associated with favorable responses to IC &amp; LMR ≥ 3 is associated with improved survival. This data correlates strongly with our published results from UMCC 9520, whereby elevated circulating CD4+ lymphocytes predict response to IC &amp; survival. This important information may help direct the design of future laryngeal preservation protocols.
MS201944-0170: A phase IIa study to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in patients with advanced squamous NSCLC.
Authors: Fortunato Ciardiello, Manuel Cobo Dols, Oscar Juan Vidal, Luis G. Paz-Ares, Javier de Castro Carpeño, Enriqueta Felip, Rosario Garcia Campelo, Gyorgy Losonczy, Zsuzsanna Szalai, David Vicente, Andreas Schröder, Frank Beier, Prasad Bhandge, Gabriella Galffy
Journal: Journal of Clinical Oncology (2019)

TPS9123 Background: Preclinical studies have demonstrated that cetuximab plus chemotherapy results in immunogenic cell death and an increase in CD8+ T cells in the tumor microenvironment. Avelumab (an anti–PD-L1 antibody) has previously shown antitumor activity in NSCLC. We hypothesize that the combination of cetuximab with platinum-based chemotherapy and avelumab may have synergistic antitumor activity. Methods: This phase IIa, single-arm, multicenter study is investigating the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in patients with advanced squamous NSCLC who are treatment naive in the advanced setting (NCT03717155). Eligibility criteria include histologically confirmed stage IV, metastatic or recurrent NSCLC with squamous histology, with no prior systemic therapy for metastatic NSCLC, no prior therapy with any antibody/drug targeting T-cell coregulatory proteins, and ECOG PS of 0 to 1. Patients with a tumor harboring an activating EGFR mutation or ALK rearrangement are excluded. Patients will receive doublet chemotherapy (cisplatin 75 mg/m 2 on day 1, gemcitabine 1250 mg/m 2 on days 1 and 8), cetuximab on days 1 (250 mg/m 2 ) and 8 (500 mg/m 2 ), and avelumab 800 mg on days 1 and 8 for a total of four 3-week cycles. Thereafter, avelumab (800 mg) and cetuximab (500 mg/m 2 ) will be administered as maintenance treatment Q2W until disease progression, unacceptable toxicity, or withdrawal. Enrollment in a safety run-in, which will evaluate the safety and tolerability of avelumab in combination with cetuximab plus gemcitabine and cisplatin, is planned for the first 6 patients. Enrollment began on October 30, 2018. Study enrollment will continue until approximately 40 evaluable patients have been recruited. The primary endpoint is confirmed best overall response per RECIST 1.1 by investigator assessment. Secondary endpoints include safety (NCI CTCAE v5.0) and tolerability of the combination, duration of response, survival, and tumor biomarkers. The study is ongoing at sites in Hungary and Spain. Clinical trial information: NCT03717155.
THU0113 RHEUMATOID ARTHRITIS ASSOCIATED INTERSTITIAL LUNG DISEASE, CLINICAL CHARACTERISTICS AND PREDICTORS OF MORTALITY
Authors: Charlotte Hyldgaard, Torkell Ellingsen, Ole Hilberg, Elisabeth Bendstrup
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Interstitial lung disease (ILD) is a serious extraarticular manifestation of rheumatoid arthritis (RA) associated with excess mortality. No evidence-based approach to therapy for RA-ILD exists, but ongoing studies investigate the role of antifibrotic therapies for progressive fibrosing ILD, including progressive fibrosing RA-ILD. <h3>Objectives</h3> The aim of the present study was to investigate the frequency of progressive fibrosing ILD, the clinical characteristics and mortality of RA-ILD in a well-characterised, population-based cohort. <h3>Methods</h3> We identified patients with RA-ILD diagnosed and followed at the ILD referral center in Aarhus, Denmark between 2004 and 2016. Adjusted hazard rate ratios for death were estimated using Cox regression models. The presence of progressive fibrosing ILD was assessed using recently proposed definitions of relative forced vital capacity (FVC) decline ≥10%, relative diffusion capacity of the lung for carbon monoxide (DLco) decline ≥15% or worsening symptoms or a worsening radiological appearance accompanied by a ≥ 5-&lt;10% relative decrease in FVC. <h3>Results</h3> We identified 102 patients with RA-ILD. Mean follow-up was 3.8 years and median survival was 7.1 years. Thirty-eight patients died during follow-up, and the majority of deaths were from respiratory causes. Predictors of mortality in a multivariate model were DLco and high titers of IgM rheumatoid factor, but not the presence of a UIP-pattern on high resolution computed tomography. Fifty-three patients (52%) had progressive fibrosing ILD. *&gt;3 x upper limit of normal ** typical and probable UIP vs NSIP Clinical characteristics for progressive fibrosing RA-ILD and stable RA-ILD at the time of the ILD diagnosis and stratified by HRCT pattern. <h3>Conclusion</h3> Progressive fibrosing RA-ILD was common and the associated mortality was high. IgM rheumatoid factor and DLco were independent predictors of mortality. <h3>Acknowledgement</h3> None <h3>Disclosure of Interests</h3> None declared
Survival of gastric cancer (GC) patients is not determined by the predominant genomic ancestry (PGA): Results from an ethnically admixed Brazilian cohort of GC patients.
Authors: Helano C. Freitas, Luiza Ferreira Araujo, Diana Noronha Nunes, Maria D. Begnami, Thais Fernanda Bartelli, Maria Galli de Amorim, Israel Tojal da Silva, Renan Valieris, Alexandre Defelicibus, Mariana Pinheiro Xerfan, Wilson L. Costa, Victor Hugo Fonseca Jesus, Melissa Pizzi, Emmanuel Dias-Neto
Journal: Journal of Clinical Oncology (2019)

e15588 Background: Clinical characteristics, treatment response and overall survival of GC patients differ between Asian and non-Asian countries. Here we evaluated the possible associations between PGA, clinical characteristics and survival in an admixed GC Brazilian cohort. Methods: We included 112 GC pts diagnosed and treated at AC Camargo Cancer Center (São Paulo, Brazil) before 2013. The study was approved by local IRB. Genomic DNA was used for capture-based enrichment of a customized gene panel including 99 genes. Libraries were sequenced in the NextSeq 500 platform (Illumina), using paired-end reads (2x75bp). Ancestries were determined through a set of ancestry informative markers (AIMs), covered by target and off-target reads, described by Elhaik et al. (2014). Results: An average of 406 AIMs were recovered from the available samples, revealing average ancestries was as follows: 55.4% European, 27.7% Asian, 8.9% African; 8% of subjects were highly admixed (HA; &lt; 50% of any ancestry). We found no association between PGA and age at diagnosis (p = 0.58), tumor location (p = 0.34), Lauren (p = 0.24) and staging (p = 0.68). There was an association between PGA and gender (p = 0.04) and a marginal association between PGA and EBV (p = 0.056). BRCA2 was the only gene enriched in the Asian subgroup, compared to the other groups combined (p = 0.009). The median follow-up time was 95 months. We found no differences in median overall survival (OS) (p = 0.4) or disease-free survival (DFS) (p = 0.6) according to PGA. The HA subgroup presented worst survival outcomes compared to the other groups aggregated (mOS 34m; 95%CI 5-80 x mOS 71m; 95% CI 44-85, respectively), but the difference was not statistically significant (HR 1,73; 95% CI 0.74-4.05; p = 0.2). Even for patients with &gt; 75% AIMs for any given ancestry, we found no differences in OS between Europeans (n = 25; mOS 86m; 95%CI 80-NA), Asians (n = 22; mOS 83m; 95%CI 51-NA) and Africans (n = 5; mOS 67m; 95%CI 22-NA), p = 0.4. Conclusions: The most prevalent ancestries in this Brazilian GC cohort were European, followed by Asian and African. Although we found associations between ancestry and a few clinical aspects, PGA was not associated with survival.
Differentiated pharmacokinetic and pharmacodynamic properties of a highly selective MET kinase inhibitor, OMO-1: Implications for efficacy and safety.
Authors: Timothy Pietro Suren Perera, Marion Libouban, Ellen Jansen, Marc Tjwa, Eric Ciamporcero, Ann Meulemans, Annegret Van der Aa, Glen Clack, Martijn P. Lolkema
Journal: Journal of Clinical Oncology (2019)

e14674 Background: The MET kinase is an established therapeutic target in a range of cancer indications, being a primary oncogenic and therapy resistance driver. Methods: OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2) that is currently being explored in a Phase I/II study (NCT03138083). Results: Pre-clinical data for OMO-1 indicates that anti-tumor efficacy against MET driven tumor models does not require 24/7 exposure in the plasma. PK/PD assessments indicate that OMO-1 efficacy is AUC driven. Exposures above a trough concentration of ~600ng/ml for a period of 6-8hr and an AUC of 3000ng.h/ml result in complete target inhibition sufficient to induce regression or stasis of MET driven in-vivo models. Dosing of OMO-1 at 12.5mg/kg BD 4hr apart, or split over 4 doses 2hr apart, with a dosing-free period of 18-20hr was sufficient to obtain the effects preclinically. The ongoing Phase I/II study in patients with solid tumours utilised learnings from the pre-clinical and FIH study (NCT01964872) where ascending single doses and multiple doses were evaluated. The selected starting dose for the patient study (100mg BD, 4 hr apart) achieved exposures above the predicted MBAD. Paired tumor biopsies were obtained from a higher dose level (200mg BD). A MET exon 14 skipping mutation NSCLC patient at this dosed demonstrated near-complete inhibition of phospho MET accompanied by signs of clinical benefit and lesion shrinkage, thereby matching the preclinical data. Certain ‘class effect’ adverse events, such as edema, were not observed. Conclusions: OMO-1 is an oral, potent MET TKI with a novel dosing regime, identified during preclinical optimization (BD 4hr apart), that demonstrates encouraging signs of clinical activity without certain ‘class-specific’ adverse events. Further evaluation of this differentiated and efficacious agent is warranted and ongoing.
Antiviral therapy to reduce hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: A randomized controlled trial.
Authors: Gang Huang, Peng-Peng Li, Wan Yee Lau, Ze-Ya Pan, Ling-Hao Zhao, Zhen-Guang Wang, Meng-Chao Wang, Wei-Ping Zhou
Journal: Journal of Clinical Oncology (2019)

1510 Background: Despite antiviral treatment has been shown to reduce hepato- cellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. Methods: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were ran- domly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. Results: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P 1/4 0.016, P 1/4 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409– 0.884; P 1/4 0.010] and 0.509 (95% CI, 0.333–0.778; P 1/4 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recur- rence (hazard ratio [HR] 1/4 0.316, 95% CI 0.157 – 0.637; P 1/4 0.001) but not of early tumor recurrence (HR 1/4 0.782, 95% CI, 0.493–1.240; P 1/4 0.296). Conclusions: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection. Clinical trial information: ChiCTR-IPR-15006587.
Cost of oral cancer drugs: Trends in the United States Medicare population in 2013 and 2015.
Authors: Kira Rose-Madison Seiger, Emily S Ruiz
Journal: Journal of Clinical Oncology (2019)

6631 Background: Rising pharmaceutical costs threaten affordability and access to cancer care. Methods: The 2013 and 2015 Medicare Part D claims databases were queried for CareFirst’s 2017 list of oral cancer drugs. Drugs with on-label indications for conditions other than cancer were excluded. Cost in 2013 were adjusted for inflation to 2015 dollars according to the Bureau of Labor Statistics consumer price index. Results: The total cost of oral cancer drugs paid by Medicare nearly doubled from 2013 to 2015, rising from over $4.8 billion to over $9.1 billion. The number of prescriptions increased by 21.6% from 640,193 to 778,357, suggesting that increased spending is driven more by rising drug prices than by increased utilization. Cost per patient increased for 81% (46) of the 57 drugs prescribed in both years and decreased for the remaining 19% (11). While only seven drugs cost more than $50,000 per patient in 2013, more than fifteen drugs cost more than $50,000 per patient in 2015. The overall average cost per beneficiary increased by 56% from $7,521.64 to $11,734.68, and seven drugs more than doubled in per patient cost. Cost per patient increased by 4.5 times for imbruvica (ibrutinib), 3.5 times for targretin (bexarotene), 3.2 times for soltamox (tamoxifen citrate), 3.1 times for nilandron (nilutamide), 2.6 times for gilotrif (afatinib dimaleate), 2.6 times for cyclophosphamide, and 2.5 times for iclusig (ponatinib hydrochloride). Conclusions: Medicare costs for oral cancer drug nearly doubled from 2013 to 2015, largely due to increased per patient costs. [Table: see text]
The effect of induction chemotherapy on tumor volume changes in patients with locoregionally advanced nasopharyngeal carcinoma.
Authors: Guang Han, Ying Li, Yuan Wu, Jianping Bi, Yanping Li, Dandan Zheng, Conghua Xie, Desheng Hu
Journal: Journal of Clinical Oncology (2019)

e17557 Background: The use of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (NPC) for radiotherapy target volume reduction is increasing, however, the number of cycles is still varying. The purpose of this study was to observe changes in the gross tumor volumes of nasopharynx primary lesion (GTV_T), metastatic retropharyngeal lymph node (GTV_RP), and metastatic cervical lymph node (GTV_N) on longitudinal CT images during multi-cycle IC, and identify the optimal number of IC cycles. Methods: Eighteen patients with locoregionally advanced NPC received 3 cycles of platinum-based doublet IC. Each patient underwent an initial CT scan before the first cycle, followed by repeat CT (rCT) scans 14 days after each IC cycle. GTV_T, GTV_RP, and GTV_N were contoured on each CT. Wilcoxon signed-rank test was used for the comparing the longitudinal tumor volume changes. Results: The volume reductions of GTV_T, GTV_RP, and GTV_N following IC were found to have different magnitudes. Compared with GTV_T 0 (before IC), the volume changes of GTV_Tn (n = 1, 2, 3) after IC were -3.1±0.7 cm 3 , -7.0 ±1.9 cm 3 and -6.9 ±2.0 cm 3 , respectively, corresponding to relative reductions of 12.0%, 22.5%, and 20.1%, respectively. The GTV_T volume reduction was significant following the first two cycles of IC ( P&lt; 0.05) but insignificant following the third cycle. Similarly, compared with GTV_RP 0 , the volume changes of GTV_RPn (n = 1, 2, 3) after IC were -1.4±0.4 cm 3 , -2.5±0.5 cm 3 and -2.4±0.5 cm 3 , respectively, corresponding to relative reductions of 26.0%, 44.1%, and 42.2%, respectively. Again, the volume significantly decreased following the first two IC cycles ( P&lt; 0.05) but remained unchanged or even slightly increased after the third cycle. In contrast, compared with GTV_N 0 , the volume changes of GTV_Nn (n = 1, 2, 3) after IC were -7.3±1.7 cm 3 , -13.5±2.9 cm 3 and -17.2±3.4 cm 3 , respectively, corresponding to relative reductions of 25.3%, 43.2%, and 54.7%, respectively. For GTV_N, significant volume reduction ( P&lt; 0.05) was observed following each of the three IC cycles. All patients experienced grade 1 or 2 adverse events. Conclusions: A two-cycle IC is recommended for patients with large GTV_T and GTV_RP volumes before radiotherapy. However, for patients with a large GTV_N volume, a 3-cycle IC before radiotherapy is recommended.
The clinical utility of strict laboratory monitoring of CDK 4/6 inhibitors in metastatic breast cancer patients.
Authors: Urvi Patel, Jane Lowe Meisel, Meagan Spencer Barbee, Kristina Frinzi, Elizabeth Sakach, Zhengjia Chen
Journal: Journal of Clinical Oncology (2019)

1062 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) are widely used in the treatment of hormone receptor positive, metastatic breast cancer (MBC). CDK 4/6is are well-tolerated and highly effective, but can cause neutropenia. Therefore, the FDA mandates assessment of the absolute neutrophil count (ANC) every 2 weeks for the first 2 cycles of therapy and monthly thereafter. Strict ANC monitoring is optimal in theory, but presents a challenge in the real world, impacting quality of life for patients (pts) and adding financial burden to the healthcare system. This study aims to evaluate whether strict monitoring of ANC significantly impacts treatment decisions, pt safety, and disease outcomes. Methods: A retrospective chart review of 160 pts with MBC was conducted at the Winship Cancer Institute in pts prescribed CDK 4/6is from Feb 2015 to Jan 2019. The pt’s ANC at C1D1, C1D14, C2D1, C2D14 were recorded along with various pt outcomes. Pts were divided into strict monitoring (SM) or relaxed monitoring (RM) groups. SM is defined as pts who received ANC testing within 72h of C1D14, C2D1, and C2D14. RM was defined as not meeting those criteria. Results: Palbociclib was used in 152 pts; abemaciclib was used in 8. Average age was 58. Study population was 55% Caucasian; 38% African American; 6% Asian. Pts had an average of 3 lines of prior therapy and average of 9 cycles on a CDK 4/6i. 71% of pts suffered neutropenia (40% grade 3, 4% grade 4, 2.5% febrile neutropenia). PFS and OS did not statistically differ between groups (Table), but OS data is immature. Conclusions: This study analyzed a more diverse and heavily pre-treated MBC population than previous CDK 4/6 studies. The prevalence of neutropenia (grade 3/4) aligns with results described in the PALOMA trial. PFS was higher in the RM group than in the SM group, suggesting strict monitoring for neutropenia does not improve PFS. If ANC monitoring parameters could be safely relaxed for CDK 4/6i, it could improve quality of life and decrease financial toxicity across the system. This is a topic worthy of further study. [Table: see text]
Mutational analysis of &gt;14,000 solid tumor NGS tests from community oncology practices: The Sarah Cannon molecular landscape.
Authors: Andrew McKenzie, Daniel Schlauch, Yasha Sharma, Shaita Picard, Connor Higgins, Amanda Misch, Yonghong Xiao, Rebecca Lachs, Niall OConnor, Mick Correll, David R. Spigel, Howard A. Burris, Suzanne Fields Jones, Holli Hutcheson Dilks
Journal: Journal of Clinical Oncology (2019)

e18065 Background: Utilization of NGS-based testing for patients in community oncology settings continues to grow. A comprehensive analysis of the molecular landscape of &gt; 14,000 patients with commercial tissue-based and plasma-based NGS (tbNGS and pbNGS) testing from Sarah Cannon’s (SC) network of community oncologists between 2012 and 2018 was performed. These data aid clinical trial design/feasibility and identify rare and actionable mutations in the community oncology setting. Methods: Medical Oncologists in the SC network ordered NGS-based molecular profiling for their patients as standard of care. Data from multiple commercial vendors starting in 2012 were harmonized and analyzed. Results: On average, tbNGS (n = 8938) and pbNGS (n = 5419) tests revealed 14 and 4 mutations/sample, respectively. The top 10 mutated genes from both tbNGS and pbNGS - tests are in the table. The most predominant mutation-types detected were SNVs in both tbNGS and pbNGS tests, and gene amplifications were detected in ~40% of tbNGS and ~22% of pbNGS tests. MET amplifications (range: 2 - 40 copies (pbNGS) and 6 - 82 copies (tbNGS)) and ERBB2 amplifications (range: 2.1 - 90.2 copies (pbNGS) and 4 - 293 copies (tbNGS)) were detected in 1.6% (MET-tbNGS) and 4.6% (MET-pbNGS) and 4.2% (ERBB2-tbNGS) and 2.69% (ERBB2-pbNGS) of patients, respectively, and informed clinical trial enrollment. Of the fusions detected, 28 NTRK rearrangements were detected (NTRK1 – 16, NTRK2 – 5, NTRK3 – 7) by tissue-based testing and 3 (NTRK1) fusions were detected by plasma-based tests. Conclusions: These data describe the mutational landscape of NGS tests ordered within community oncology practices. SC’s data infrastructure links NGS-based testing data and clinical data to support real world evidence research, and highlights the need for healthcare IT systems to marry clinical and genomic data for clinical decision support and clinical research. [Table: see text]