tbuckley/cabot-search huggingface dataset:
Regorafenib and nivolumab combination therapy for advanced and metastatic solid tumors: Phase I clinical trial (EPOC1603).
Authors: Shota Fukuoka, Hiroki Hara, Satoshi Shimizu, Hideaki Takahashi, Masafumi Ikeda, Hitomi Tamura, Yuichi Mikamoto, Miki Fukutani, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

TPS3124 Background: Immune checkpoint inhibitors (CPIs) have shown promising efficacies in several types of malignancies. However, still around half of patients with most tumor types experienced disease progression at the initial tumor assessment. One possible reason for resistance to CPIs is suspected to be based on interaction with cancer niche which include suppressive immune cells such as myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Previous in vivo study showed that selective inhibition of VEGF pathway with anti-VEGF antibody or anti-VEGF tyrosine kinase inhibitors (TKIs) suppress tumor growth and decrease MDSC, Tregs and TAMs. In addition, suppression of stem cell factor (SCF)-mediated signaling though c-Kit also decreases MDSC expansion and tumor angiogenesis, which may overcome resistance to CPIs. Therefore, we initiated phase I study to assess efficacy and safety for the combination of nivolumab and regorafenib as a multi-kinase inhibitor targeting both VEGF and SCF signaling. Methods: The main eligibility criteria is patients with unresectable recurrent solid tumors who are refractory or intolerant to standard chemotherapy. Primary objective is to examine the safety and tolerability of repeated dosing of regorafenib and nivolumab and to investigate the maximum tolerated dose (MTD) and recommended dose (RD). Dose escalation cohort was designed to determine the recommended expansion cohort dose in a “3+3” cohort-based dose escalation design of regorafenib (80 mg once dairy for 21 days on 7 days off on level 1, 120 mg on level 2 and 160 mg on level 3) with nivolumab (3.0 mg/kg q2w). In expansion cohort, approximately 30 patients with selected solid tumors such as gastric, coloretcal, hepatocellular cancer will be enrolled at the RD. We also investigate several biomarkers using pre- and post-treatment samples from both biopsied tumor and blood. First three patients were enrolled and treated in level 1 as of January 2018. Clinical trial information: NCT03406871.
Hospital volume and post-discharge mortality in Medicare beneficiaries aged 65 and older with acute leukemia.
Authors: Michael P Thompson, Teresa M Waters, Erin Kaplan, Caitlin N McKillop, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

6560 Background: While the hospital volume-outcome relationship has been established for many complex surgeries and invasive procedures, the impact of hospital volume on outcomes for acute leukemia is less certain. Methods: We used 2013 fee-for-service claims data from 10,101 Medicare beneficiaries aged 65 and older receiving acute leukemia care in 2,045 hospitals to rank-order facilities by increasing annual case volume. Hospitals were categorized as very high (N = 38), high (N = 109), and low volume (N = 1,898). We used hierarchical logistic regression models to estimate 30-day and 1-year mortality rates, adjusting for demographics, acute leukemia subtype, receiving chemotherapy, emergent admission status, transfer status, relapsed cancer, and Charlson comorbidity index. Odds ratios estimated the adjusted effect of very high and high hospital volume on mortality, compared to low volume hospitals. We also estimated number of deaths averted if patients were treated in higher volume hospitals. Results: The median case volume for very high, high, and low volume hospitals was 46, 17, and 2 cases, respectively. As volume increased, adjusted 30-day mortality rates fell (p < 0.001): very high– 37.5%, high– 40.5%, and low volume – 40.9%. At one year, mortality rates for very high, high, and low volume hospitals rose to 69.4%, 71.1%, and 71.5%, respectively (p < 0.001). Compared to low volume hospitals, patients treated in very high volume hospitals had reduced odds of mortality at 30 days (OR = 0.66; 95% CI: 0.57, 0.76; p < 0.001) and 1 year (OR = 0.71; 95% CI: 0.62, 0.82; p < 0.001). Patients treated in high volume hospitals also had reduced odds of mortality at 30 days (OR = 0.87; 95% CI: 0.77, 0.98; p < 0.05) and 1 year (OR = 0.84; 95% CI: 0.74, 0.95; p < 0.05), compared to low volume hospitals. Our results indicate that treating all patients in very high volume hospitals could avert 21.2% of 30-day mortality and 6.2% of 1-year mortality. Conclusions: Medicare beneficiaries aged 65 and older with acute leukemia have significantly reduced likelihood of death within one year of discharge when treated in higher volume hospitals. Future work should further elucidate reasons for the clinical benefit associated with higher volume centers.
Immune-related tumor response dynamics in melanoma patients (pts) treated with pembrolizumab: Identifying markers for clinical outcome and treatment decisions.
Authors: Mizuki Nishino, Anita Giobbie-Hurder, Michael P Manos, Nancy Bailey, Elizabeth Iannotti Buchbinder, Patrick Alexander Ott, Nikhil H. Ramaiya, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2017)

9521 Background: PD-1 inhibitors have shown marked efficacy in advanced melanoma and are associated with unique response patterns. We aimed to characterize the tumor burden dynamics and identify quantitative imaging markers for overall survival (OS) in melanoma pts treated with pembrolizumab. Methods: The study included 107 advanced melanoma pts (63 males; median age: 63) treated with pembrolizumab monotherapy at DFCI. Tumor burden dynamics were assessed on serial CT scans during therapy by irRECIST, which uses unidimensional measurements and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. The relationships between tumor burden dynamics and OS were studied. Results: Among 107 pts, 96 pts had measurable tumor burden at baseline and 11 had non-target lesions alone at baseline. Among the 96 pts, maximal tumor shrinkage ranged from -100% to 567% (median:-18.5%). Overall response rate was 44% (42/96; irCR in 5, irPR in 37). Tumor burden remained &lt; 20% increase from baseline throughout therapy in 57 pts (55%). Using a 3-month landmark analysis, pts with &lt; 20% tumor burden increase from baseline at 3 months had longer OS than pts with ≥ 20% increase (12-month OS rate: 82 vs. 53%). In extended Cox models, pts with &lt; 20% tumor burden increase during therapy had significantly reduced hazards of death (HR = 0.19, 95%CI: 0.08–0.43, p &lt; 0.0001 univariate; HR = 0.18, 95%CI: 0.08-0.41, p &lt; 0.0001, multivariable). Five pts (5%) experienced pseudoprogression; 3 pts had increase of target lesions with subsequent response, which was noted after confirmed irPD on consecutive scans. Two pts with no measurable tumor burden progressed with new/non-target lesions that subsequently regressed. Conclusions: Tumor burden increase of &lt; 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical prognostic marker to guide treatment decisions. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response assessment. Evaluations of non-measurable tumor burden may require further attention in the clinical setting of immuno-oncology.
Role of anti-EGFR monoclonal antibody in EGFR FISH positive NSCLC patients: A meta-analysis of phase III randomized controlled trials.
Authors: Nikita Patel, Madhusmita Behera, Rathi Narayana Pillai, Taofeek Kunle Owonikoko, Suchita Pakkala, Chandra Prakash Belani, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2016)

e20650 Background: Monoclonal antibodies against epidermal growth factor receptor (EGFR) have been developed in combination with chemotherapy for NSCLC management. EGFR gene copy number by fluorescent in situ hybridization (FISH) has been proposed as a predictive biomarker for efficacy. We conducted a meta-analysis of randomized control trials (RCTs) that evaluated standard chemotherapy with or without an EGFR monoclonal antibody in EGFR FISH positive patients. Methods: An electronic literature search was performed of public databases (MEDLINE, EMBASE, COCHRANE) and conference proceedings for phase III randomized trials comparing standard chemotherapy alone (C) versus chemotherapy in combination with EGFR monoclonal antibody (C+mAb). Studies that did not test for EGFR FISH were excluded. A formal meta-analysis was conducted with Comprehensive Meta-Analysis software (Version 2.2) using fixed and random effect models. Outcome data were pooled and reported as hazard ratios (HR) and weighted estimates. Results: Four phase III randomized control trials reported between 2010 and 2015 enrolling a total number of 2,253 patients were eligible for this analysis. Patient characteristics (%C+mAb vs. C): Median age 62.5/64, male 65/63.5, smokers 91/90, white 91/88, performance status (0-1) 88/89.5; 34% of patients were EGFR FISH positive. The overall survival (OS) was superior in the C+mAb group (pooled HR 0.84 95% CI 0.72-0.99; p = 0.03) with a similar trend for progression free survival (PFS) (pooled HR 0.87 95% CI 0.74-1.02 P = 0.08). Weighted median OS was 12.6 vs. 9.8 months (p = 0.6)in the C+mAb and C respectively; weighted median PFS was 5.4 vs. 4.8 months (P = 0.8). Histology specific data were only reported in two trials. Conclusions: The combination of anti-EGFR monoclonal antibodies and standard chemotherapy in EGFR FISH positive advanced NSCLC patients is associated with modest improvement in overall survival in this pooled analysis.
P23 Stage IIIb NSCLC and Curative Intention Treatment: Difficulties and Disparities in Brazil
Authors: C. Baldotto, E. Cronemberger, F. Marinho, P. De Marchi, L. Araujo, F. Franke, P. Salles, A. Calabrich, T. Almeida, M. Custodio, M. Massaoka, C. Araujo, M. Horacio, A. Santa Maria, G. Castro
Journal: Journal of Thoracic Oncology (2018)
SAT0374 Lesinurad (LESU) adjunctive therapy with allopurinol (ALLO) in patients not responding to allo monotherapy: pooled post hoc safety and efficacy analysis in a patient subgroup using concomitant diuretics at baseline (BL)
Authors: T. Bardin, R.G. Karra, A. So, A.-K. Tausche, I. Wild, H. Hagedorn, P. Kandaswamy, F. Perez-Ruiz
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> LESU is approved as adjunctive therapy in combination with xanthine oxidase inhibitors (XOI) for gout PT not responding to XOI alone<sup>1</sup>. Gout PT often have hypertension (HT) for which diuretics especially thiazide and thiazide-like diuretics (TTLD) are prescribed. TTLD contributes to hyperuricemia<sup>2</sup> by acting on OAT4 transporter, which is inhibited by LESU. <h3>Objectives</h3> To assess the efficacy and safety of LESU+ALLO in the subgroup of PT using concomitant diuretics at BL in CLEAR 1 and CLEAR 2, two randomised, double-blind, placebo-controlled Phase 3 studies that evaluated LESU200/400 mg daily in combination with ALLO <i>vs</i> ALLO +placebo. <sup>3&amp;4</sup>. <h3>Methods</h3> Data from both trials of 1,213 PT, was pooled and PT group using diuretics at baseline was compared to non-users with respect to sUA target and TEAE. <h3>Results</h3> Totally 221 PT received diuretics,&gt;90% due to HT and ~80% being TTLD. In both groups, LESU +ALLO doubled the number of PT reaching sUA target of &lt;6.0 mg/dL vs ALLO +PBO at month 6 (m-6) and 12 (m-12) (table 1). At m-12, the response rate in PT receiving TTLD was 60.8%, 61.5% in the LESU 200 and 400 mg group, and 26.6% in the ALLO alone group, and 47.5%, 50.5%, and 25.7% in PT not receiving TTLD respectively. The safety profile was comparable except for transient and reversible serum creatinine elevations in the LESU groups. (table 1). <h3>Conclusions</h3> LESU +ALLO doubled the number of PT reaching sUA target of &lt;6.0 mg/dL at m-6 and sustained at m-12, irrespective of TTLD use. Adjunctive therapy with LESU +ALLO is safe and efficacious even in PT subgroups using concomitant TTLD. <h3>References</h3> [1] Zurampic®(lesinurad) SmPC. Grünenthal GmbH, February 2016. [2] Bruderer S, et al. Arthritis Rheumatol2014Jan;66(1):185–96. [3] Saag KG, et al. Arthritis Rheumatol2017;69:203–12. [4] Bardin T, et al. Ann Rheum Dis2017;76:811–20. <h3>Disclosure of Interest</h3> T. Bardin Grant/research support from: Astrazeneca, Ipsen, Menarini, Consultant for: Grunenthal, Speakers bureau: Astrazeneca, Ipsen, Menarini, Grunenthal, Novartis, R. Karra Employee of: Grunenthal, A. So Consultant for: Grunnenthal, Sobi, A.-K. Tausche Consultant for: Berlin-Chemie, Menarini, Ipsen, Sobi, Novartis, Ardea Biosciences/AstraZeneca, I. Wild Employee of: Grunenthal, H. Hagedorn Employee of: Grunenthal, P. Kandaswamy Employee of: Grunenthal, F. Perez-Ruiz Consultant for: Grünenthal, Menarini, Spanish Society of Rheumatology, Cruces Hospital Rheumatology Association.
From Hepatocyte to Cholangiocyte: The Remarkable Potential of Transdifferentiation to Treat Cholestatic Diseases
Authors: Binita Kamath, Cara Mack
Journal: Hepatology (2018)

Kamath, Binita M.D.; Mack, Cara M.D.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information
A phase I study of multi-HLA-binding HSP70 + GPC3 peptides and combination adjuvants of LAG3-Ig + Poly-ICLC against gastrointestinal cancers.
Authors: Shoichi Hazama, Koji Tamada, Keiko Udaka, Yasunari Koki, Toshinari Uematsu, Hideki Arima, Tomomitsu Satoh, Shun Doi, Tomoya Miyakawa, Hiroto Matsui, Shinsuke Kanekiyo, Yukio Tokumitsu, Kazuhiko Sakamoto, Nobuaki Suzuki, Shigeru Takeda, Shigeru Yamamoto, Shigefumi Yoshino, Tomio Ueno, Hiroaki Nagano
Journal: Journal of Clinical Oncology (2018)

e15167 Background: Based on the exploratory analysis of our previous studies of peptide vaccine, we concluded that the combination of adjuvants hLAG-3Ig + Poly-ICLC is essential for controlling negative immune checkpoints and enhancing CTLs induction to overcome the traditional peptide studies. Another issue with peptide vaccines is human leukocyte antigen (HLA) restriction. Hence, we developed novel multi-HLA-binding peptides derived from the tumor antigens, HSP70 and GPC3, and confirmed the high expression in many types of cancer. After the presentation at ASCO 2017, we expanded pts in recommended dose to confirm safety and explored biomarkers for efficacy. Methods: We identified HSP70- and GPC3-peptide that have high binding affinity to each of HLA-A2402, 0201, and 0206 by a binding prediction system (NEC Corporation). In this phase I study of a novel peptide cancer vaccine for metastatic solid cancer, the primary objective was to evaluate its safety and toxicity. Secondary objective was to examine the immune and clinical response, and also to confirm the recommendable dose. This study used a three-tiered dose-escalation strategy with 3 pts’ cohorts. In addition to the 3 scheduled cases, 8 more cases were added and 11 cases were enrolled at the recommended dose. Results: Seventeen HLA-A*24:02-, 02:01-, and 02:06-matched pts (esophagus (EC), 5; colon (CRC), 6; liver (HCC), 4; pancreas, 1; stomach, 1) were treated in this study. No severe adverse effects related to the treatment were encountered. Peptide-specific CTL induction to HSP70 and GPC3 was observed in 15 and 16 pts, respectively. We observed decreased tumor marker expression in 10 cases, and disease control was observed in 5 pts (18, 4, 3, 3, 2 M). OS rates in CRC, HCC, and EC were 80%, 100%, and 60% at 6M, and 60%, 75% and 0% at 12M, respectively. Low CD4+PD-1+ (p = 0.02) and low Treg Fraction II (p = 0.03) were the significant favorable biomarker for OS. Conclusions: The combination cancer vaccine therapy using multi-HLA-restricted peptides and hLAG-3Ig + Poly-ICLC was safe and effective for treating solid tumors. CD4+PD-1+ and Treg Fraction II were the significant biomarker for OS. Clinical trial information: 000020440.
Variable DNA mismatch repair-associated gene profiles in colorectal versus uterine cancers.
Authors: Tabari Baker, Safoora Deihimi, Lainie P. Martin, Michael J. Hall, Heather Hampel, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2017)

11610 Background: DNA mismatch repair (MMR) plays an important role in maintaining DNA synthesis fidelity in the genome. Mutation in MMR genes occurs in colorectal and uterine cancers and leads to increased mutation burden that is associated with response to immune checkpoint inhibitors. It is unknown if there is an MMR gene-specific mutation signature in MMR-deficient tumors, or whether mutations in MMR genes drive specific mutation patterns. Methods: The study cohort consisted of 1060 uterine cancer (UtCa), and 797 colorectal cancer (CRC) cases consecutively submitted to Caris Life Science for molecular profiling using multiple technologies, including next generation sequencing (NGS), immunohistochemistry (IHC), and in situ hybridization (ISH). Mutation, IHC-positive, and ISH-positive frequencies were compared using Fisher’s exact test (p-value &lt; 0.05 considered significant). Results: In total, 1,857 tumors were examined. Of the 797 CRC cases, 115 (14.4%) had at least one mutation in MLH1, MSH2, or MSH6. Nineteen (19; 2.3%) of the CRC cases had mutations in multiple MMR related genes. Of the 1060 UtCa cases, 52 (4.9%) had at least one mutation in MLH1, MSH2, or MSH6. Twenty-two (22; 2.1%) of the UtCa cases had mutations in multiple MMR related genes. Colorectal cancers that were MLH1, MSH2, and MSH6 mutated enriched for rare, lineage specific co-mutations, including KRAS A146T (4/32 MLH1-mutated cases; 12.5%). Uterine cancers that were MLH1, MSH2, and MSH6 mutated also enriched for several co-mutations, including ARID1A (8/9 MLH1-mutated cases; 88.9%), a SWI-SNF chromatin remodeling complex family member. Further analyses revealed differences in PD-L1 positivity between MMR mutated CRCs versus UtCa (8/131; 6.1% versus 8/51; 15.7%). Tumor mutational load (defined as the total number of non-synonymous mutations per Mb sequenced) was 35 mutations per Mb in CRC and 51 mutations per Mb in UtCa. Conclusions: There are differences in mutation signatures between uterine and colorectal cancer, and possible additional molecular targets for combination with immune checkpoint therapies. Further analysis of MMR gene-specific differences in molecular profiles is ongoing and will be discussed.
Is FOLFOXIRI alone or combined with targeted therapy administered as first-line treatment a reasonable choice for most patients with mCRC? Systematic review and network meta-analysis.
Authors: Mingyi Zhou, Ping Yu, Dengue Hernick, Yanrong Li, Yuanhe Wang, Lingyu Fu, Jingdong Zhang
Journal: Journal of Clinical Oncology (2017)

e15018 Background: Controversy surrounds the question of whether the prognosis of most patients with metastatic colorectal cancer (mCRC) is improved using intensive administration of folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) alone or combined with target therapy as first-line treatment. Methods: We queried PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, the databases of the European Society for Medical Oncology and the American Society of Clinical Oncology to identify abstracts of randomized controlled trials evaluating the efficacies and toxicities of intensive therapies used for first-line treatment of patients with mCRC. The search included articles dated from the inception of these resources until December 31, 2016. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risks (RRs) for the objective response rate (ORR), the R0 resection rate, and toxicities. Results: Nine RCTs comprising 2,256 patients were included in this network meta-analysis. The PFS of patients administered FOLFOXIRI plus target therapy experienced prolonged PFS and OS and improved ORRs compared with FOLFOX or FOLFIRI plus target therapy (PFS: HR 0.65, 95% CI 0.46–0.91; OS: HR 0.80, 95% CI 0.65–0.98; ORR: HR 1.70, 95% CI 1.16–2.49; R0 resection rate: HR 2.66, 95% CI 1.86–3.82). There were no significant differences between PFS, OS, ORRs, or R0 resection rates and toxicities of patients administered FOLFOXIRI and FOLFOX or FOLFIRI plus target therapy. Further, FOLFOXIRI plus target therapy did not increase toxicities compared with FOLFOX or FOLFIRI plus target therapy, except for neutropenia. Conclusions: FOLFOXIRI plus target therapy when administered as first-line treatment of patients with mCRC is the best choice and did not significantly increase toxicities. FOLFOXIRI is as effective as FOLFOX or FOLFIRI plus target therapy.
The impact of patient age on toxicity and efficacy of immunotherapy agents.
Authors: Shuai Zhang, Amit Samani, Laura Spiers, Zayd Tippu, Ali Abdulnabi Suwaidan, Sophie Merrick, Mieke Van Hemelrijck, Miranda Payne, Guy Faust, Sophie Papa, Debra Hannah Josephs
Journal: Journal of Clinical Oncology (2018)

e15116 Background: Little data exists for the use of immune checkpoint inhibitors (ICI) in patients ≥80y old. Ageing is associated with immunosenescence, which may impact the efficacy and toxicity of immune-based therapies. Here we provide efficacy and immune related adverse event (irAE) data for patients ≥80y old and younger patient cohorts treated in routine clinical practice at 3 UK Cancer Centres: Guy’s and St Thomas’ NHS Foundation Trust, Oxford University Hospitals NHS Foundation Trust and University Hospitals of Leicester NHS Trust. Methods: Melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) patients treated with ICIs between March 2016 – August 2018 were identified, and divided into five age-defined cohorts: &lt; 50y, 50-59y, 60-69y, 70-79y, ≥80y. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method with data censored on 5th February 2018. Frequency and severity of five common irAEs were determined: hepatitis, endocrinopathies, immune-related gastrointestinal, skin and rheumatological. Results: 386 patients aged 22 – 98y (median 67y) received single-agent nivolumab (21%), pembrolizumab (62%), ipilimumab (10%) or combination ipilimumab and nivolumab (7%). 12% of patients were aged &lt; 50y, 18% were 50-59y, 29% were 60-69y, 28% were 70-79y and 13% were ≥80y. Response rates (partial + complete response) were similar across all age groups (53% &lt; 50y, 29% 50-59y, 48% 60-69y, 43% 70-79y and 47% ≥80y). Median PFS was 10.6, 10.3, 10.0, 5.8 and 19.7 months and OS was not reached, not reached, 29.0, 18.3, and 20.9 months for patients &lt; 50y, 50-59y, 60-69y, 70-79y and ≥80y, respectively. The rate of any grade irAEs was lowest in patients ≥80y (59%), and highest in patients &lt; 50y (92%). Grade 3-5 irAEs were also less frequent in patients ≥80y (10%) than those &lt; 50y and 60-69y (both 18%). Conclusions: Of 386 patients 13% were ≥80y with response rates comparable to younger patient cohorts and rates of irAEs lower than younger patient cohorts in this retrospective analysis of a heterogenous patient population. Our data suggests that ICIs are well-tolerated and efficacious in elderly patients and that age alone should not preclude ICI use.
Abstract 15967: Identifying Ventricular Arrhythmia Cases and Their Predictors by Applying Machine Learning Methods to Electronic Health Records (EHR) of Hypertrophic Cardiomyopathy (HCM) Patients
Authors: Moumita Bhattacharya, Dai-Yin Lu, Prasanth Lingamaneni, Shibani Kudchadkar, Gabriela Villareal, Sanjay Sivalokanathan, Pam C Villalobos, Stefan Zimmerman, Theodore P Abrahram, M. Roselle Abraham, Hagit Shatkay
Journal: Circulation (2017)

Introduction: Ventricular arrhythmias (VA) are a major cause of death in hypertrophic cardiomyopathy (HCM) patients. We develop a machine learning method to effectively identify VA in HCM patients ...