tbuckley/cabot-search huggingface dataset:
Phase Ib study of cetuximab + BYL719 + IMRT in stage III-IVB head and neck squamous cell carcinoma (HNSCC).
Authors: Lara Dunn, Nadeem Riaz, Shrujal S. Baxi, Sean Matthew McBride, Eric Jeffrey Sherman, Loren Michel, Sofia Haque, Nora Katabi, Richard J. Wong, Han Xiao, Nancy Y. Lee, Matthew G. Fury, Alan Loh Ho, David G. Pfister
Journal: Journal of Clinical Oncology (2017)

6081 Background: Activation of the PI3K/mTOR signaling pathway is common in HNSCC. PI3K inhibitors have been shown to enhance radiosensitivity. BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, an FDA-approved radiosensitizing agent in HNSCC. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods: This is a single-institution, phase I study. Patients with Stage III-IVB HNSCC received cetuximab 400 mg/m 2 IV loading dose prior to intensity modulated radiation therapy (IMRT), followed by 250 mg/m 2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels (DLs): 1) 200 mg, 2) 250 mg, and 3) 300 mg per day in a standard 3 + 3 dose escalation design. Results: 11 patients are evaluable; median age-60 years (36-73); Stage III-1, IVA-9, IVB-1; oropharynx primary-9, unknown primary-2; HPV-positive -10. 8 patients completed treatment. 3 patients were treated on DL 1 and 2 without a dose limiting toxicity (DLT). Both patients on DL 3 experienced a DLT of grade 3 mucositis. Related adverse events (AEs) of any grade experienced by all 8 patients include: mucositis, weight loss, and hyperglycemia. Related grade 3 and 4 AEs in at least 2 patients include: mucositis (4), dysphagia (4), and decreased lymphocyte count (2). An additional 3 patients have been enrolled onto DL 2 and are undergoing treatment. All other patients had a complete response (CR) on post-treatment PET (from 6/2015 - 9/2016) and remain free of disease. Of 6 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intra-treatment MRIs. Conclusions: BYL719 administered at DLs 200 mg or 250 mg oral daily with cetuximab and IMRT resulted in expected AEs of radiation-based treatment with cetuximab and tolerable class-related AEs of PI3K inhibitors. BYL719 300 mg oral daily exceeds the maximum tolerated dose; the phase II recommended dose is pending completion of expansion of DL 2. All patients who completed treatment had a CR. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab + IMRT in the treatment of locally advanced HNSCC is warranted. Clinical trial information: NCT02282371.
Development and Validation of a Prediction Model for Mortality and Adverse Outcomes Among Patients With Peripheral Eosinopenia on Admission for <i>Clostridium difficile</i> Infection
Authors: Audrey S. Kulaylat, Erica L. Buonomo, Kenneth W. Scully, Christopher S. Hollenbeak, Heather Cook, William A. Petri, David B. Stewart
Journal: JAMA Surgery (2018)

Recent evidence from an animal model suggests that peripheral loss of eosinophils in Clostridium difficile infection (CDI) is associated with severe disease. The ability to identify high-risk patients with CDI as early as the time of admission could improve outcomes by guiding management decisions.To construct a model using clinical indices readily available at the time of hospital admission, including peripheral eosinophil counts, to predict inpatient mortality in patients with CDI.In a cohort study, a total of 2065 patients admitted for CDI through the emergency department of 2 tertiary referral centers from January 1, 2005, to December 31, 2015, formed a training and a validation cohort. The sample was stratified by admission eosinophil count (0.0 cells/μL or >0.0 cells/μL), and multivariable logistic regression was used to construct a predictive model for inpatient mortality as well as other disease-related outcomes.Inpatient mortality was the primary outcome. Secondary outcomes included the need for a monitored care setting, need for vasopressors, and rates of inpatient colectomy.Of the 2065 patients in the study, 1092 (52.9%) were women and patients had a mean (SD) age of 63.4 (18.4) years. Those with an undetectable eosinophil count at admission had increased in-hospital mortality in both the training (odds ratio [OR], 2.01; 95% CI, 1.08-3.73; P = .03) and validation (OR, 2.26; 95% CI, 1.33-3.83; P = .002) cohorts in both univariable and multivariable analysis. Undetectable eosinophil counts were also associated with indicators of severe sepsis, such as admission to monitored care settings (OR, 1.40; 95% CI, 1.06-1.86), the need for vasopressors (OR, 2.08; 95% CI, 1.32-3.28), and emergency total colectomy (OR, 2.56; 95% CI, 1.12-5.87). Other significant predictors of mortality at admission included increasing comorbidity burden (for each 1-unit increase: OR, 1.13; 95% CI, 1.05-1.22) and lower systolic blood pressures (for each 1-mm Hg increase: OR, 0.99; 95% CI, 0.98-1.00). In a subgroup analysis of patients presenting without initial tachycardia or hypotension, only patients with undetectable admission eosinophil counts, but not those with an elevated white blood cell count, had significantly increased odds of inpatient mortality (OR, 5.76; 95% CI, 1.99-16.64).This study describes a simple, widely available, inexpensive model predicting CDI severity and mortality to identify at-risk patients at the time of admission.
Emerging immunotherapy and decade of early phase drug development: Systematic review of multiple myeloma treatment.
Authors: Warda Faridi, Shaunak Pandya, Ceren Durer, Seren Durer, Mitchell Ross, Saad Malik, Arveen Saeideh Asghar, Atif Sohail, Sabina Saeed, Pavan Tenneti, Muhammad Sardar, Aparna Nallagangula, Hani M. Babiker, Faiz Anwer
Journal: Journal of Clinical Oncology (2018)

e20016 Background: With the emergence of immunotherapy, genomics, and precision medicine, the future of multiple myeloma (MM) treatment is rapidly evolving. We reviewed the efficacy of (non-FDA approved) monoclonal antibodies (mAbs), chimeric antigen receptor-modified (CAR-T) cells, novel drugs, and novel targets tested through phase I/II. Methods: Literature research was performed according to PRISMA guidelines in PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. Results: 79 studies were included. Conjugate antibodies (ADCs) and mAbs used in combination with lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd) such as indatuximab-ravtansine + Rd, siltuximab + Vd, isatuximab + Rd, lorvotuzumab-mertansine + Rd, pembrolizumab + Rd showed objective response (OR) of 78%, 66%, 64.5%, 56.4% and 50% respectively. Among CAR-T cell targets, maximum OR of 100% reported with BCMA CAR-T cells. Among novel drugs, bendamustine showed an OR of 81.8%, histone deacetylase inhibitors i.e. vorinostat, romidepsin, ricolinostat, CKD-581, citarinostat, AR-42 (mean OR 55.5%). Newer agents under development like SGN-CD352A, sotatercept, GBR-1342, AVL-292, BION-1301, sonidegib, novel proteasome inhibitors (oprozmib, marizomib, and mTOR inhibitors (everolimus, temsirolimus, TAK-228) have shown efficacy. Key mutations identified as potential targets for precision medicine included overactivation of Wnt pathway from Cyclin D loss, V600E activating mutation in BRAF kinase, constitutive activation of NF-kB pathway. Other potential inhibitors under testing for MM include drugs to target aurora kinases, PARP, PD-1 / PDL-1, tyrosine kinases, BCL-2, EZH2, MEK, EGFR pathway, nuclear export, CD47-SIRPα, and overactive JAK / STAT pathway. Conclusions: For MM, ADC and mAbs used in combination with Rd or Vd exhibited positive results. Further studies are required to explore the role of newer drugs, various CAR-T cell constructs and drugs targeting aberrant intracellular pathways
Comparison the anti-tumor effect of pyrotinib, afatinb and T-DM1 in lung cancer organoids and PDX models with HER2 mutation.
Authors: Yan Wang, Zhen Qin, Quanren Wang, Chris Rivard, Tao Jiang, Guanghui Gao, Hui Yu, Shengxiang Ren, Hongbin Ji, Caicun Zhou, Fred R. Hirsch
Journal: Journal of Clinical Oncology (2018)

e24281 Background: Targeted therapy for patients of NSCLC with HER2 mutations is still on unmet need in clinical setting. Pyrotinib, a HER2 and EGFR tyrosine kinase inhibitor, has showed encouraging anti-tumor effect with a ORR of 54.5% (6/11) in our preliminary data of phase 2 trial. This study aimed to investigate the anti-cancer effect and the potential different mechanism of pyrotinib in organoids and PDX models with HER2 mutation, compared with the other anti-HER2 drugs, afatinib and T-DM1. Methods: Organoids and PDX models were established from the therapeutic naïve patient with HER2-mutant lung cancer. Anti-tumor efficacy,and downstream signaling pathways inhibition were analyzed and compared in afatinb, T-DM1 and different dose of pyrotinib groups in both the organoids and PDX models. Results: Patient-derived organoids and xenografts were established from a 42-year-old female with HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma. When the organoids were treated with afatinib and pyrotinib, at 29nM and 180nM respectively(adopted from the plasma concentrations of previous phase 1 clinical trials) , pyrotinib significantly inhibited the cell growth compared with afatinib(p = 0.0038). The in vivo PDX model study showed that pyrotinib(mouse,80mg/kg,adopted from clinical trial recommended dose) showed a significantly superior anti-cancer effect than afatinib of 15 mg/kg (p = 0.0471), T-DM1 of 10 mg/kg (p = 0.0138) and lower dose of pyrotinib 5 mg/kg(p = 0.0001) and 20 mg/kg(p < 0.0001). Pyrotinib(80mg/kg) also showed a robust ability to inhibit pHER2, pERK and pAkt both in the IHC and western blot analysis. Meanwhile, the body weight of PDX model mice receiving afatinib of 15mg/kg showed a significantly decrease compared with pyrotinib of 80mg/kg(p < 0.0001). Conclusions: Pyrotinib, afatinb and T-DM1 all showed the ability to inhibit HER2 in lung cancer models, while pyrotinib showed a significantly better tolerance and anti-cancer effect than afatinib and T-DM1, which might contribute the encouraging results of our previous phase 2 trial.
Safety and metabolic effects of cyclic fasting mimicking diet (FMD) in cancer patients.
Authors: Filippo G. De Braud, Monica Milano, Giovanni Fucà, Gabriella Mariani, Giuseppe Capri, Giulia Valeria Bianchi, Paola Corsetto, Valter Longo, Licia Rivoltini, Claudio Vernieri
Journal: Journal of Clinical Oncology (2018)

e14549 Background: In preclinical studies, a plant-based, low-calorie, low-carbohydrate, low-protein diet, also known as fasting mimicking diet (FMD), has demonstrated anticancer activity that is mediated by changes in systemic metabolism. In healthy volunteers, cyclic FMD is safe and produces similar metabolic modifications. However, its effects in cancer patients (pts) remain unexplored. Methods: Our ongoing prospective monocentric trial NCT03340935 is evaluating the safety, feasibility and metabolic effects of a cyclic 5-day FMD regimen (300-700 KCal/day) in pts with any-stage malignant neoplasms, alone or in combination with standard anticancer treatments. The FMD is repeated every 21-28 days. Exclusion criteria include: BMI < 20 kg/m2, recent unintentional weight loss > 5% and insulin-dependent diabetes. Blood and urine samples are collected before and at the end of each FMD cycle to measure changes in metabolites and growth factors. Here we present preliminary study results during the first 3 FMD cycles. Results: We recruited 63 pts between February 2017 and November 2017. Of them, 46 (73%) had metastatic disease and 58 (92%) received concomitant anticancer treatments. Breast (29), lung (6), colorectal (6), and prostate (5) cancer were the most represented malignancies. 62 pts (98.4%) completed one FMD cycle and 38 (60.3%) completed three cycles. The most common FMD-related adverse events (AEs) were fatigue (77.8%), dizziness (19%) and headache (14.3%). G3-G4 AEs occurred in 4 (6.3%) patients. In 61 evaluable pts, the FMD reduced median plasma glucose by 16.1-21%, serum IGF-1 by 33-34% and insulin by 30.5-45%. Conclusions: The proposed FMD scheme is safe, well tolerated and produces remarkable modifications of systemic metabolism that are conserved across subsequent cycles. Future studies are needed to assess the anticancer activity of the FMD in specific clinical settings. Clinical trial information: NCT03340935.
Patterns of relapse and implications for post-nephrectomy surveillance for patients with high-risk non-clear cell renal cell carcinoma: Subgroup analysis of the phase 3 ECOG-ACRIN E2805 trial.
Authors: Vivek Narayan, Maneka Puligandla, Pearl Subramanian, Robert Uzzo, Robert S. DiPaola, Naomi B. Haas
Journal: Journal of Clinical Oncology (2018)

4564 Background: Non-clear cell renal cell carcinomas (non-ccRCC) comprise a diverse subgroup, with biology and clinical behavior that is distinct from clear cell RCC (ccRCC). However, the natural history of non-ccRCC remains poorly defined, and clinical practice relies on consensus guidelines largely intended for ccRCC. We evaluated the patterns of relapse and the implications for post-nephrectomy surveillance for patients with non-ccRCC enrolled on the first and largest randomized trial of adjuvant anti-angiogenic therapy for high-risk RCC. Methods: Retrospective subgroup analysis of patients with non-ccRCC enrolled on E2805. For recurrence rates (RR) by site, the cumulative incidence was estimated accounting for competing risks. Gray’s test was used to compare the incidence between groups. The 2017 NCCN recommendations were used to evaluate the adequacy of strict adherence to post-nephrectomy surveillance guidelines. Results: 403 non-ccRCC patients were enrolled (37% papillary, 28% chromophobe, 21% mixed, 14% unclassified). 144 recurrences were detected over a median follow-up of 6.2 years. 5-year RRs (95% CI) were 22% (11, 28) and 49% (41, 56) for Int-High and Very-High UISS risk groups, respectively. Abdominal recurrences were most frequently identified, including lymph node (39%), nephrectomy bed (17%), and liver (13%). While overall 5-year RRs were comparable between non-ccRCC and ccRCC patients (34.6% vs 39.5%), non-ccRCC patients were significantly more likely to develop abdominal site relapse (5-yr RR 26.4% vs 18.2%, p = 0.0008) and less likely to relapse in the chest (5-yr RR 13.7% vs 20.9%, p = 0.0005). Surveillance imaging for 5.3 years would be required to capture 95% of abdominal non-ccRCC recurrences. Conclusions: This is the largest, standardized evaluation of the natural history of non-ccRCC following curative-intent nephrectomy. Our findings demonstrate that non-ccRCC exhibits a distinct pattern of relapse when compared to conventional ccRCC, and emphasize the importance of continued long-term imaging for patients with high-risk resected non-ccRCC.
Does neoadjuvant chemotherapy affect postoperative complication rates in elderly patients treated with radical cystectomy for bladder cancer?
Authors: Nozomi Hayakawa, Eiji Kikuchi, Ryuichi Mizuno, Mototsugu Oya, Kimiharu Takamatsu
Journal: Journal of Clinical Oncology (2018)

e16526 Background: Although the survival benefit of neoadjuvant chemotherapy (NAC) in bladder cancer patients receiving radical cystectomy (RC) has been established, the NAC associated complication rate is not well-known, especially in elderly patients. Methods: We identified 427 patients who had undergone RC for clinical TanyN0M0 bladder cancer from 2005 to 2015 at our 7 institutions. Among them, 118 (27.6%) were treated with gemcitabine and cisplatin (GC)-NAC. The details of the complication rate during and after RC were recorded according to the Clavien-Dindo classification. We evaluated the association between the complication rate for RC with NAC and patient age. Results: Overall, 60 (14.0%), 306 (71.7%), and 61 (14.3%) patients were < 60, 60-79, and ≥ 80 years old, respectively. Overall, 190 (44.5%) patients had some kind of postoperative complication and there was no difference in the postoperative complication rate between the NAC and non-NAC groups (37.3% vs 47.2%: p = 0.065). However, the incidence rate of post-operative ileus in the NAC group was 9.3%, which was significantly lower than that in the non-NAC group (19.1%, p = 0.013). Sixteen (26.7%), 93 (30.4%) and 9 (14.8%) patients in the < 60, 60-79, and ≥ 80 age groups, respectively, received GC-NAC. Among patients < 60 years old, the complication rates for post-operative ileus, pyelonephritis and wound infection were 12.5%, 18.8%, and 0% in the NAC group, which were not significantly different from those in the non-NAC group (9.1%, 6.8%, and 13.6%, respectively). Among 60-79 year-old patients, the corresponding complication rates were 8.6%, 11.8%, and 9.7% in the NAC group, which were not significantly different from those in the non-NAC group (17.8%, 9.9%, and 9.4%, respectively). Among patients ≥ 80 years old, the rates were 11.1%, 11.1%, and 33.3% in the NAC group, which were not significantly different from those in the non-NAC group (28.8%, 11.5%, and 13.5%, respectively). Furthermore, in patients treated with GC-NAC, no association was observed in the complication rates among patients < 60 years, 60-79 years, and ≥ 80 years old. Conclusions: NAC could be provided safely at the time of RC regardless of patient age.
Tumor specific methylation of NPY compared to RAS mutation in plasma DNA in the monitoring of colorectal cancer patients treated with last-line regorafenib.
Authors: Lars Henrik Jensen, Caroline Brenner Thomsen, Rene K Olesen, Anders Kindberg Boysen, Torben Hansen, Lise Nottelmann, Birgitte Mayland Havelund, Rikke Fredslund Andersen, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2018)

e15541 Background: Regorafenib has a proven but small significant effect in refractory colorectal cancer. The objective of the present, post-marketing trial was to investigate the clinical outcome in Danish patients. Further, we aimed at identifying new tumor specific prognostic markers. Methods: Eligible patients with metastatic disease and progression on standard chemotherapy were enrolled prospectively. Patients received regorafenib daily for three weeks in four week cycles. Effect was evaluated by CT scan every two cycles. All tumors underwent RAS/RAF mutation analysis. Plasma samples were collected before treatment and at every cycle. RAS/RAF mutations found in the tumor were quantified by droplet digital PCR. Methylation of the NPY gene was analysed using bisulfite conversion and methylation specific droplet digital PCR. Results: The study included 100 patients and 95 received regorafenib. Grade 3-4 toxicity was reported in 51 episodes. Seventy-five patients were evaluable for response. Stable disease seen in 60% and 40% progressed. The median PFS and OS was 2.9 months and 5.2 months, respectively. A RAS/RAF mutation was found in 49 patients (52%) available for monitoring. Methylated NPY could be quantified in 90 patients (95%). There was a strong correlation between paired observations of the fraction of RAS mutation and of NPY methylated DNA. Spearman’s rho ranged between 0.83 and 0.87 for the first three longitudinal samples (p < 0.001). A division according to the median values indicated that both mutated DNA and methylated DNA hold significant (p < 0.01) but almost identical prognostic information. A substantial increase preceded progression with a relevant clinical lead time. Conclusions: NPY methylation and RAS mutation analysis to determine tumor specific DNA are interchangeable, but NPY is superior, as it is applicable in 95% of the patients. The baseline level holds important prognostic information. Monitoring plasma NPY methylation during treatment may serve as an early predictor of progression. We suggest NPY methylation analysis as an easy and universally applicable method for monitoring tumor specific DNA in colorectal cancer patients.
Risk of gastrointestinal and hepatic toxicities in patients with hormone receptor-positive HER2-negative breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials.
Authors: Aung Tun, Kyaw Zin Thein, Yu Yu Thar, Asha Nayak, Elizabeth Guevara
Journal: Journal of Clinical Oncology (2017)

e18284 Background: CDK4/6 inhibitors are proven to be beneficial in patients with hormone receptor-positive HER2-negative breast cancer. Studies have suggested an increased risk of gastrointestinal (GI) events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the risk of GI and hepatic toxicities. Methods: We systematically conducted a comprehensive literature search using MEDLINE and EMBASE databases through January 1, 2017. RCTs that mention GI symptoms and/or elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Results: Five RCTs with a total of 2021 patients were eligible for analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, and ribociclib-letrozole while the control arm used placebo with letrozole or fulvestrant. The relative risks of all-grade elevated AST was 2.6 (95% CI: 1.15–5.86; p = 0.02); all-grade elevated ALT: 2.82 (95% CI: 1.25–6.36; p = 0.01); all-grade stomatitis: 3.32 (95% CI: 2.09-5.28; p &lt; 0000.1); all-grade nausea: 1.79 (95%CI: 1.25-2.58; p = 0.002); all-grade vomiting:1.55 (95% CI: 0.92-2.63; p = 0.10); and all-grade diarrhea: 1.59 (95% CI 1.28-1.98; p &lt; 0.0001). The relative risks of high-grade elevated AST was 3.08 (95% CI: 1.42–6.67; p = 0.004); high-grade elevated ALT: 7.2 (95% CI: 2.81–18.43; p &lt; 0.0001); high-grade stomatitis: 2.01 (95% CI: 0.22-18.02; p = 0.53); high-grade nausea: 0.76 (95%CI: 0.12-4.78; p = 0.77); high-grade vomiting: 0.88 (95% CI: 0.19-4.13; p = 0.87); and high-grade diarrhea: 1.23 (95% CI 0.52-2.92; p = 0.64). Conclusions: Our meta-analysis demonstrated that CDK 4/6 inhibitor-based regimens are associated with a higher risk of all-grade and high-grade elevated AST and ALT. Moreover, the regimen is associated with increased risk of all-grade stomatitis, nausea and diarrhea. Recognizing these adverse effects may help clinicians in delivering proper supportive care and thereby enhancing patients’ quality of life.