tbuckley/cabot-search huggingface dataset:
Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC).
Authors: Justin F. Gainor, Dae Ho Lee, Giuseppe Curigliano, Robert Charles Doebele, Dong-Wan Kim, Christina S Baik, Daniel Shao-Weng Tan, Gilberto Lopes, Shirish M. Gadgeel, Philippe Alexandre Cassier, Matthew H. Taylor, Stephen V. Liu, Benjamin Besse, Michael Thomas, Viola Weijia Zhu, Hui Zhang, Corinne Clifford, Michael Palmer, Christopher D. Turner, Vivek Subbiah
Journal: Journal of Clinical Oncology (2019)

9008 Background: RET fusions are targetable oncogenic drivers in up to 2% of NSCLC, yet no selective RET inhibitors are approved. BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations, including those that confer resistance to multikinase inhibitors (MKIs). We provide an update on the registration-enabling ARROW study (NCT03037385) of BLU-667 in pts with RET-fusion+ NSCLC. Methods: The global ARROW study includes DE (30-600 mg daily [QD or BID]) and dose expansion (DX) at the recommended phase 2 dose (RP2D; 400 mg QD) in pts with advanced solid tumors. Primary objectives are overall response rate (ORR; RECIST 1.1) and safety. Results: As of 19Dec2018, 79 pts (21 DE, 58 DX) with advanced RET fusion+ NSCLC (44 KIF5B, 16 CCDC6, 19 other/pending) received BLU-667. Median number of prior therapies was 2 (range 0-8) and includes chemotherapy (76%), immunotherapy (41%), and MKI (27%). 39% had baseline brain metastases. ORR among 57 response-evaluable pts with measurable disease and at least one follow-up disease assessment was 56% (95% CI: 42, 69; 32 partial responses (PR), 9 PR pending confirmation, 20 stable disease, 5 progressive disease). 91% (29/32) of responding pts remain on treatment; 6 have achieved response duration ≥ 6 months. Disease control rate (DCR) was 91% (52/57). Among 30 pts at the RP2D previously treated with platinum chemotherapy, ORR was 60% (18 PRs; 7 pending confirmation). Responses occur regardless of prior treatment or RET fusion genotypes. Intracranial activity has been observed with shrinkage of brain metastases. 80% of NSCLC pts treated at RP2D remain on treatment and only 3% discontinued due to related adverse event. In NSCLC patients, treatment-related toxicity (TRT), generally low-grade and reversible (28% had ≥ grade 3 events), included increased AST (22%), hypertension (18%), increased ALT (17%), constipation (17%), fatigue (15%) and decreased neutrophils (15%). Conclusions: BLU-667 demonstrated potent, durable and broad antitumor activity and was well tolerated in pts with advanced RET-fusion+ NSCLC. Enrollment of the expansion is ongoing with registrational intent. Clinical trial information: NCT03037385.
Fibrinolytic Therapy to Reduce Microvascular Obstruction After Myocardial Infarction—Reply
Authors: Colin Berry, Peter J. McCartney, Annette M. Maznyczka
Journal: JAMA (2019)

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Identifying cancer patients’ care needs after discharge hospital using health claim data linked with Hospital-based Cancer Registry data in Japan.
Authors: Ayako Okuyama, Yukie Takemura, Takahiro Higashi
Journal: Journal of Clinical Oncology (2019)

e18012 Background: In 2018, the 3 rd Cancer Control Plan developed in Japan. This plan recommends that we should create a better society for cancer patients to keep living at their homes after leaving hospital. In order to grasp the continuous health care needs, we investigated independence degree of Activities of Daily Living (ADL) at the time of discharge for cancer patients by hospital types. Methods: We analyzed the health insurance claims database linked with the hospital-based cancer registry of 230 cancer care hospitals covered the period from October 2012 to December 2014. Data were abstracted from patients who 1) were diagnosed with breast, lung, liver, colorectal, stomach, pancreas, or prostate cancer in 2013; 2) were 20 years or older at the time of the diagnosis; and 3) received the first course or continuous treatment at the hospital. Ministry of Health, Labor and Welfare designates cancer care hospitals (DCCHs) to provide a high quality of cancer care. In each prefecture, one hospital is designated as Type 1 DCCH, and it has the role of supporting other DCCHs in that prefecture. Remaining DCCHs are Type 2 DCCHs. Hospitals which are not designated as DCCHs are categorized into other hospitals. We assessed the differences of patient’ ADL status by these hospital types. Results: We extracted 37,523 patients’ discharge data (8,271 from Type 1 DCCHs, 28,200 from Type 2 DCCHs, and 1,052 from other hospitals). The mean age (SD) at the time of diagnosis was 65.6 (11.7) at Type 1 DCCHs, 69.1 (11.0) at Type 2 DCCHs, and 70.0 (12.3) at other hospitals. The percentage of clinical stage IV in other hospitals (25.3%) was slightly higher than others (22.5%). In total, 16.2% of patients need all assistance for bathing, while only 3.5% of patients need all assistance for eating. More patients at other hospitals were need assistance for ADL compared to patients at DCCHs. For example, 10.6% of patients need all assistance for bathing in type 1 DCCHs, while 25.2% of patients need it in other hospitals. Conclusions: Many patients discharged in not DCCHs need more assistance for their daily living. We should take these situation into account when we provide appropriate support for cancer patients.
Full adaptome repertoire analysis of immunotherapy to predict responsiveness and correlation with CD8-LAG3, sLAG3, and hepatocyte growth factor levels in patients with renal cancer.
Authors: Michael T. Lotze, Leonard Joseph Appleman, Shuyan Zhai, Yue Yolanda Wang, Alexa Forte, Wenjing Pan, Miranda L. Byrne-Steele, Jian Han
Journal: Journal of Clinical Oncology (2019)

e16116 Background: Aldesleukin (recombinant interleukin-2, IL-2), the first checkpoint inhibitor overcoming Tregs, was FDA-approved for mRCC with a 5-10% rate of durable CRs and 25% ORR. Hydroxychloroquine (HCQ) inhibits autophagy, promoting tumor apoptosis. In murine models, IL-2 and HCQ is associated with diminished toxicity and increased efficacy. We hypothesized that a novel deep seven chain analysis of the TCR and BCR repertoire would correlate with sLAG3, CD8 cytosolic LAG3, and HGF levels, associated with outcomes in RCC patients treated with this regimen. Methods: Patients (pts) received high dose IL-2, 600,000 IU/kg, every 8 hours up to 14 doses/cycle. HCQ was administered orally, starting 2 weeks prior to IL-2 and continued up to one year. The HCQ dose was 600 mg (17pts) or 1200 mg (13pts) daily. A newly available seven chain TCR/BCR Adaptome dimer avoidance multiplex-PCR followed by NextGen Sequencing allowed identification of CDR3’s associated with response and increasing clonal diversity. Results: Of 30 pts in the study, 29 were evaluable for response (3CR, 3PR) with serum samples and seven chain analysis of PBMC with 330x10 6 total reads of the TCR αβ, TCR γδ, IgH, and κλ light chains. HGF (p &lt; .009) was a significant negative predictor of OS at Day 1 after IL-2 and OS at Day -14 (p &lt; .005). Surprisingly this correlated with the TCRδ/γ ratio (p &lt; .01). Similarly serum sLAG3 and CD8LAG3 + both &gt; median predicted improved PFS (p = 0.019) correlating with total TCRδγ expression, p &lt; .01. Diversity of the TCR αβ but not the TCR γδ nor the IgH, and κλ light chains predicted response, p = .005. Conclusions: IL-2 plus HCQ was well tolerated and clinically active with encouraging increase in the PFS of &gt; 17 months at the 600 mg HCQ dose ( &gt; 4x greater than historical controls). Powerful new technology identifying enhanced responsiveness correlating significantly with diversity of the TCR αβ identifies a novel method for predicting responsiveness to immunotherapy. This unbiased examination of the full repertoire ('Adaptome') measured in the same bioassay correlates with other novel biomarkers and should be widely applicable in the further evolution of immunotherapy. NCT01550367 ; approved as IRB 11-074. Clinical trial information: NCT01550367.
Transcriptional characterization of immune microenvironment and their prediction role for the prognosis of local advanced lung adenocarcinoma.
Authors: Yuqiao Chen, Xinying Shi, Xue Song, Lingling Gao, Beibei Mao, Henghui Zhang, Yuan Zhou, Wei Zhuang
Journal: Journal of Clinical Oncology (2019)

e20625 Background: The resection of early stage NSCLC offers patients the best hope of a cure. However, the recurrence rate post-resection remains high. As the mechanisms involved in the process is still not clear due to the unavailability of accurate targets, our study was aimed to integrate the impact of different immune context present in lung adenocarcinoma (LUAD) microenvironment on patients’ prognosis. Methods: RNA targeted sequencing was performed on 24 primary tumor specimens from the resected local advanced LUADs . Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The limma package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the prognosis (PFS, progression free survival) post-resection. Results: 23 DEGs were detected in primary tumor between the better (PFS &gt; 18months, n = 12 ) and worse (PFS≤18months, n = 12 ) prognosis group. The combined prediction model containing MPO, IL-6, CXCR2, FCGR3B, ADGRE5 could identify the favorable prognosis of patients. GSVA and Log Rank test of survival data demonstrated that the antigen processing and lymphocyte activation pathway enrichment may associate with better prognosis (p = 0.01), whereas higher Neutrophils cell infiltration in primary tumor demonstrated a shorter PFS (p = 0.008). Conclusions: In LUAD, the immune related genes such as MPO, IL-6, CXCR2, FCGR3B, ADGRE5, can effectively profile the landscape of tumor immune microenvironment and predict the survival in early stage of lung adenocarcinoma. Accordingly immune pathways were correlated with prognosis of these patients. Our findings suggest that immune-related RNA expression pattern in locally advanced LUAD may provide a potential predictive marker for early recurrence after surgical resection.
Effect of pre-treatment anxiety and depression on long term survival of prostate cancer patients treated radically with radiation and hormone therapy.
Authors: Lauren Jones, Micheal O'Cathail, Shaymaa Usama Hosni, Jessica Little, Ashley Cox, Eamonn Fergusson, Santhanam Sundar
Journal: Journal of Clinical Oncology (2019)

e23087 Background: The evidence for effect of anxiety and depression on cancer survival rates is contradictory (Ref : Prostate-JCO 2014.32:2471, Breast-JCO 1987. 5:768, Lung-JPSM 2017.53:1057). We assessed the effect of prospectively collected HADS score (Hospital Anxiety and Depression Scale) on subsequent long term survival. Methods: After ethics approval &amp; informed consent, 145 prostate cancer patients (pts) were enrolled, onto a QOL study. HADS questionnaire was prospectively completed at baseline &amp; at 3 mths after start of androgen deprivation therapy (ADT). Survival data collected in Jan 2019. PATIENT CHARACTERISTICS: Median age 69 (range 50 to 78); T stage T2:63.5%, T3:28.4%. Gleason 7 in 53.4% and 8-10 in 39.2%; Median PSA 10.2 (0.3 to 102); Median testosterone 11.6 (0.6 to 26.7); ADT duration median 6 mths (2 to 60 mths); Median overall survival 10.11 yrs Results: At baseline, HADS anxiety scores normal (0-7) in 78%; abnormality mild (8-10) in 12%; moderate (11-14) in 6% and severe (15-21) in 2%.. At &gt; 3 mths, respective anxiety scores (%) were 71.3, 17.5, 7.7 and 3.5. At baseline, HADS depression scores (%) were 91.2, 5.2, 1.4 and 0.7. At &gt; 3 mths, respective depression scores were (%) 83.9, 11.2, 3.5 and 1.4 Although median survival was numerically lower in pts scoring high on HADS at baseline, the survival rates were not statistically significant on Log rank test. Moreover, on Cox regression analysis with Age, Gleason Score, T Stage, baseline PSA as co-variates, there was no increased hazard from higher HADS scores (Table). Conclusions: Biological factors probably outweigh the influence of psychological factors on overall survival. [Table: see text]
Efficacy and safety of pembrolizumab (pembro) alone or in combination with chemotherapy (chemo) in patients (pts) with advanced gastric or gastroesophageal (G/GEJ) cancer: Long-term follow up from KEYNOTE-059.
Authors: Zev A. Wainberg, Harry H. Yoon, Daniel V.T. Catenacci, Shadia Ibrahim Jalal, Kei Muro, Marcelo Garrido, Talia Golan, Toshihiko Doi, Ravit Geva, Geoffrey Yuyat Ku, Jonathan Scott Bleeker, Yung-Jue Bang, Hiroki Hara, Hyun Cheol Chung, Jiang Dian Wang, Andrea Hazzard, Sukrut Shah, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2019)

4009 Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1positive or negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1positive or negative) received pembro + cisplatin (80 mg/m 2 day 1) + 5-fluorouracil (800 mg/m 2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m 2 twice daily) as first-line. Cohort 3 pts (PD-L1positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1positive, and 6.4% (3-13) in PD-L1negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1positive, and 37.5% (9-76) in PD-L1negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.
The relationship between mesenchymal stem cells, monocyte-macrophages, endothelial progenitor cells, and prognosis of hepatocellular carcinoma.
Authors: Kun Yan
Journal: Journal of Clinical Oncology (2019)

e14507 Background: This experiment is designed to investigate the clinical correlation between mesenchymal stem cells, macrophages, endothelial progenitor cells and hepatocellular carcinoma, furthermore to assess their diagnostic value. Methods: A prospective cohort study was conducted to collect patients who admitted to the Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University. The peripheral blood samples of patients with hepatocellular carcinoma (HCC) who diagnosed by pathology from September 2014 to August 2016 were collected. The mesenchymal stem cells, macrophages and endothelial progenitor cells (EPCs) were analyzed by flow cytometers. Results: There was no correlation between hepatocellular carcinoma and peripheral blood mesenchymal stem cells (p &gt; 0.05), and there was correlation between hepatocellular carcinoma and macrophages and endothelial progenitor cells (p &lt; 0.01). The positive correlated coefficient is 0.938 in macrophages, and the negative correlated coefficient is -0.835 in the endothelial progenitor cells. Conclusions: The differentiated pathways of mesenchymal stem cells in hepatocellular carcinoma play key roles in the progression and prognosis of hepatocellular carcinoma.
FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.
Authors: David Michael Hyman, Lipika Goyal, Petros Grivas, Funda Meric-Bernstam, Josep Tabernero, Youyou Hu, Yulia Kirpicheva, Valerie Nicolas-Metral, Anna Pokorska-Bocci, Anne Vaslin, Claudio Zanna, Keith Flaherty
Journal: Journal of Clinical Oncology (2019)

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases &lt; 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H 0 : ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.
WHO opioid guidelines are “marketing materials for Purdue,” say US members of Congress
Authors: Owen Dyer
Journal: BMJ (2019)

Key guidelines from the World Health Organization on prescribing opioids for adults and children are tainted by drug industry influence and peddle dangerous and discredited myths that understate the dangers of addiction, a report by two representatives of the US Congress has found.

Katherine Clark, a Massachusetts Democrat, and Hal Rogers, a Kentucky Republican, collaborated to produce the report, which uses flow charts to allege that the marketing message of Purdue Pharma was transmitted through influential physicians and pressure groups, often handsomely reimbursed, to the committees that wrote WHO’s guidance.1

The report singles out two current WHO guidelines—one from 2011 suggesting national policy approaches to controlled substances and one from 2012 on persistent pain in …
A phase II clinical study of pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors.
Authors: Jason R. Fangusaro, Franco Locatelli, Maria Luisa Garré, Lynley V. Marshall, Maura Massimino, Bouchra Benettaib, Noha Biserna, Jennifer Poon, Jackie Quan, Erin Conlin, John Lewandowski, Mathew Simcock, Neelum Jeste, Darren R Hargrave, Francois P. Doz, Katherine E. Warren
Journal: Journal of Clinical Oncology (2019)

10035 Background: Central nervous system (CNS) tumors are the most common cause of pediatric cancer mortality and novel therapies are needed for refractory disease. Pomalidomide (pom) is an oral immunomodulatory agent with CNS penetration, anti-angiogenic, anti-inflammatory and cytotoxic activity. Methods: This Phase 2 study evaluated both safety and efficacy of pom in pediatric patients with recurrent/progressive CNS tumors. Using a Simon’s two-stage design, patients were stratified to high-grade glioma [HGG], ependymoma, medulloblastoma or diffuse intrinsic pontine glioma [DIPG] cohorts. Patients received pom 2.6 mg/m 2 for 21 days of a 28-day cycle. The primary endpoint was objective response rate (complete response [CR], partial response [PR]) or prolonged stable disease [SD] (defined as ≥ 6 cycles, or ≥ 3 for DIPG). Stage 1 required ≥ 2/9 subjects, within each cohort, to have a response or prolonged SD to move into Stage 2, and ≥ 5/20 responders or patients with prolonged SD at the end of Stage 2 for pom to be deemed effective. Results: Of 52 treated patients (median age 11.5 y/o; range 4-18), 47 were evaluable for primary endpoint. Median treatment duration was 2 cycles (range 1-16). Only the HGG cohort met protocol-defined criteria to advance to Stage 2, with one PR and one prolonged SD in Stage 1. Forty-six of 47 evaluable patients discontinued pom, due to adverse event (n = 1; pneumonia), withdrawal by parent/guardian (n = 2), death (n = 4; 3 progressive disease, 1 sepsis), or progressive disease (n = 39). Nineteen of 52 treated patients experienced ≥ 1 grade 3–4 treatment-emergent adverse event (TEAE) related to pom, neutropenia (n = 15) being the most commonly reported. Twenty-six patients died on study. All deaths were attributed to either disease progression or complications from disease. Conclusions: Single agent pomalidomide failed to meet a clinically meaningful level of efficacy in children with recurrent/progressive HGG, DIPG, medulloblastoma or ependymoma. However, it should be noted that a sustained response was observed in a child with HGG, replicating the outcome observed in one child with HGG in the Phase 1 (PBTC-043) trial. Clinical trial information: NCT03257631.