bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC)
Authors: Llovet J. , Ricci S. , Mazzaferro V. , Hilgard P. , Raoul J. , Zeuzem S. , Poulin-Costello M. , Moscovici M. , Voliotis D. , Bruix J. 
Published: March 2020

LBA1 Background: HCC is the 3rd cause of cancer death globally with most deaths occurring within 1 year of diagnosis. No standard therapy exists for advanced HCC. Sorafenib (Sor) is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity, with clinical activity in a phase II HCC trial. This large, multicenter, randomized, placebo-controlled phase III trial evaluated the efficacy and safety of Sor vs placebo (P) in pts with HCC. Methods: Patients with advanced measurable HCC, no prior systemic treatment, ECOG PS 0–2 and Child-Pugh status A received Sor 400 mg bid or P. Primary efficacy endpoints were overall survival (OS) and time to symptomatic progression (TTSP). Time to progression (TTP) and disease control rate (DCR; CR+PR+SD for at least 2 cycles) were secondary endpoints.Treatment arms were compared for OS and TTSP using a 1-sided log-rank test [overall a of 0.02 (OS) and 0.005 (TTSP)] stratified by region, ECOG PS and tumor burden. An O’Brien-Fleming-type error spending function determined criteria for early stopping for efficacy. Results: 602 pts (Sor n=299; P n=303) were randomized. Baseline characteristics were similar for Sor vs P: median age (67 vs 68 y), male (87% vs 87%), ECOG PS 0 (54% vs 54%), Child-Pugh A (95% vs 98%), and BCLC stage C (82% vs 83%). Based on 321 deaths (Sor n=143; P n=178), the hazard ratio (HR) for OS (Sor/P) was 0.69 (95% CI: 0.55, 0.87; p=0.0006), representing a 44% improvement in OS vs P which met early stopping criteria. Median OS was 10.7 vs 7.9 mos (Sor vs P). Primary TTSP analysis demonstrated no statistically significant difference for Sor vs P. HR for TTP (independent assessment) was 0.58 (95% CI: 0.45, 0.74; p=0.000007). Median TTP was longer (5.5 vs 2.8 mos) and DCR was higher (43% vs 32%) with Sor vs P. Incidence of serious adverse events was similar for Sor vs P (52% vs 54%). The most frequent grade 3/4 events were diarrhea (11% vs 2%), hand-foot skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%) for Sor vs P. Conclusions: Sorafenib was well tolerated and is the first agent to demonstrate a statistically significant improvement in OS for pts with advanced HCC. This effect is clinically meaningful and establishes sorafenib as first-line treatment for these pts. [Table: see text]
Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group
Authors: Rajkumar S. V. , Jacobus S. , Callander N. , Fonseca R. , Vesole D. , Williams M. , Abonour R. , Siegel D. , Greipp P. 
Published: March 2020

LBA8025 Background: We compared lenalidomide plus high (standard) dose Dex (R+HighD) versus lenalidomide plus low dose Dex (R+LowD) in newly diagnosed MM. Methods: Pts with untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO days 1–21 every 28 days. In addition, pts in the R+HighD arm received Dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the R+LowD arm received Dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary null hypothesis was that response rates at 4 months on the 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. Pre-planned interim analysis is performed by an independent DMC when full information is available on 25%, 50% and 75% of accrual. All analysis were intent to treat. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to R+HighD, 222 to R+LowD. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities included thromboembolism (22.1% with R+HighD vs 6.1% in R+LowD), infection/pneumonia (15.7% vs 7.5%) and hyperglycemia (9.7% vs 6.6%). Grade 3 or higher non-hematologic toxicities occurred in 65.9% (R+HighD) versus 54.9% (R+LowD) respectively; corresponding grade 4 or higher rates were 20.3% vs 13.1% respectively. Overall survival (OS) at first interim analysis was significantly superior with R+LowD, P<0.001; one year survival 96.5% (R+LowD) versus 86% (Rev+HighD). OS differences in favor of R+LowD were seen in pts <65 (P=0.015; one year rate 98% vs 90%) and pts 65 and older (P=0.004; one year rate 95% vs 83%), respectively. DMC recommended release of survival results, and recommended switching all pts to R+LowD. DMC also recommended closure of an expansion phase trial of R+HighD investigating optimal thromboprophylaxis. Conclusions: Lenalidomide plus low-dose dexamethasone is associated with superior OS compared to lenalidomide plus high-dose dexamethasone. This study has major implications for future use of high-dose dexamethasone in the treatment of MM. No significant financial relationships to disclose.
A translational study to investigate the association between smoking-induced lung inflammation and lung metastases (LM) from breast cancer (BC).
Authors: Morris Patrick Glyn , Zhou Xi Kathy , Milne Ginger L , Goldstein Daniel A. , Hawks Laura , Uzunaslan Didem , Dang Chau T. , Keenan Kathleen , Modi Shanu , Fornier Monica Nancy , Sklarin Nancy T. , D'Andrea Gabriella , Lake Diana , Theodoulou Maria , Traina Tiffany A. , Dickler Maura N. , Goldfarb Shari Beth , Hudis Clifford , Dannenberg Andrew J 
Published: March 2020

10514 Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE2. To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P<0.001). In univariate analysis, smoking pack year was associated with PGE-M (ρ=0.13, P=0.01), and ever smokers with LM had the highest PGE-M (med 7.4; range 0.8-28.9). In a multivariable model ever smokers with LM had higher PGE-M than never smoking CTRLS (P=0.03). Pts with >24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P<0.001), pack year smoking hx (P=0.02), receipt of chemoRx ≤1 mth (P=0.003) and BMI (P=0.002) were all associated with higher PGE-M. Conversely, receipt of NSAIDs ≤7 days was associated with lower PGE-M (P<0.001). Conclusions: Increased lung inflammation, as characterized by PGE-M, occurs in ever smokers with LM from BC, supporting the hypothesis that changes in the lung microenvironment (“soil”) predispose to metastasis. [Table: see text]
Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).
Authors: Heinrich Michael C. , Jones Robin Lewis , von Mehren Margaret , Bauer Sebastian , Kang Yoon-Koo , Schoffski Patrick , Eskens Ferry , Mir Olivier , Cassier Philippe Alexandre , Serrano Cesar , Tap William D. , Trent Jonathan C. , Rutkowski Piotr , Patel Shreyaskumar , Chawla Sant P. , Meiri Eyal , Zhou Teresa , Mamlouk Khalid Kevin , Roche Maria , George Suzanne 
Published: March 2020

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.
Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: Initial results from TRANSCEND NHL 001.
Authors: Abramson Jeremy S. , Palomba Maria Lia , Arnason Jon E. , Lunning Matthew Alexander , Solomon Scott R. , Farazi Thalia , Garcia Jacob , Xie Benhuai , Newhall Kathryn J. , Dehner Christine , Siddiqi Tanya 
Published: March 2020

7515 Background: No clinical studies have yet evaluated CAR T cell therapies in pts with R/R B-cell NHL who have secondary CNS lymphoma. We report data from this pt subgroup receiving liso-cel (JCAR017), an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the phase 1 TRANSCEND NHL 001 study. Methods: Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. Pts with secondary CNS lymphoma could enroll or, if it developed on study, could continue to receive liso-cel. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels (DL): DL1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Efficacy was evaluated per the Lugano criteria. Pts achieving a complete response could be retreated with liso-cel upon progressive disease. Results: At data cutoff, 9 pts with secondary CNS lymphoma at initial treatment (n = 6), retreatment (n = 2), or cycle 2 (n = 1) received liso-cel. 4 pts were treated at DL1 and 5 at DL2. The median (range) age was 60 (47‒73) years and number of prior lines of therapy was 3 (2‒7). Median time to peak CAR+ T cell expansion was 12.5 (7–112) days. 1 of 9 pts had grade (G)2 cytokine release syndrome (CRS) and 1 of 9 pts had a neurological event (NE; G3 decreased level of consciousness). No retreatment pts had CRS or NE; however, 1 retreatment pt had an NE of G2 temporal edema with initial treatment with liso-cel. 5 pts received prophylactic levetiracetam. 1 pt received corticosteroids and tocilizumab. Other toxicities were predominantly cytopenias. There were no treatment-related deaths. 4 pts responded to liso-cel; all had a best response of complete response, of which 2 are ongoing at 270 and 545 days post-liso-cel. All 4 responses occurred after initial liso-cel treatment; no retreated pts responded. Conclusions: In the ongoing TRANSCEND NHL 001 study, liso-cel continues to demonstrate the ability to be safely delivered to pts with R/R B-cell NHL, including those with secondary CNS lymphoma, a population of pts with a highly unmet medical need. No excess NE was noted in this population. This cohort continues to be evaluated. Clinical trial information: NCT02631044.
Managing cytokine release syndrome (CRS) and neurotoxicity with step-fractionated dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).
Authors: Bartlett Nancy L. , Sehn Laurie Helen , Assouline Sarit E. , Bosch Francesc , Magid Diefenbach Catherine S. , Flinn Ian , Hong Jungyong , Kim Wonseog S , Matasar Matthew J. , Nastoupil Loretta J. , Schuster Stephen J , Shadman Mazyar , Yoon Sung-Soo , Bender Brendan , Kwan Antonia , Cunlin Wang , Wei Michael C. , Yin Shen , Yousefi Kasra , Budde L. Elizabeth 
Published: March 2020

7518 Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]
MET inhibitor resistance in patients with MET exon 14-altered lung cancers.
Authors: Guo Robin , Offin Michael , Brannon A. Rose , Chow Andrew , Delasos Lukas , Somwar Romel , Wilkins Olivia , Scott Kerry , Tian Yuan , Cecchi Fabiola , Hembrough Todd A. , Li Bob T. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Rekhtman Natasha , Paik Paul K. , Ladanyi Marc , Zehir Ahmet , Drilon Alexander E. 
Published: March 2020

9006 Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; ≥2 TKIs n = 19). 91% received crizotinib as their 1st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/µg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS ≥700 amol/µg vs ORR 50% (n = 7/14) < 700 amol/µg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On-target acquired resistance is found in < 25% of patients; HGF amplification is a novel mechanism. Off-target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.
Tumor mutation burden and depression in lung cancer: Association with inflammation.
Authors: McFarland Daniel Curtis , Jutagir Devika R , Rosenfeld Barry , Miller Andrew H. , Nelson Christian J. , Breitbart William 
Published: March 2020

e23159 Background: Depression and inflammation are both associated with lung cancer. Tumor Mutation Burden (TMB) can be used to predict immunotherapy response which relies on tumor immunogenicity, a form of inflammation. This study evaluated whether higher TMB was associated with increased depression and various forms of inflammation. Methods: Patients with metastatic Non-small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) receiving anticancer treatments were evaluated for depression severity using the Hospital Anxiety and Depression Scale (HADS). TMB was measured using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Inflammation was evaluated using C - reactive protein (CRP) and the Neutrophil to Lymphocyte Ratio (NLR). Results: Ninety-six out of 140 participants with adequate TMB testing were evaluated (68.6%). The average number of mutations was 10.8 (SD 10.8). Twenty-four percent met screening criteria for depression. TMB correlated with depression severity (r = .34, p = .001) and NLR (r = .37, p = .002) and absolute neutrophil count (r = .3, p = .006) but not CRP (r = .193, p = .06). TMB was higher in patients receiving chemotherapy (12.0) and immunotherapy (14.4) over targeted therapy (4.8). A multivariate model found that TMB (β = .25, p = .032) and CRP (β = .36, p = .003) predicted for depression severity. Conclusions: TMB is an independent predictor of depression. Inflammatory indices suggest a possible relationship but the exact mechanism should be further evaluated and the results warrant replication. Ultimately, these findings may help identify lung cancer patients at risk for depression. [Table: see text]
Inherited Missense Mutation Occurring in Arginine76 of theSRYGene Does Not Account for Familial 46, XY Sex Reversal
Authors: Wang Nan , Zhu Wenjiao , Han Bing , Wang Hao , Zhu Hui , Chen Yingchao , Chen Yan , Liu Jianhua , Liu Yang , Zhao Shuangxia , Song Huaidong , Qiao Jie 
Published: March 2020

AbstractBackgroundSRY (sex determining region of Y) is one of the important genes involved in the process of human sex determination. The disturbed sex determination caused by an SRY mutation accounts for 10% to 15% of cases with 46, XY sex reversal. Recently, 3 distal enhancers were identified upstream of the SOX9 gene.ObjectivesThe purpose of this study was to investigate the molecular etiology of 46, XY sex reversal in 3 familial patients and a sporadic patient.DesignNext-generation sequencing was used to reveal the genotype and inherited pattern. Copy number variations and single nucleotide polymorphism haplotyping were analyzed to observe the alteration of enhancers of SOX9. Transcriptional activity of SRY mutation were assessed by a dual luciferase reporting system, and nuclear translocation was observed by confocal microscopy.ResultsTwo novel SRY gene mutations, p.Arg76Leu and p.Glu89flx15, were identified. In the pedigree with multiple patients, p.Arg76Leu mutation in SRY and p.Gly212Ser mutation in NR5A1 were identified in the proband. The heterozygous deletion far upstream of the SOX9 gene in chromosome 17 was identified in the 3 patients in this family, containing the distal enhancer eSR-A of SOX9 but not eSR-B and eALDI. The frameshift mutation p.Glu89flx15 was revealed to inhibit the transcriptional activity of the target gene, whereas the missense mutation p.Arg76Leu barely showed an effect.ConclusionIn contrast to sporadic cases, inherited single nucleotide variations of SRY are not the main cause of the severe phenotype of 46, XY sex reversal, and the enhancers of SOX9 should be investigated carefully in such patients.
p53, cancer and the immune response
Authors: Blagih Julianna , Buck Michael D. , Vousden Karen H. 
Published: March 2020

ABSTRACT
The importance of cancer-cell-autonomous functions of the tumour suppressor p53 (encoded by TP53) has been established in many studies, but it is now clear that the p53 status of the cancer cell also has a profound impact on the immune response. Loss or mutation of p53 in cancers can affect the recruitment and activity of myeloid and T cells, allowing immune evasion and promoting cancer progression. p53 can also function in immune cells, resulting in various outcomes that can impede or support tumour development. Understanding the role of p53 in tumour and immune cells will help in the development of therapeutic approaches that can harness the differential p53 status of cancers compared with most normal tissue.