bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of tazemetostat, an enhancer of zeste-homolog 2 inhibitor, in patients with relapsed or refractory malignant mesothelioma.
Authors: Zauderer Marjorie Glass , Szlosarek Peter Wojciech , Le Moulec Sylvestre , Popat Sanjay , Taylor Paul , Planchard David , Scherpereel Arnaud , Jahan Thierry Marie , Koczywas Marianna , Forster Martin , Cameron Robert B. , Peikert Tobias , Argon Evren Kocabas , Michaud Neil , Yang Jay , Kansra Vikram , Fennell Dean A. 
Published: May 2020

9058 Background: Breast cancer gene 1 (BRCA1)-associated protein 1 (BAP1), a nuclear deubiquitinase, is commonly inactivated in malignant mesothelioma. Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of enhancer of zeste-homolog 2 (EZH2), a methyltransferase implicated as an oncogenic driver in this tumor. This study evaluated the safety and efficacy of tazemetostat (TAZ), a potent and selective EZH2 inhibitor, in relapsed/refractory (R/R) malignant mesothelioma with BAP1-inactivation. Methods: EZH-203 (NCT02860286) was a 2-part, open-label, phase 2 study that assessed the pharmacokinetics (PK), safety, and efficacy of TAZ in pts with R/R malignant mesothelioma. In part 1, pts received TAZ 800 mg QD on day 1 (D1) and 800 mg BID, beginning day 2 of cycle 1 (C1). In part 2, pts received 800 mg of TAZ BID on D1 of C1. A two-stage Green-Dahlberg design was used for part 2. Primary endpoints were PK profiling of TAZ in all pts (part 1), and disease control rate (DCR) at week 12 in pts with BAP1-deficient R/R malignant mesothelioma (part 2). Secondary endpoints included safety, overall response rate (ORR), progression-free survival, overall survival, and duration of response (DOR). Results: The study enrolled 74 pts with R/R malignant mesothelioma, 70 pts (95%) were centrally confirmed to be BAP1-deficient. Median prior lines of therapy were 2 (range, 1-9). Observed clinical data in the presence of CYP3A4 inhibitors and inducers suggest a low DDI potential of TAZ. The 12 week DCR was 47% (n = 35). The ORR per RECIST version 1.1 was 3% [complete response: 0%; partial response (PR): 3% (n = 2)]. Of the 2 patients with PR, 1 had a DOR of 21 weeks and the other is ongoing (15.3 weeks at data cut off). 47 pts (64%) and 21 pts (28%) had stable disease (SD) and progressive disease, respectively. Overall, 91% pts discontinued, either due to disease progression (n = 65), death (n = 5), or treatment discontinuation (n = 1). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in ≤5% of patients, most commonly anemia (5%) and dyspnea (4%). No pts discontinued due to TEAEs. There were no treatment related deaths. Conclusions: Based on disease control rate and stable disease, TAZ showed antitumor activity in pts with BAP1-deficient R/R malignant mesothelioma. TAZ monotherapy was generally well-tolerated. The current data support further clinical evaluation of TAZ in these pts. Furthermore, this trial presents an optimal paradigm for drug development in molecularly-enriched cohorts in mesothelioma. Clinical trial information: NCT02860286.
Role of immunotherapy in stage IV large cell neuroendocrine carcinoma of the lung.
Authors: Komiya Takefumi , Powell Emily 
Published: May 2020

9060 Background: Despite approvals of immune checkpoint inhibitors in both small cell and non-small cell lung cancers, role of immunotherapy in large cell neuroendocrine carcinoma (LCNEC) in lung is undefined. Methods: Using National Cancer Database (NCDB), Stage IV LCNEC cases diagnosed in 2014-2016 with at least 30-day follow up were analyzed. Clinical demographics included age (20-69 vs. 70+), sex (male vs. female), race (whites vs. others), insurance (uninsured vs. others), institution (academic vs. others), Charlson-Deyo score (0-1 vs. 2-3), brain metastasis (Yes vs. No), liver metastasis (Yes vs. No). Information regarding cancer treatment was limited to first course of therapy, including surgery for primary lesion (Yes vs. No), radiation (Yes vs. No), chemotherapy (Yes vs. No), and immunotherapy (Yes vs. No). Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analyses. A two-sided p-value < 0.05 was considered as significant. Results: Among 661 eligible cases, 37 patients were treated with immunotherapy. No significant association between use of immunotherapy and clinical demographics was observed except for use of chemotherapy (p = 0.0008). Chemotherapy was administered in 34 (92%) and 406 (65%) of cases in immunotherapy and non-immunotherapy groups, respectively. Use of immunotherapy was associated with improved overall survival (Log-rank p = 0.0168). Landmark analysis in the immunotherapy group showed 12 and 18-month survival of 34.0% and 29.1%, respectively, as compared with 24.1% and 15.0% in the non-immunotherapy group Multivariate analysis demonstrated that female sex, presence of liver metastases, surgery, use of chemotherapy and immunotherapy (HR = 0.64, p = 0.0164) had significantly improved survival. Propensity score matching in overall survival showed a nonsignificant trend (p = 0.0733) in favor of immunotherapy group. Conclusions: This retrospective study using one of the largest cancer databases suggests that use of immunotherapy may improve survival of LCNEC patients. Prospective studies are warranted for further validation.
Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).
Authors: Udagawa Hibiki , Ikeda Takaya , Umemura Shigeki , Daga Haruko , Toyozawa Ryo , Harada Daijiro , Sakakibara-Konishi Jun , Morise Masahiro , Yamamoto Noboru , Takahashi Toshiaki , Kato Terufumi , Shingyoji Masato , Ushio Ryota , Hara Satoshi , Takata Saori , Nomura Shogo , Matsumoto Shingo , Niho Seiji , Sato Akihiro , Goto Koichi 
Published: May 2020

9064 Background: Development of targeted therapy for SCLC based on a large-scale genomic screening is an innovative challenge. Gedatolisib is a highly potent dual inhibitor of PI3K/mTOR and is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. SCLC harboring this pathway alterations is rare. Thus, we conducted a phase II study based on a nationwide genomic screening network in Japan (LC-SCRUM-Japan) to develop novel targeted therapies. Methods: SCLC pts with targetable genetic alterations were screened at 154 institutions in Japan. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of gedatolisib in advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The primary endpoint was objective response rate (ORR). The planned sample size was 19 (threshold and expected ORR of 20% and 50%, one-sided alpha of 5%, and power of 80%). Results: 930 SCLC pts were screened from July 2015 to January 2020. Targetable genetic alterations were identified in 148 pts (16%), including 53 PI3K/AKT/mTOR (6%), 81 MYC family (9%), 10 EGFR (1%) and 15 KRAS (2%). A total of 12 pts with genetic alterations in the PI3K/AKT/mTOR pathway (5 PIK3CA, 6 PTEN, and 1 AKT1 mutation) were enrolled in the phase II study. The median age was 67 years (range 58-79), 7 pts were male and 5 pts received 2 or more prior chemotherapy (range 1-4). The ORR was 0% and disease control rate was 25%. The median progression-free survival (PFS) was 0.9 months (95% CI, 0.4 to 3.0). The median overall survival was 5.8 months (95% CI, 1.1 to NR). Treatment-related G3 adverse events (hypertension, hypoalbuminemia, oral mucositis, ALT increased and creatinine increased) were observed in 4 pts. One patient with PTEN I8fs mutation had a long duration of stable disease (PFS; 6.7 months). Conclusions: This Large-scale nationwide genomic screening network was effective to identify rare targetable genetic alterations and had a potential role to develop targeted therapies in SCLC. This phase II study didn’t show promising clinical benefit of gedatolisib for advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The safety profile of gedatolisib was similar to that reported previously. Clinical trial information: UMIN000020585.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.
Authors: Kim Joseph W. , Hafez Navid , Soliman Hatem Hussein , Fu Siqing , Kato Shumei , Lara Primo , Vaishampayan Ulka N. , Abdul Razak Albiruni Ryan , Cardin Dana Backlund , Munster Pamela N. , Eder Joseph Paul , Swisher Elizabeth M. , Nixon Andrew B. , Patel Abhijit , Shyr Yu , Ivy S. Percy , LoRusso Patricia 
Published: May 2020

9065 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in > 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]
The efficacy and safety profile of anlotinib with etoposide plus cisplatin/carboplatin in treatment-naive extensive-stage small cell lung cancer(SCLC) patients: Results from a phase II single-arm trial.
Authors: Deng Pengbo , Yang Huaping , Chen Cen , Hu Chengping , Cao Liming , Gu Qihua , An Jian , Li Bin , Tang Yongjun , Meng Jie , Feng Juntao 
Published: May 2020

9066 Background: Combination of etoposide and cisplatin/carboplatin is the most commonly used initial chemoptherapy regiment in extensive-stage small cell lung cancer. A meta-analysis released that, there is no significant difference was observed in Objective response rate(ORR), progression-free survival (PFS), or overall survival(OS) in patients(pts) receiving cisplatin-base versus carboplatin-based regimens. We performed a single-arm phase II trial to determine if maintain of single-agent anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, after 4-6 cycles of anlotinib + etoposide + cisplatin/carboplatin would improve PFS and ORR. Methods: SCLC pts (18~70 yrs, extensive-stage SCLC, no prior systematic chemo/ICI therapy) received anlotinib( 12mg QD from day 1 to 14 of a 21-day cycle) +etoposide( 100mg/m2, d1~3 of 21-day cycle)+ cisplatin( 75-80mg/m2,Q3W)/ carboplatin( AUC = 5~6,Q3W) for 4~6 cycles, and anlotinib maintenance. The dual-primary endpoint were PFS and ORR. Results: Between Oct.2018 to Dec.2019, 27 pts enrolled and included in the efficacy and safety analysis: age: median 62 (range:44-71); male 93%; cisplatin/ carboplatin/ both 11%/78%/11%; 37%(10/27) of pts required chemotherapy dose modification only, and the other 30% (8/27) of pts required anlotinib+ chemotherapy dose modification.The median PFS was 9.61 months ( 95%Cl:7.80-11.42). ORR was 77.78% (21/27), disease control rate (DCR) was 96.30% (26/27).Toxicities≥grade 3 included: neutropenia 22%, leukopenia 11%, hand-foot syndrome 15%, nausea 4%, mucositis 4%, edema 4%, anorexia 4%, xerostomia 4% and fatigue 4%; there were no grade 5 toxicities. Conclusions: Combined treatment with anlotinib plus etoposide and cisplatin/carboplatin for treatment-naive extensive-stage SCLC was well tolerated with promising PFS and ORR to date but showed no new risk for AEs. Based on these encouraging results, phase III trial of anlotinib plus etoposide and cisplatin/carboplatin for treatment-naive SCLC has been warranted.
Characterization of 1,387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms.
Authors: Awad Mark M. , Lee Jessica Kim , Madison Russell , Classon Anthony , Kmak Jamie , Frampton Garrett M. , Alexander Brian Michael , Venstrom Jeffrey , Schrock Alexa Betzig 
Published: May 2020

9511 Background: METex14 SA are oncogenic drivers in NSCLC. Due to the numerous sites around ex14 that bind the spliceosome complex, many variations can result in deleterious alterations (alts). We present a comprehensive overview of these ex14 SA across 1,387 NSCLCs and characterized potential AR mechanisms. Methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on samples from 60,495 NSCLC patients (pts). A scoring system was applied leveraging our large database of samples with METex14 SA to optimize accurate reporting of these variants. Paired samples were collected ≥ 60 days apart (median 462). Results: 1,393 METex14 SA were identified in samples (1,278 tissue, 109 circulating tumor DNA (ctDNA)) from 1,387 NSCLC pts (2.3%) spanning multiple functional sites: donor (42%), acceptor (4.7%), poly-pyrimidine tract (15%), acceptor and polypyrimidine tract (13%), D1010 (23%), Y1003 (2.1%), and whole exon deletions (0.3%). 6 samples (5 tissue, 1 ctDNA) harbored 2 METex14 SA, each including a mutation (mut) at the donor or acceptor site. MDM2 and CDK4 amplifications (amps) co-occurred in 32% and 19% of METex14 samples, respectively, but were more common with polypyrimidine tract (37% and 23%) vs donor site (32%, p = 0.07 and 18%, p = 0.07) alts. MET co-amp was present in 12% of cases and frequency did not significantly differ by functional site. 66 (4.8%) cases (57 tissue, 9 ctDNA) had known NSCLC co-drivers, including KRAS (68%) and EGFR (14%) mut, a subset of which may represent AR. Paired samples with a METex14 SA in the 1st sample were available for 36 pts. The METex14 SA was detected in the 2nd sample for 32 pts, excluding 3 with low ctDNA. 22/36 (61%) had reportable acquired alts detected including 9 with ≥1 acquired MET muts [D1228X (4), Y1230X (3), Y1003F (1), D1228A/E/H + L1195V (1)] and 3 with acquired MET amp. Other acquired alts included ERBB2 amp and mut (1 each), EGFR ex19ins (1), KRAS amp (1), PIK3CA mut (1), AKT2 amp (1) and others with unknown functional significance. Potential AR alts were present with primary METex14 SA spanning all functional sites. Conclusions: In a dataset of > 60,000 advanced NSCLCs, METex14 SA were present in 2.3% of cases, and represented 6 major subtypes. Among paired cases, potential AR mechanisms included secondary MET alts (33%), and acquired alts in EGFR, ERBB2, KRAS, and PI3K pathways. Acquired alts were independent of the type of METex14 SA. Characterizing common co-occuring may be critical for predicting responses to MET inhibitors and informing rational combination strategies.
Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC).
Authors: Park Keunchil , John Thomas , Kim Sang-We , Lee Jong Seok , Shu Catherine A. , Kim Dong-Wan , Viteri Ramirez Santiago , Spira Alexander I. , Sabari Joshua K. , Han Ji-Youn , Trigo Jose Manuel , Lee Chee Khoon , Lee Ki Hyeong , Girard Nicolas , Lorenzini Patricia A , Xie John , Roshak Amy , Thayu Meena , Knoblauch Roland Elmar , Cho Byoung Chul ,   on behalf of the CHRYSALIS Investigators
Published: May 2020

9512 Background: EGFR exon20ins-mutated NSCLC is generally refractory to EGFR tyrosine kinase inhibitors (TKIs) and is associated with poor prognosis. Amivantamab (JNJ-61186372) is a novel, fully human anti-EGFR-MET bispecific antibody whose mechanism of action can target both EGFR- and MET-driven disease and has shown monotherapy activity in patients (pts) with diverse EGFR mutant disease characterized by EGFR C797S, T790M, exon20ins, and MET amplification. We present preliminary results of pts with advanced NSCLC harboring exon20ins mutations from CHRYSALIS, an ongoing phase 1 study of amivantamab (NCT02609776). Methods: This study comprises a dose escalation phase in pts with advanced NSCLC and a dose expansion phase in pts with EGFR- and MET-mutated disease. This analysis includes all enrolled pts with exon20ins disease who received the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg, pts ≥80 kg) amivantamab. Response was assessed by investigator per RECIST v1.1. Results: As of 30 Oct 2019, 50 pts with exon20ins mutations had received amivantamab at the RP2D. 39/50 pts were response-evaluable and had ≥2 disease assessments or had discontinued therapy prior to the assessment period; among these pts, 29 had prior platinum-based chemotherapy (PBCT). Median age for response-evaluable pts was 61 y (40–78), 51% were female, and median prior lines was 1 (0–7). In the 50 pts harboring exon20ins mutations treated at the RP2D, the most common adverse events (AEs) reported were rash (72%), infusion related reaction (60%), and paronychia (34%). Additional EGFR-related AEs included stomatitis (16%), pruritus (14%), and diarrhea (6%). Grade ≥3 AEs were reported in 36% of pts; 6% were treatment-related. One grade 3 diarrhea and no grade ≥3 rash was reported. Among the 39 response-evaluable pts, with a median follow-up of 4 months (1–26), the overall response rate (≥partial response [PR]) was 36% (95% CI, 21–53), and 41% (95% CI, 24–61) for the 29 pts who had prior PBCT. The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 67% for response-evaluable pts and 72% for pts who had prior PBCT. Among all 14 responders, median duration of response was 10 months (1–16), with ongoing responses in 9 pts at data cutoff. Median progression-free survival was 8.3 months (95% CI, 3.0–14.8) for response-evaluable pts and 8.6 months (95% CI, 3.7–14.8) for pts who had prior PBCT. Conclusions: Amivantamab demonstrates robust and durable antitumor activity in pts with exon20ins disease, with a manageable safety profile. Clinical trial information: NCT02609776 .
Correlation of baseline molecular and clinical variables with ALK inhibitor efficacy in ALTA-1L.
Authors: Camidge D. Ross , Niu Huifeng , Kim Hye Ryun , Yang James Chih-Hsin , Ahn Myung-Ju , Li Jacky Yu-Chung , Hochmair Maximilian , Delmonte Angelo , Spira Alexander I. , Campelo Rosario Garcia , Barlesi Fabrice , Liu Geoffrey , Tiseo Marcello , Li Cong , Williams Miguel , Shin Hyunjin , Zhang Pingkuan , Popat Sanjay 
Published: May 2020

9517 Background: Efficacy of ALK TKIs in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) varies. We evaluated the impact of EML4-ALK fusion variants and other baseline (BL) molecular and clinical variables on clinical efficacy of brigatinib (BRG) vs crizotinib (CRZ) as first ALK TKI therapy in pts with ALK+ NSCLC in the phase 3 ALTA-1L (NCT02737501) trial. Methods: Plasma samples were collected at screening for molecular genetic analysis of ALK and other genes implicated in NSCLC by next-generation sequencing. Exploratory analyses were performed to identify associations of clinical outcomes with oncogenic alterations including ALK fusion variants and TP53 status. Results: 124 BL samples were collected from 136 BRG-treated pts and 127 from 137 CRZ-treated pts. Pts with plasma samples were representative of the intent-to-treat population. BL ALK fusion detection rate was 52% (65/124) and 54% (68/127) in the BRG and CRZ arms, respectively, of which 83% (54/65) and 93% (63/68) were EML4-ALK fusions. In pts with detectable EML4-ALK fusions, the three predominant EML4-ALK fusion variants (V1, V2, V3) were equally distributed between arms; V1 and V3 were most prevalent (BRG/CRZ: V1, 42%/47%; V3, 42%/33%) but V1 was more frequent than V3 in pts without BL brain metastasis (47% vs 36%) or prior chemotherapy (45% vs 35%). Gender and age did not impact variant type. BRG showed higher ORR and improved mPFS vs CRZ in all variant subgroups; pts with V3 had poorer PFS compared with V1 and V2 regardless of treatment (Table). In pts with V3, BRG showed significantly improved PFS (HR=0.273, 95% CI 0.125, 0.597) and higher ORR (84% vs 67%) vs CRZ. TP53 mutation was detected in 30% (37/124) of pts in BRG arm and 26% (33/127) in CRZ arm. In pts with detectable ALK fusion, TP53 mutation showed poorer PFS in both arms than nonmutant/undetected cases (Table). BRG had better ORR and PFS vs CRZ in pts regardless of TP53 mutation status. Additional analyses of BL variables are ongoing. Conclusions: EML4-ALK fusion variant 3 and TP53 mutation were identified as poor prognosis biomarkers in ALK+ NSCLC. BRG demonstrated better efficacy than CRZ as first-line therapy in pts regardless of EML4-ALK fusion variant and TP53 mutation status. These findings may help define areas of greatest unmet need. Clinical trial information: NCT02737501 . [Table: see text]