bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported outcomes (PROs) in the randomized, phase III IMpower110 study of atezolizumab (atezo) vs chemotherapy in 1L metastatic NSCLC.
Authors: de Marinis Filippo , Giaccone Giuseppe , Herbst Roy S. , Oprean Cristina-Marinela , Szczesna Aleksandra , Boukovinas Ioannis , Bonomi Lucia , Kim Young-Chul , Summers Yvonne J. , Kurata Takayasu , Komatsubara Kimberly Mayumi , Chen Megan , Deng Yu , Kuriki Hiroshi , Mocci Simonetta , Phan See , Jassem Jacek , Spigel David R. 
Published: May 2020

9594 Background: IMpower110 (NCT02409342) evaluated atezo (anti–PD-L1) monotherapy as 1L treatment in PD-L1–selected patients (pts) with metastatic NSCLC and met its primary endpoint with statistically significant and clinically meaningful OS benefit in TC3 or IC3 wild-type (WT; EGFR/ALK-negative) pts. PROs were prespecified endpoints to assess pt perspectives on overall clinical benefit. Methods: Pts were randomized 1:1 to receive atezo 1200 mg IV q3w (Arm A) or platinum-based chemo (Arm B; 4 or 6 21-day cycles). Arm B non-squamous pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed 500 mg/m2 IV q3w; Arm B squamous pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. PROs were assessed by the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and lung cancer module QLQ-LC13. Time to confirmed deterioration (TTD) in QLQ-LC13 lung cancer symptoms (secondary endpoint) and change from baseline (BL) in global health status (GHS), functioning and lung cancer symptoms (exploratory endpoints) were analyzed in TC3 or IC3-WT pts. Clinically meaningful change was defined as a ≥10-point deterioration from BL. Results: Completion rates at BL (atezo, n = 107; chemo, n = 98) were high in both arms for the QLC-C30 (90% atezo, 86% chemo) and the QLC-LC13 (89% atezo, 85% chemo), and remained > 80% at most visits. Mean BL scores for GHS, physical functioning, and role functioning were moderate, symptom burden was low, and all were similar in both arms. No differences in TTD were seen between arms for cough (HR, 0.98; 95% CI: 0.48, 2.03), chest pain (HR, 1.02; 95% CI: 0.47, 2.22), dyspnea (HR, 0.96, 95% CI: 0.57, 1.60), and 3-symptom composite score (HR, 0.92; 95% CI: 0.59, 1.44). Mean change in physical function from BL to wk 42 was modestly improved with atezo and greater than or similar to chemo. No clinically meaningful worsening in dyspnea, cough or chest pain was seen with atezo vs chemo. Mean change in cough and chest pain from BL numerically improved immediately after start of treatment and was maintained to wk 48 with atezo. Fatigue and nausea/vomiting scores numerically improved immediately with atezo and were maintained to wk 48. Conclusions: QLQ-C30 and QLQ-LC13 completion rates were high at BL and most study visits. TTD of lung cancer-related symptoms was similar in both arms, indicating pts’ low BL symptom burden was maintained for a similar duration. Pts receiving atezo vs chemo sustained numerical improvements in physical function and no worsening in lung cancer-related symptoms. Clinical trial information: NCT02409342 .
A phase II study of osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer harboring EGFR mutations: The OCEAN study (LOGIK 1603/WJOG 9116L).
Authors: Wakuda Kazushige , Yamaguchi Hiroyuki , Kenmotsu Hirotsugu , Fukuda Minoru , Ebi Noriyuki , Suetsugu Takayuki , Inonue Koji , Tanaka Kentaro , Yokoyama Toshihide , Kirita Keisuke , Hataji Osamu , Miura Satoru , Chibana Kenji , Yoshimura Kenichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki , Sugio Kenji 
Published: May 2020

9597 Background: Approximately 15%–30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression. Although radiotherapy is a standard treatment for CNS metastasis, the efficacy of radiotherapy against CNS is poor. The aim of OCEAN study was to assess the efficacy of osimertinib for patients with radiotherapy-naïve CNS metastasis of NSCLC harboring EGFR mutations. Methods: OCEAN study was two-cohort phase II trial, 65 patients (T790M cohort; 40 patients and first-line cohort; 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive NSCLC was included. Patients were treated with osimertinib 80 mg once daily. The primary endpoint was the response rate of brain metastasis (BMRR) assessed by the PAREXEL criteria. We set a threshold value of 50% and an expected value of 70% based on the overall response rate (ORR) of AURA trial. Based on one-sided alpha = 0.05 and power = 0.8, the sample size of T790M cohort was calculated to be 40. Key secondary endpoints were progression-free survival (PFS), and ORR, BMRR assessed by the RECIST criteria. We are exploratorily assessing the blood concentration of osimertinib at day 22, which considered to represent steady state. In this report, we present the results of T790M cohort. Results: Between October 2016 to July 2019, 40 participants were recruited in the T790M cohort. The median age was 66.5 with 30.0% male. Eight patients had symptomatic CNS metastasis and most patient had multiple CNS metastasis (77.5%). BMRR assessed by PAREXEL criteria was 66.7% (95%CI: 54.3 – 79.1%) and BMRR assessed by RECIST was 70.0% (95%CI, 49.9 – 90.1%). Median PFS was 7.1 months (95%CI, 3.4 – 13.6 months) and ORR assessed by RECIST was 40.5% (95%CI, 24.7 – 57.9%). Treatment related pneumonitis was observed in 4 patients (10.0%). There was no grade 3 or higher toxicities that were found in more than 10%. Conclusions: This first study assessed the efficacy of osimertinib for patients with radiotherapy-naïve CNS metastasis of EGFR T790M mutation-positive NSCLC. The OCEAN study met primary endpoint. The results of this study suggested that patients with brain metastasis harboring EGFR T790M mutations had better to receive osimertinib prior to brain radiotherapy. Clinical trial information: 071180017 .
ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).
Authors: Han Ji-Youn , Ahn Myung-Ju , Kim Sang-We , Lee Ki Hyeong , Cho Eun Kyung , Lee Yun-Gyoo , Kim Dong-Wan , Kim Joo-Hang , Lee Jong-Seok , Lee Gyeong-Won , Shim Byoung Yong , Kim Jin-Soo , Chun Sang Hoon , Lee Sung Sook , Min Young Joo , Shin Sang Won , Yablonovitch Arielle , Espenschied Carin R. , Jang Hyunwoo , Cho Byoung Chul 
Published: May 2020

9601 Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .
Phase II study of TAK228 in patients with advanced non-small cell lung cancer (NSCLC) harboring NFE2L2 and KEAP1 mutations.
Authors: Paik Paul K. , Ahn Linda Su Hyun , Plodkowski Andrew J. , Fan Pang-Dian , Rudin Charles M. 
Published: May 2020

9607 Background: Despite past efforts, no targeted therapies exist for squamous cell lung cancer (LUSC) pts. We identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~15% of LUSCs. NFE2L2 encodes NRF2, a transcription factor involved in the oxidative stress response and targeted for degradation by KEAP1. NFE2L2 mutations (mut) occur only in an exon 2 hotspot (Neh2 domain), which is the binding site for KEAP1. Mutations in this region disrupt KEAP1 binding, leading to NRF2 nuclear translocation and increased mTOR signaling via RagD. We report translational studies and results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in biomarker-selected pts. Methods: Cell line and xenograft experiments were performed using LK-2 LUSC (NFE2L2 E79K mut), A549 ADCL (KRAS G12S + KEAP1 loss), and SK-MES-1 LUSC cells (NFE2L2/KEAP1 WT) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV LUSC harboring NFE2L2 or KEAP1 mut and ADCL harboring KRAS + KEAP1 co-mut were treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (NCT02417701). Primary endpoint: ORR. Secondary endpoint: PFS. The study used a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited differential anti-tumor activity over TORC1 rapalogs in LK-2 and A549 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM) in LK-2 cells; all other rapalogs had IC50s > 10μM. This was associated with marked decrease in TORC1/2 & MAPK signaling (decreased pS6, pAKT, pERK). Anti-tumor response was seen in LK-2 and A549 xenografts treated with TAK228. No anti-tumor/growth inhibitory responses were seen with any other rapalog. N = 21 evaluable pts have been treated (10 NFE2L2, 6 KEAP1, 5 KRAS+NFE2L2/KEAP1). Median age = 70; median prior lines tx = 2, smokers = 100%, median pack yrs = 39. Most common AEs included hyperglycemia (72%), fatigue (32%), diarrhea (32%), decreased appetite (32%). In NFE2L2 mut LUSC pts, ORR = 20% (2/10 confirmed PR), DCR = 100% with median PFS = 8.9mos (95%CI 7-NR). In KEAP1 mut LUSC pts, ORR = 17% (1/6 confirmed PR), DCR = 67% with PFS range = 1.8-8.6 mos. In KRAS + NFE2L2/KEAP1 mut ADCL pts, ORR = 0% and DCR = 0%. Conclusions: TAK228 is tolerable with differential activity in NFE2L2 (primary endpoint met) and KEAP1 mutant LUSC. A randomized phase 2 trial of TAK228 + docetaxel vs. SoC chemotherapy in advanced LUSC pts with NFE2L2/KEAP1 mut is in development (LungMAP S1900D) as is an NCI CTEP phase 1/1b trial of TAK228 + CB-839 in advanced NSCLC patients with NFE2L2/KEAP1 mut (NCI #10327). Clinical trial information: NCT02417701 .
Clinical and genomic analysis of non-small cell lung cancer (NSCLC) patients with MET exon14 skipping (METex14) mutations and responses to anti-MET therapy.
Authors: McKenzie Andrew , Fisher Arielle , Correll Mick , Jones Carissa , Correia Jessica , Thurber James , Misch Amanda , Heritage Jessica , Sturgill Emma , Jones Suzanne Fields , Johnson Melissa Lynne , Spigel David R. 
Published: May 2020

9613 Background: MET is a validated oncogene for molecular targeted therapy in non-small-cell lung cancer (NSCLC), and METex14 mutations result in MET overexpression. Studies with MET-targeting therapies have demonstrated high objective response rates and prolonged disease control. There are few clinical and genomic analyses of patients with METex14-positive NSCLC in the community setting. We herein characterize key clinical and genomic findings for patients harboring METex14 mutations. Methods: Sarah Cannon provides clinical research to partnering medical oncology practices who order broad-based NGS, from both tissue and blood, as a part of standard of care. Genospace, a clinico-genomic software tool, was used for identification of patients for clinical trials and analysis of clinical and genomic data. Results: Of 6521 lung cancer patients with NGS results, 66 (1.01%) harbored METex14 mutations (45.5% from blood and 54.5% from in tissue). The mean age at diagnosis was 75.7 and 21.2% developed brain metastases. Of the 66 patients with METex14 mutations, 69.5% are current/former smokers. Nineteen percent of former/current smokers and 7.6% of never smokers had PD-L1 scores of > 50%, respectively. The majority of METex14-positive patients either received standard of care (66.7%) or were unable to take (19.7%) 1st-line therapy. Patients who received chemotherapy (Chemo), immunotherapy (IO), and Chemo/IO in the first and second line settings responded to SOC treatment, and patients receiving anti-MET therapy benefited from therapy even after front-line SOC (table). Genomic analysis revealed the most common co-occurring mutations to be EGFR, MET, NF1, KRAS, and BRCA2 (Freq = 8.7%, 8.7%, 8.7%, and 7.6%, respectively). Conclusions: Genospace enables real-time patient identification of METex14-positive NSCLC cases and analysis of these cases indicates that anti-MET therapy may be effective at any line of treatment. Genospace’s clinico-genomic database was used to analyze treatment history, clinical correlates, and co-occurring mutations that may reveal novel treatment combination strategies or resistance mechanisms. [Table: see text]
Randomized phase I trial to evaluate Concurrent or Sequential Ipilimumab, Nivolumab, and stereotactic body Radiotherapy in patients with stage IV non-small cell lung cancer (COSINR Study).
Authors: Patel Jyoti D. , Bestvina Christine M. , Karrison Theodore , Jelinek Michael J. , Juloori Aditya , Pointer Kelli , Hoffman Philip C. , Pitroda Sean P. , Vokes Everett E. , Chmura Steven J. 
Published: May 2020

9616 Background: Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy following SBRT. We hypothesize that SBRT may improve outcomes for patients receiving immunotherapy through both direct cytoreduction and increased immunogenicity. Within this context, we conducted a phase 1 trial designed to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab(N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT (mSBRT) in patients with stage IV NSCLC. Methods: Treatment naïve patients (EGFR/ALK WT) with advanced NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. Brain metastases were allowed on protocol, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Patients on Seq arm received N/Ip between 1-7 days after completion of SBRT. Patients in Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, development of toxicity, or up to 2 years. Patients underwent pre- and post-treatment biopsy of one irradiated lesion. Results: A total of 35 patients (Seq/Con 19/16) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27%. PD-L1 expression: 0% (16), 1-49% (10), >50% (9). Median number of metastases treated with SBRT was 3.2. 6 patients experienced DLT (4 pneumonitis), resulting in dose reduction in central lung Seq cohort of the organs at risk (OAR) by 20%. Median PFS by RECIST (total/Seq/Con) was 5.9 mo, 95% CI: 4.9-13.1/ 6.2 mo, 95% CI: 3.5-12.6/ 5.9 mo, 95% CI: 3.1-18.0. RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. Treatment past first progression was allowed, and time to second line therapy (chemotherapy) by arm (Seq/Con) was NR/17.5 months. Median OS has not been reached with median follow up of 15mo. PDL1 status did not impact PFS (p = 0.64) nor OS (p = 0.77). Conclusions: Multisite SBRT and concurrent N/Ip was well tolerated. Responses appear durable as median OS was not reached. Multimodality therapy with mSBRT and dual checkpoint inhibitor therapy resulted in impressive tumor control and clinical benefit with promising efficacy. Clinical trial information: NCT03223155 .
FLT3 ligand (CDX-301) and stereotactic radiotherapy for advanced non-small cell lung cancer.
Authors: Ohri Nitin , Halmos Balazs , Garg Madhur , Levsky Jeffrey M , Cheng Haiying , Gucalp Rasim A. , Bodner William Raymond , Kabarriti Rafi , Berkowitz Aviva , Yellin Michael Jay , Keler Tibor , Kalnicki Shalom , Guha Chandan 
Published: May 2020

9618 Background: In a murine non-small cell lung cancer (NSCLC) model, we demonstrated synergy between localized radiotherapy and the dendritic cell growth factor fms-like tyrosine kinase 3 (FLT3) ligand. We now present results from a phase II study testing this combination in patients with advanced and treatment-refractory NSCLC. Methods: Advanced NSCLC patients with multifocal active disease after at least one line of systemic therapy and ECOG performance status 0-2 received 5 daily subcutaneous injections of CDX-301 (75 µg/kg) concurrent with stereotactic body radiotherapy (SBRT, 30-54 Gy in 1-5 fractions based on target size and location) directed at a single site of disease. Additional “cycles” of SBRT and CDX-301 could be administered at least four months after the initial study treatment, at the discretion of the treating physicians. The primary endpoint was progression-free survival four months after treatment initiation (PFS4), with a hypothesis that the PFS4 rate would exceed 40%. Secondary endpoints included overall survival (OS) duration, responses on PET (PERCIST criteria) and CT (RECIST criteria), and dose-limiting toxicities (grade ≥3 adverse events within 30 days). Lesions targeted with SBRT were excluded from response assessments. The intended sample size was 29 subjects. Blood samples were obtained for flow cytometry and other analyses of immune activation. Results: Twenty-nine subjects received study therapy between October 2016 and January 2020. Subjects received a median of 3 lines (range: 1-5) of systemic therapy prior to study enrollment, including immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in 26 subjects (90%). At the time of this analysis, the actuarial PFS4 rate is 60%, which exceeds our pre-specified efficacy objective. With a median follow-up duration for living patients of 12 months, the actuarial 12-month OS rate is 55%. Partial response of lesions not targeted with SBRT (“abscopal effect”) was observed in 9 subjects (31%) using PET criteria and in 4 subjects (14%) using CT criteria. Seven subjects (24%) received a second course of SBRT and CDX-301 after initial study therapy. No dose-limiting toxicities have been observed. Only six subjects (21%) have received additional chemotherapy or immunotherapy after study treatment. Conclusions: The combination of CDX-301 and SBRT is well-tolerated and has activity as systemic therapy for advanced NSCLC. Additional studies to maximize the efficacy of this in situ vaccination approach with the addition of an agonist anti-CD40 antibody (CDX-1140) are planned. Clinical trial information: NCT02839265 .
Progression-free survival estimates in non-small cell lung cancer when RECIST is unavailable: Project GENIE’s integration of genomic, therapeutic and phenomic data.
Authors: Lavery Jessica A. , Panageas Katherine , LeNoue-Newton Michele , Sweeney Shawn , Sheffler-Collins Seth , Rudolph Julia E , Rizvi Hira , Schultz Nikolaus , Lepisto Eva M. , Kehl Kenneth L. , Warner Jeremy Lyle , Dang Kristen , Phillip John , Park Ben Ho , Riely Gregory J. , Schrag Deborah 
Published: May 2020

9622 Background: Molecular tumor profiling has become an integral component of oncology practice but linked genomic-phenomic data remain scarce. Recurrence, treatment response and progression are not structured consistently in medical records and this deficit has been a roadblock to discovery of biomarkers that are associated with favorable outcomes. Methods: The Genomics Evidence Neoplasia Information Exchange (GENIE) consortium is an AACR sponsored project to link and share genomic and phenomic data to promote discovery in precision medicine. 3 cancer centers that routinely perform somatic tumor profiling for advanced cancers agreed to curate anti-neoplastic treatment exposures and outcomes including recurrence, progression, response and survival using a standard method. 6 cancer types (lung, colorectal, breast, prostate, pancreas and bladder) were selected and a REDCAP database captures anti-neoplastic treatments, and specific elements from pathology, radiology and oncology reports. Curators abstract data using data fields that rely on the PRISSMM standard. “Real world” progression free survival (PFS) was identified based on curation of: 1) the text of radiologists’ reports for CT, PET/CT, PET and MRI scans (PFSI) and 2) medical oncologists’ notes (PFSM). PFSI and PFSM were estimated from the start of 1st line anti-neoplastic systemic therapy until progression or death for all patients with molecularly characterized non-small cell lung cancer (NSCLC). Results: Genomic sequencing was performed between 2015 and 2017 for 748 patients with NSCLC treated at three major cancer centers. Median age at diagnosis was 66 years (interquartile range 58, 73) and 43% were male. As shown in the table, when RECIST assessments are unavailable, estimates of PFS vary based on whether they are derived from radiologists’ or oncologists’ interpretations. Conclusions: Radiologists’ reports and oncologists’ reports provide different PFS estimates. Cohort studies should specify the method used to define “real world” endpoints. Project GENIE will have 1800 NSCLC patients with curated endpoints by the ASCO meeting. [Table: see text]