bluuebunny/crossref_metadata_2025_split huggingface dataset:
ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions.
Authors: Piotrowska Zofia , Wang Yating , Sequist Lecia V. , Ramalingam Suresh S. 
Published: May 2020

9513 Background: EGFR exon 20 insertions (ins20), which comprise 4-10% of EGFR-mutant NSCLC, are generally refractory to first- and second-generation EGFR TKIs. While the clinical activity of the third-generation EGFR TKI osimertinib against EGFR ins20 is unknown, preclinical studies suggest its favorable therapeutic window may allow for inhibition of EGFR isn20 at clinically-achievable doses (Hirano, Oncotarget 2015). We report the results of EA5162, a single-arm, phase II study of osimertinib 160 mg in NSCLC pts with EGFR ins20 (NCT03191149). Methods: Pts with advanced NSCLC with an EGFR ins20 mutation identified by any local, CLIA-certified tissue assay were treated with osimertinib 160 mg daily until progression, intolerable toxicity or withdrawal. At least one prior line of therapy was required; stable, asymptomatic brain metastases were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival. The estimated sample size was 19 patients. Results: 21 pts were enrolled between 4/2018 and 7/2019 (median age 65; 15 female, 6 male; median 2 prior therapies); 1 patient did not meet eligibility criteria due to laboratory studies obtained 1 day out of window. As of 1/21/20, 6 pts remain on treatment. Among the 20 eligible pts, the best response was PR in 4 pts and CR in one pt, for a confirmed ORR of 25%; 12 (60%) pts had SD. The median PFS was 9.7 months (95% CI, 4.07, NA), median duration of response (DOR) was 5.7 months (95% CI, 4.73, NA.) Grade > 3 treatment-related adverse events (TRAE) observed in > 1 pt included anemia (n=2), fatigue (n=2), prolonged QT interval (n=2.) One pt had grade 4 respiratory failure, there were no grade 5 TRAEs. One pt discontinued study treatment due to grade 3 anemia. Conclusions: Osimertinib 160mg daily is well-tolerated and showed clinical activity in EGFR ins20-mutant NSCLC with a response rate of 25%, disease control rate of 85%, and mPFS of 9.7 months. The adverse events with osimertinib 160 mg QD in this cohort were consistent with other reports of this regimen; grade 3 rash and diarrhea were not observed. Clinical trial information: NCT03191149 .
PREDICT1: An observational study for identifying blood biomarkers associated with clinical benefit from carboplatin and pemetrexed (CbP) treatment in patients with non-squamous (NS) non-small cell lung cancer (NSCLC) (CJLSG1201).
Authors: Hase Tetsunari , Yanagisawa Kiyoshi , Fukatsu Asuki , Kimura Tomoki , Kojima Eiji , Abe Takashi , Imaizumi Kazuyoshi , Horio Yoshitsugu , Oguri Tetsuya , Yamamoto Masashi , Ogasawara Tomohiko , Sugino Yasuteru , Morise Masahiro , Nakatochi Masahiro , Ando Masahiko , Kondo Masashi , Saka Hideo , Saito Hiroshi , Hasegawa Yoshinori , Takahashi Takashi ,   Central Japan Lung Study Group, Chubu Regional Consortium for Advanced Medicine
Published: May 2020

9524 Background: At present, platinum-doublet chemotherapy or in combination with an immune check point inhibitor are standard treatment for patients with metastatic or recurrent NSCLC which lacks somatic gene alterations. Although CbP is one of the commonly used treatment options for NS-NSCLC, its clinical utility is limited due to lack of optimal biomarkers. Methods: Chemotherapy-naïve patients with pathologically proven advanced or recurrent NS-NSCLC received carboplatin (area under the curve = 5-6, at investigator’s discretion) plus pemetrexed (500 mg/m2) every 3 weeks followed by maintenance pemetrexed until disease progression. Blood samples were collected before treatment for proteomic analysis using mass spectrometry (MS). A classifier was constructed based on both an objective response assessed by radiologist independent of attending physicians in accordance with RECIST v1.1 and expression profiles of protein in a training cohort. The constructed classifier was then assessed with a validation cohort evaluating prediction accuracy of good responder, progression free survival (PFS) and overall survival (OS). Results: Of 244 patients with NS-NSCLC in a training cohort, proteomic profiles in blood from 96 patients who responded or progressed after treatment with CbP were analyzed to develop a classifier based on weighted voting. Details of the classifier will be presented at the 2020 ASCO Annual Meeting. The classifier was then applied to validation cohort (n = 94), and we successfully identified patients who benefit from the treatment (55 in good MS group) or not (39 in poor MS group). The objective response rate of the good MS group was significantly higher than that of the poor MS group (30.9% vs. 5.1%; p = 0.0018). The good MS group showed a significantly improved survival compared to the poor MS group (median PFS, 6.0 m vs. 2.3 m; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.09-0.27; p < 0.001; median OS, 25.7 m vs. 5.1 m; HR, 0.18; 95% CI, 0.1-0.34; p < 0.001). Conclusions: In the present study, we successfully developed and validated a predictive classifier using proteomic analyses with blood samples collected from patients before treatment with CbP, suggesting the clinical utility of the classifier in selecting NS-NSCLC patients for treatment with CbP. Clinical trial information: UMIN000008476 .
RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts).
Authors: Nishio Kazuto , Sakai Kazuko , Seto Takashi , Nishio Makoto , Garon Edward B. , Reck Martin , Goto Koichi , Kato Terufumi , Nakanishi Yoichi , Takahashi Toshiaki , Yamamoto Nobuyuki , Kiura Katsuyuki , Ohe Yuichiro , Tamura Tomohide , Visseren-Grul Carla M , Hozak Rebecca R. , Wijayawardana Sameera R. , Enatsu Sotaro , Nakagawa Kazuhiko 
Published: May 2020

9527 Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p<.0001). To understand baseline genetic mutations and treatment-emergent (TE) resistance mechanisms, this exploratory liquid biopsy substudy examined biomarkers in ctDNA from participating Japanese pts by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). Methods: Plasma samples were collected at baseline, during treatment (Cycle 4, 13, and every 6 cycles to Cycle 53) and post-study treatment discontinuation (30-day follow-up [30d FU]). Mutations were assessed at baseline and 30d FU by NGS (Ion AmpliSeq Colon and Lung Cancer panel). EGFR mutations and MET and ERBB2 copy number (CN) were assessed at all time points by ddPCR. Baseline markers were analyzed in pts with any detectable baseline mutation (to confirm ctDNA presence; NGS N=84, ddPCR N=74). TE mutations were analyzed in pts with any detectable mutation at baseline and 30d FU (NGS N=26, ddPCR N=28). Among these pts, 81% and 57% for NGS and ddPCR, respectively, had progressed by 30d FU. Results: By plasma NGS, baseline EGFR activating mutations (exon 19 deletion or exon 21 [L858R] mutation) were detected in 83.3% of pts. Common co-occurring baseline mutations were TP53 (42.9%), PTEN (7.1%) and KRAS (6.0%). Baseline TP53 mutation rate was higher in men vs women (p=.02). No difference in PFS was detected by baseline TP53 status (interaction predictive p=.45, prognostic p=.33). TE mutations were detected in EGFR (including T790M), FGFR3, KRAS and TP53. Slightly higher rates of TE KRAS (p=.03) and TP53 (p=.07) mutations were detected in RAM+ERL than in PL+ERL. TE total EGFR mutations (p=.65) or TE T790M (p=.69) did not differ by arm. By ddPCR, baseline EGFR activating mutations were detected in all pts. T790M was detected at baseline in 2/37 pts/arm (5.4%) and was TE in 6/11 (55%) RAM+ERL pts and 7/17 (41%) PL+ERL pts. There was a trend (p=.054) for greater ERBB2 CN in RAM+ERL vs PL+ERL at Cycle 4. MET CN decreased slightly at Cycle 4 in both arms (significant in PL+ERL, p=.003). Biomarker levels by ddPCR across all time points will be presented. Conclusions: Though limited by sample size and likely inconsistent tumor shedding, this exploratory study identified potential differences in TP53, KRAS, ERBB2 and MET by demographics, treatment and/or time. Clinical trial information: NCT02411448 .
Effect of performance status on survival with pembrolizumab monotherapy in advanced non-small cell lung cancer (NSCLC).
Authors: Sehgal Kartik , Bindal Poorva , Koshy Anita Geevarghese , Gill Ritu R. , McDonald Danielle C , Rangachari Deepa , Costa Daniel Botelho 
Published: May 2020

9533 Background: Pembrolizumab (P) is now widely used as standard of care (SOC) in advanced NSCLC. We sought to identify prognostic factors influencing survival with it in a real-world setting. Methods: We conducted a retrospective cohort study of with advanced NSCLC patients who initiated treatment with SOC P monotherapy at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. Survival time was defined from start of P. Cox proportional hazards and logistic regression were utilized. Results: Of 74 patients with median follow up of 83.9 weeks, 30 (40.5%) were alive at cutoff. Patient characteristics at start of therapy were: 36 (48.6%) female, median age 68.5 yr (range 33-87), 10 (13.5%) with symptomatic brain metastases; 54 (72.9%) treatment-naïve, 29 (39.2%) with ECOG performance status (PS) ≥2. Tumor characteristics were: 53 (71.6%) with PD-L1 tumor proportion score (TPS) ≥50%, median PD-L1 TPS 75% (range 1-100), tumor mutational burden (TMB) tested in only 37 (50%) patients, median TMB 8 mut/mB (range 1-62). Any grade immune-related adverse events (irAE) occurred in 33 (44.6%) patients, while 16 (21.6%) received systemic steroids. Median survival was 43.3 wks (95% CI 29-104.1). Multivariable regression showed ECOG PS of ≥2 as the strongest risk factor for death (Table). We next evaluated differences in characteristics of patients who were alive vs dead within 12 wks of starting P, by which initial response assessments are completed in routine practice. ECOG PS was the only significantly different baseline variable, even after multivariable adjustment (p = 0.002). Conclusions: ECOG PS of ≥2 is a poor prognostic risk factor associated with P monotherapy in advanced NSCLC. Though comprising a clinically significant subset of patients in real-world, they were not included in landmark trials (KEYNOTE-024 & 042). Prospective evaluation is warranted. [Table: see text]
Interaction between CAF and CD8+ T cells in non-small cell lung cancer affects prognosis and efficacy of immunotherapy.
Authors: Zheng Xinlong , Zeng Dongqiang , Peng Wenying , Li Pansong , Li Lifeng , Gao Xuan , Zhou Zhipeng , Bai Jing , Li Junhui , Ding Jianming , Wang Deqiang , Zheng Suya , Miao Qian , Jiang Kan , Wu Biao , Long Feng , Li Chao , Xu Haipeng , Yin Yi , Gen Lin 
Published: May 2020

9536 Background: Cancer-related fibroblasts (CAFs) are important components of the tumor microenvironment (TME) and play a key role in tumor progression. There is growing evidence that CAF levels in tumors are highly correlated with treatment response and prognosis. However, the effect of CAFs on immunotherapy response remains unknown. Methods: RNA-seq and clinical data were downloaded from TCGA and GEO. The SVA package ComBat function was used to remove batch effects. The ssGSEA algorithm was used to assess the level of cell infiltration in each sample. OS (overall survival) and DFS (disease free survival) were analyzed using the Kaplan–Meier method. GO enrichment analysis was used to assess the biological processes of subgroup differential genes. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and subclass mapping were used to predict the clinical response to immune checkpoint blockade. Results: We evaluated the infiltration abundance of 24 types of immune cells and fibroblasts in 1768 NSCLC samples and found that almost all IMFRs (immune cells / fibroblasts) are beneficial to the prognosis. This phenomenon is called “CAFs-mediated immune resistance pattern (CMIRP)”. We evaluated the infiltration abundance of 24 types of immune cells and fibroblasts in 1768 NSCLC samples and found that almost all IMFRs (immune cells / fibroblasts) are beneficial to the prognosis. This phenomenon is called “CAFs-mediated immune resistance pattern (CMIRP)”. The prognosis according to CD8+ T cells was not strong, but CD8+ T cells / fibroblasts (CFR) were significant protective prognostic factors [n = 1588; hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.56–0.78; P < 0.001]. Multivariate analysis revealed that the CFR was an independent prognostic biomarker. The TCGA pan-cancer cohort confirmed the widespread presence of CMIRP in cancer. We further defined the CFR high and CFR low subgroups. CFR high samples were enriched with immune activation pathways including T cell activation, cytolysis, and antigen presentation, while CFR low was associated with immunosuppression including activation of transforming growth factor β, epithelial-mesenchymal transition, and angiogenesis pathways. Finally, we combined TIDE and submap to speculate that CFR is a potential prognostic marker of immunotherapy for NSCLC. Conclusions: We proposed the term “CMIRP” to shed light on a more accurate assessment of immune status. CFR is a potential marker for prognosis and predictive efficacy of immunotherapy in NSCLC.
Early pulmonary function changes associated with brigatinib initiation.
Authors: Ng Terry L. , Johnson Amber , Osypuk Andrea Abeyta , Smith Derek , Jordan Kimberly R. , Nguyen Anna Tram Anh , Conti Nicole , van Bokhoven Adrie , Hsieh Elena , Camidge D. Ross , Schenk Erin Lynn 
Published: May 2020

9538 Background: Phase I-III studies reported symptomatic pulmonary toxicity within the first week of initiating brigatinib in 6% patients post-crizotinib and 3% in TKI naive patients with standard dosing (90mg QD for 7 days then 180mg QD as tolerated). A prospective observational study of pulmonary function testing (PFT) on initiating brigatinib was conducted. Methods: Patients PS≤2, with resting O2 sats on RA ≥90% and Hg ≥10 g/dL, without significant heart/lung disease or steroid use initiating brigatinib 90 mg QD were eligible. PFT with DLCO, Borg dyspnea and 6-minute walk tests were performed at baseline (prior to brigatinib), and on day 2 (D2), 8 (D8), and 15 (D15) of brigatinib. D15 analyses were initially as clinically indicated but became mandatory if DLCO had not returned to baseline by D8. Peripheral blood was collected at baseline, D2 and D8 for CyTOF analysis. The primary endpoint was the incidence of Early Onset Pulmonary Events (EOPEs), defined as a DLCO reduction of ≥ 20% from baseline. An interim analysis was performed on the first 10 patients due to a higher than expected incidence of DLCO reduction. Results: D2 and D8 measurements were captured in all 10 patients, D15 in 7 patients. Ninety percent (9/10) of patients experienced DLCO reduction with nadir occurring on D2 in 4/9 and on D8 in 5/9 patients. Median DLCO nadir was −13.33% from baseline (range: −34.44 to −5.00). Three patients (30%) met EOPE criteria, all on D8, all without symptoms. Brigatinib was not held and all 10 patients escalated to 180mg on D8. Despite continued dosing, 4/9 patients recovered DLCO to baseline or above by D15 (2/3 EOPEs cases), 2/9 recovered above nadir but below baseline by D15 (1/3 EOPE case), and 3/9 did not have improvement from nadir values but no D15 assessment was performed. Dyspnea and 6-minute walk test did not correlate with DLCO changes. Patients who experienced an EOPE had significantly higher levels of activated neutrophils (pERKhi) at baseline. On the day of the EOPE event, patients who met EOPE criteria had significantly higher levels of activated neutrophils and fewer activated CD4+ effector memory T cells. Conclusions: Modest DLCO reduction occurred in 90% (9/10) patients during the first 8 days of brigatinib-dosing without associated symptoms. When rechecked on D15, DLCO improved in 100% patients (6/6) despite continued dosing and standard dose escalation at D8. Patients unlikely to tolerate even this modest, short-lived change should consider shallower step-up dosing or alternative drugs. CyTOF analysis suggests levels of pretreatment neutrophils may be a biomarker for developing EOPEs. Clinical trial information: NCT03389399 .
SRC-homology 2 domain-containing phosphatase 2 (SHP2) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD).
Authors: Rosell Rafael , Ito Masaoki , Codony-Servat Jordi , Giménez-Capitán Ana , Serra-Mitjans Mireia , Pérez-Ochoa Francisco , Llige David , Chaib Imane , Rami-Porta Ramón , Obiols Carme , Call Sergi , Belda-Sanchis José , Tarroch-Sarasa Xavier , Karachaliou Niki , Molina Vila Miguel Angel , Okada Morihito 
Published: May 2020

9540 Background: Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts). Methods: We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2. Results: Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio = 1.83 and 2.28, respectively. p = 0.03 and p = 0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocalizes SHP2 into the cytoplasm membrane, limiting AKT and ERK activation. Conclusions: High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.
Circulating and tumor-associated neutrophil subtypes discriminate hyperprogressive disease (HPD) from conventional progression (PD) upon immune checkpoint inhibitors (ICI) in advanced non-small cell lung cancer (NSCLC) patients (pts) and in vivo models.
Authors: Ferrara Roberto , Lo Russo Giuseppe , Signorelli Diego , Proto Claudia , Prelaj Arsela , Galli Giulia , De Toma Alessandro , Viscardi Giuseppe , Lobefaro Riccardo , Brambilla Marta , Talarico Giovanna , Bassani Barbara , Spanò Sestina Maria , Molino Giuliano , Zilembo Nicoletta , Ganzinelli Monica , Vitale Stefania , Colombo Mario Paolo , Garassino Marina Chiara , Sangaletti Sabina 
Published: May 2020

9547 Background: HPD occurs in ≃10-25% of NSCLC pts upon single-agent ICI and correlates with poor prognosis. High circulating neutrophil count and neutrophils/lymphocytes ratio have been associated with shorter survival and HPD in NSCLC pts. In mouse lung cancer models, interleukin-17 (IL-17) promoted tumour growth upon ICI increasing intratumoral neutrophils. The role of specific circulating and/or tumour-associated neutrophils in driving HPD is currently unknown. Methods: NSCLC pts treated with single agent ICI were assessed for HPD and circulating neutrophils’ phenotype. Conventional PD was defined by RECIST 1.1. HPD required 3 tumour assessments (2 before ICI, 1 upon ICI) and was defined as delta tumour growth rate (TGR) (TGR upon ICI – TGR before ICI) > 50% and/or TGR ratio (TGR upon ICI/ TGR before ICI) ≥2. Correlations with continuous variables were performed by Mann-Whitney test. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry (FC) on peripheral blood mononuclear cells (PBMCs) from fresh blood samples. LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10− and CD10−CD16− LDNs. The occurrence of HPD upon anti-PD-1 treatment was tested in C57BL/6 immune competent mice bearing Lewis Lung Carcinoma and treated with anti-murine PD-1. Tumour associated neutrophils’ phenotype was assessed by FC. Results: Of 52 NSCLC, 65% were > 65 years, 83% had stage IV, 25% PD-L1 on tumour cells ≥50%, 67% received 1st line ICI. PD and HPD occurred in 21 (40%) and 5 (10%) pts, respectively. Before ICI start, HPD pts had higher circulating immature neutrophils measured as median percentage of CD10− LDNs [41.9 (min 26.7; max 83.5) vs 10.1 (min 0.69; max 79.3), p = 0.01] and of CD16− cells among CD10− LDNs [93 (min 89.5; max 98.4) vs 86.3 (min 24.2; max 99), p = 0.03] compared to conventional PD pts. PD and HPD occurred in 17 (71%) and 3 (12.5%) of 24 immune competent mice treated with anti-murine PD-1. The median percentage of IL-17+ tumour associated neutrophils (Gr1highLy6Clow) was significantly higher in HPD compared to PD mice [0.25 (min 0.14; max 0.63) vs 0.06 (min 0.02; max 0.32), p = 0.02]. Conclusions: Circulating immature (CD10− and CD10− CD16−) LDNs and IL-17+ tumour associated neutrophils discriminate HPD from conventional PD upon ICI in NSCLC pts and in vivo models, respectively. Functional characterization of specific neutrophil subsets is ongoing.