bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and association of ARID1A with driver alterations and immune checkpoint inhibitor (ICPi) biomarkers in cell-free circulating tumor DNA (ctDNA) from 27,000 non-small cell lung cancer (NSCLC) patients.
Authors: Gandara David R. , Weipert Caroline , Saam Jennifer , Riess Jonathan W. , Lenz Heinz-Josef , Kurzrock Razelle 
Published: May 2020

9523 Background: Recent data suggest that the tumor suppressor gene ARID1A is associated with high anti-tumor immunity and may have value as a predictive biomarker for response to ICPi therapy in NSCLC. We examined ARID1A alterations detected in ctDNA from a large cohort of advanced NSCLC patients using a commercially available liquid biopsy assay and explored associations of ARID1A with lung cancer driver alterations and other putative ICPi mutational biomarkers. Methods: Consecutive samples from stage IIIB/IV NSCLC patients tested from March 2016 - August 2019 using a 73- to 74-gene targeted next-generation sequencing ctDNA assay (Guardant360) were queried. Testing included analysis of single nucleotide variants, insertions/deletions, fusions, and amplifications ( KEAP1 not tested). Mutation frequencies were compared using Fisher’s exact test, with variants of uncertain significance and synonymous variants excluded. Results: Of 27,776 NSCLC patients with >1 ctDNA alteration detected, 1,094 (3.9%) had >1 functional ARID1A (f ARID1A) mutation. f ARID1A mutations were significantly more common in patients with squamous histology compared to adenocarcinoma (5.1% vs 3.8%, p = 0.0007). There were significantly fewer EGFR exon 19 deletion mutations (4.9% vs 11.1%; p < 0.0001) and EGFR L858R mutations (4.0% vs 7.0%; p < 0.0001), and significantly more BRAF V600E alterations (2.2% vs 1.4%; p = 0.0338) in patients with f ARID1A. There was no significant difference in the frequency of ALK and ROS1 fusions, nor STK11 mutations between patients with and without f ARID1A (8.0% vs 6.8%; p = 0.126). Activating KRAS mutations were significantly more frequent in patients with f ARID1A (31.1% vs 19.4%; p < 0.0001), including KRAS G12C (10.9% vs 7.0%; p < 0.0001). Conclusions: These data provide a mutational landscape for f ARID1A mutations in NSCLC. f ARID1A was associated with significant differences in the frequency of multiple lung cancer driver alterations, of particular interest in the EGFR-mutated cohort, where ICPi efficacy is low. The frequency of STK11 mutations, a possible negative predictor of ICPi efficacy, was not significantly different. KRAS mutations were significantly more frequent in patients with f ARID1A, notable given recent data reporting that KRAS mutations, particularly KRAS G12C, may be a positive predictor of ICPi response in NSCLC. Determination of ICPi efficacy in patients with f ARID1A is in-process.
A model comparing the value of broad next-gen sequencing (NGS)-based testing to single gene testing (SGT) in patients with nonsquamous non-small cell lung cancer (NSCLC) in the United States.
Authors: Pennell Nathan A. , Zhou Jie , Hobbs Brian 
Published: May 2020

9529 Background: Patients (pts) with nonsquamous (ns) NSCLC should be tested for actionable driver oncogenes (ADOs), and highly effective treatments (tx) may be available for these pts. Although EGFR and ALK single gene testing (SGT) is relatively common (>80%) in the US, testing for less common ADOs is rare. Unidentified pts with ADOs have survival comparable to pts without alterations. We interrogate plausible testing configurations and discuss their implications for the US population. Methods: Simulation was used to evaluate various levels of testing with SGT or NGS on the basis of life years gained (LYG) as well as cost per LYG. Expected prevalence of ADOs among nsNSCLC pts as well as the survival distribution of pts in the presence versus absence of an ADO tx strategy were calibrated based on current literature. Survival duration for each simulated pt was generated from Weibull distributions fit to statistical estimates of median and 5-year survival. With appropriate match between ADO and targeted tx, the Weibull distribution offered a median additional 2 years of life. ADOs included in NGS: EGFR, ALK, ROS1, BRAF, RET, MET, NTRK. SGT: EGFR and ALK. Results: Each incremental 10% increase in NGS instead of SGT produces 2630 additional LYG and a cost savings per LYG between -$49 to -$109. At the current 80% testing rate, replacing SGT with NGS would result in an additional 21,019 LYG with reduced cost per LYG of -$599. Increasing testing from 80% to 100% of eligible pts would increase LYG by 15,017 over the current state. If 100% of eligible pts were tested with NGS and every identified pt received tx, the cost per LYG of this strategy would be $16,641.57. Conclusions: In a hypothetical model where highly effective tx is available to all identified pts with ADOs, broad NGS testing compared to SGT for EGFR/ALK leads to large gains in life years at reduced cost per LYG compared to SGT, supporting universal NGS testing of all advanced nsNSCLC pts. Conversely, lower levels of testing or only testing for common ADOs (as is the current state) result in large numbers of pts being unidentified and not experiencing these benefits. [Table: see text]
Identification and in silico structural insights of rare recurrent EGFR mutations as resistance mechanisms to osimertinib in EGFR-mutated lung cancer.
Authors: Zhoutong N/a , Wu Changling , Lu Binbin , Cao Ran , Ma Yutong , Bao Hua , Ou Qiuxiang , Wu Xue , Shao Yang , Wang Zhaoxia 
Published: May 2020

9531 Background: Inevitable progression on 3rd-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib of EGFR-mutated lung cancer patients represents a great challenge in clinic. Previous studies have revealed that one-third of the resistant mechanisms are due to acquired EGFR secondary mutations, mainly on C797, L718 and L792 residues. Our study aims to gain insights into novel mechanisms of acquired resistance to osimertinib. Methods: We performed genomic profiling on a total of 1,058 EGFR-mutated lung cancer patients with progressed disease on osimertinib, and a cohort of 1,803 patients who received only 1st-generation EGFR TKIs upon progression. Recurrent EGFR mutations with a significant enrichment in the osimertinib group were identified. We further established and applied molecular dynamic simulation-based computational model of the mutant EGFR protein to predict its sensitivity to osimertinib. Results: As expected, compared with 1st-TKIs alone group, EGFR mutations, including C797S/G (22.1% vs. 0.5%), L718Q/V (6.2% vs. 0.3%), L792F/H (4.4% vs. 0.3%), were significantly more enriched in the osimertinib cohort. Our computational model has also successfully predicted their sensitivities to osimertinib: WT (-35.19 kcal/mol) > L792F (-34.10 kcal/mol) > L718Q (-30.33kcal/mol) > C797S (-28.02 kcal/mol), which are consistent with our previous in vitro validations. Importantly, a total of 14 low-frequency EGFR mutations were exclusively observed in the osimertinib group, seven of which, including EGFR G796S(n = 6), V802F(n = 3), T725M(n = 2), Q791L/H(n = 2), P794S/R(n = 2), were predicted to dramatically reduce the binding affinity of osimertinib to EGFR. Of note, analysis of the pretreatment samples of two patients supported that EGFR V802F and Q791L/H were acquired during osimertinib treatment. Interestingly, EGFR G796S was predicted to be sensitive to gefitinib, suggesting the possibility of administration of gefitinib in patients with acquired EGFR G796S to first-line osimertinib treatment. Further in vitro functional validations are currently ongoing. Conclusions: Our study represents the largest EGFR-mutated lung cancer cohort so far to investigate osimertinib resistance in a real-world setting, and has uncovered a list of recurrent low-frequency EGFR mutations that may confer acquired resistance to osimertinib. Our in silico structural model was proved to be powerful and robust in the prediction of osimertinib sensitivity of EGFR mutants.
ctDNA levels before treatment predict survival in non-small cell lung cancer patients treated with a tyrosine kinase inhibitor.
Authors: Provencio-Pulla Mariano , Serna Roberto , Franco Fernando , Sanchez Alfredo , García Girón Carlos , Domine Manuel , Camps Carlos , Sanchez Torres Jose Miguel , Oramas Rodriguez Juana Maria , Chara Velarde Luis Enrique , Ortega Ana Laura , Sala María Ángeles , Hernandez Berta , Sereno Maria , Bosch-Barrera Joaquim , Padilla Airam , Balsalobre Yago Jose , Blanco Remei , De Castro Javier , Romero Atocha 
Published: May 2020

9542 Background: Currently there is an intense debate concerning therapeutic strategies in EGFR positive NSCLC patients with advance disease. Osimertinib is superior to standard EGFR Tyrosine Kinase Inhibitors (TKIs) as first line treatment. However, it is yet unclear whether this option is superior to sequential treatment of a 1st or 2nd generation TKI followed by osimertinib. In order to clarify this issue it is important to identify which patients are at high risk of progression disease. Methods: This is a prospective, multicentre, cross-sectional study promoted by Spanish Lung Cancer Group. 698 plasma samples from 196 advanced NSCLC patients with tumors harboring an EGFR activating mutation and treated with a first line TKI (afatinib, gefitinib, erlotinib or osimertinib) were analyzed. Plasma samples were prospectively collected before treatment (T0), after 3 months of treatment (T3), after 6 months of treatment (T6) and at first disease progression. EGFR mutations were analyzed by dPCR. Multivariate Cox proportional hazards analysis was used to determine the significance of ctDNA in the prediction of prognosis. Results: The median follow up was 19.8 months. At baseline patients with plasma EGFR sensitizing mutations at allele frequency (AF) ≥ 10% had worse OS and PFS than patients in which the opposite occurred (HR = 1.86; 95 %CI: 1.09-3.17, and HR = 1.65; 95 %CI: 1.07-2.58, respectively). Noteworthy, median OS and PFS time were 18.6 and 8.8 months respectively, in patients with plasma AF≥10% before treatment initiation compared to 37.9 and 12.4 months for patients with plasma AF < 10%. Similar results were obtained when a cutoff of AF≥ 5% was used (HR = 1.73; 95%CI: 1.02-2.94 for OS, and HR = 1.72; 95%CI: 1.13-2.61 for PFS). Patients who remained ctDNA-positive after 3 months of treatment exhibited also poorer outcomes (HR = 3.24; 95%CI: 1.77-5.94 for OS, and HR = 3.1; 95%CI: 1.91-5.03 for PFS). In the same way, detectable levels of ctDNA after 6 months of treatment predicted shorter OS and PFS (HR = 3.3; 95%CI: 1.53-7.13 and HR = 2.62; 95%CI: 1.62-4.25, respectively). Conclusions: ctDNA levels significantly predict survival. Moreover, ctDNA levels before treatment initiation can be useful to assess patient’s progression risk which is not possible to assess otherwise facilitating treatment decision making.
Real-world performance of blood-based host immune profiling in first-line immunotherapy treatment in advanced-stage non-small cell lung cancer.
Authors: Mitchell R. Brian , Rich Patricia , Walker Paul R. , Schaefer Eric S , Tan Jiahuai , Nagajothi Nagaprasad , Dubay John W. , Boyd Jason Keith , Oubre David N. , Ikhlaque Nadeem , Page Ray D. , Khalil Mazen , Sinha Suman , Halawani Hafez , Boniol S. Scott , Santos Edgardo S. , Orsini James Michael , Pauli Emily K. , Akerley Wallace L. ,   INSIGHT Investigators
Published: May 2020

9545 Background: Immune checkpoint inhibition (ICI) has improved outcomes for many treatment-naïve advanced non-small cell lung cancer (NSCLC) patients. However, better biomarkers are needed to predict patient response and guide treatment decisions considering added toxicity and higher cost of combination treatments. A prospectively designed, observational study assessed the ability of a clinically validated, blood-based, host immune classifier (HIC) to predict ICI therapy outcomes. Methods: The study (NCT03289780) includes 33 US sites having enrolled over 3,000 NSCLC patients at any stage and line of therapy. All enrolled patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C) prior to therapy initiation. An interim analysis of secondary and exploratory endpoints was performed after 12- 18 months (mo) follow-up with the first 2,000 enrolled patients. We report the overall survival (OS) of HIC-defined subgroups comprising advanced stage (IIIB and higher) NSCLC patients treated with first-line regimens (284 ICI containing treatments, 877 total first-line patients). Results: In a real-world clinical setting, OS of advanced stage NSCLC treatment-naïve patients receiving platinum-based chemotherapy (n = 392) did not differ significantly from patients receiving any type of ICI containing regimen (n = 284); 11.7 mo vs. 14.4 mo; hazard ratio (HR) = 0.94 [95% confidence interval (CI): 0.76–1.17], p = 0.59. HIC-H patients experienced longer survival than HIC-C across multiple regimens, including ICI. For all ICI, median OS (mOS) was not reached for HIC-H (n = 196, CI: 15.4 mo–undefined) vs. 5.0 mo (n = 88, CI: 2.9 mo–6.4 mo) for HIC-C patients (HR = 0.38 [CI: 0.27–0.53], p < 0.0001). Similar results were seen in the ICI only (16.8 mo vs. 2.8 mo; n = 117, HR = 0.36 [CI: 0.22–0.58], p < 0.0001) and ICI/chemotherapy combination subgroups (unreached vs. 6.4 mo; n = 161, HR = 0.41 [CI: 0.26–0.67], p = 0.0003). In the PD-L1 high cohort (PD-L1 ≥50%), mOS for HIC-H was not reached (n = 81, CI: 13.9 mo–undefined) vs. 3.9 mo (n = 41, CI: 2.1 mo–7.8 mo) for HIC-C (HR: 0.39 [CI: 0.24-0.66], p = 0.0003). HIC results were independent of PD-L1 score (p = 0.81) and remained predictive of OS in first-line ICI-treated patients when adjusted for PD-L1 and other covariates by multivariate analysis (HR = 0.40 [CI: 0.28-0.58], p < 0.0001). Conclusions: Blood-based host immune profiling may provide clinically meaningful information for selecting NSCLC patients for two common ICI containing regimens independent of and complementary to PD-L1 score.
Phase III study of tislelizumab plus chemotherapy vs chemotherapy alone as first-line (1L) treatment for advanced squamous non-small cell lung cancer (sq NSCLC).
Authors: Wang Jie , Yu Xinmin , Lu Shun , Hu Yanping , Sun Yuping , Wang Zhijie , Zhao Jun , Yu Yan , Hu Chunhong , Yang Kunyu , Feng Guosheng , Ying Kejing , Zhuang Wu , Zhou Jianying , Wu Jingxun , Wu Yanjie , Lin Xiao , Liang Liang , Yang Nong 
Published: May 2020

9554 Background: Tislelizumab is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Tislelizumab in combination with chemotherapy has demonstrated a manageable tolerability profile and preliminary efficacy as 1L treatment for NSCLC. Methods: In this open-label phase 3 study (NCT03594747), Chinese pts with histologically confirmed stage IIIB or IV sq NSCLC were randomized (1:1:1) to receive IV Q3W: tislelizumab (200 mg, D1) + paclitaxel (P; 175 mg/m2, D1) and carboplatin (carb; AUC 5, D1) ( Arm A); tislelizumab + nab-P (100 mg/m2; D1, 8, and 15) and carb (AUC 5, D1) ( Arm B); or P (175 mg/m2, D1) and carb (AUC 5, D1) ( Arm C). Chemotherapy was administered for 4-6 cycles followed by tislelizumab. Patients were stratified by tumor stage and PD-L1 expression. The primary endpoint, PFS per RECIST v1.1, was assessed by Independent Review Committee; key secondary endpoints included OS, ORR, DoR, and safety/tolerability. Results: Across 360 pts, median PFS was significantly improved with tislelizumab plus chemotherapy ( Arms A and B) compared with chemotherapy alone ( Arm C) (Table). As of 6 Dec 2019, ORRs were higher and median DoRs were longer in Arms A and B vs Arm C. Across all arms, median OS was not reached and median number of treatment cycles were comparable. Adverse events (AEs) leading to discontinuation of any treatment were reported in 12.5%, 29.7%, and 15.4% of pts in Arms A, B, and C, respectively. The most commonly reported grade ≥3 AEs were hematologic in nature (eg, neutropenia) and consistent with known chemotherapy AEs. Serious treatment-related AEs (TRAEs) were reported in 72 pts (37.5% [ A]; 38.9% [ B]; 23.6% [ C]); TRAEs leading to death were reported in 6 pts (n=1 [ A]; n=2 [ B]; n=3 [ C]), none of which were solely attributed to tislelizumab. Conclusions: As 1L treatment for advanced sq NSCLC, addition of tislelizumab to P/carb or nab-P/carb chemotherapy significantly improved PFS and showed higher ORR and longer DoR than chemotherapy alone. The safety profile is in line with the known profiles of tislelizumab, chemotherapy, and underlying NSCLC; no new safety signals were identified with addition of tislelizumab to chemotherapy. Clinical trial information: NCT03594747 . [Table: see text]
A phase Ib study of abemaciclib in combination with pembrolizumab for patients (pts) with stage IV Kirsten rat sarcoma mutant (KRAS-mut) or squamous non-small cell lung cancer (NSCLC) (NCT02779751): Interim results.
Authors: Pujol Jean-Louis , Vansteenkiste Johan F. , Paz-Ares Luis G. , Gregorc Vanesa , Mazieres Julien , Awad Mark M. , Janne Pasi A. , Chisamore Michael Jon , Hossain Anwar , Chen Yanyun , Beck Joseph Thaddeus 
Published: May 2020

9562 Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase 4 and 6 inhibitor. In preclinical models, abemaciclib induced intratumor immune inflammation and synergized with PD-1 blockade to enhance antitumor efficacy in anti-PD-L1 refractory disease. Here, we report the safety and antitumor activity of abemaciclib plus the approved NSCLC treatment pembrolizumab in 2 cohorts for pts with nonsquamous and squamous NSCLC. Methods: Eligible pts for this nonrandomized, open-label, multicohort, phase 1b study were either chemotherapy-naive with ≥ 1% tumor cell (TC) PD-L1 staining, KRAS-mut nonsquamous NSCLC (Cohort A) or had a squamous subtype and received ≤ 1 prior platinum-containing chemotherapy regimen (Cohort B) for metastatic NSCLC. Primary endpoint was safety; secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-five pts with NSCLC were enrolled in each cohort. Most pts (68%) in Cohort B had received 1 prior line of chemotherapy. Safety profiles observed in both cohorts were largely consistent with previous reports for abemaciclib and pembrolizumab monotherapy. Grades 3/4 AEs in Cohorts A and B, respectively, included ALT increase (6 pts [24%]/ 0 pts), diarrhea (3 pts [12%]/ 0 pts), neutropenia (3 pts [12%]/ 0 pts), and pneumonitis (3 pts [12%]/ 1 pt [4%]). Six pts in Cohort A (24%) and 2 pts in Cohort B (8%) had a confirmed partial response for a disease control rate (CR+PR+SD) of 52% and 64%, respectively. In Cohort A, the ORR in pts with strong (≥50% TC) PD-L1 staining (n = 13) was 31% vs. 17% in pts with weak (1-49% TC) PD-L1 expression (n = 12). Median PFS and OS were 7.6 months (95% CI: 1.6, NR) and 22.0 months (95% CI: 9.9, NR) in Cohort A and 3.3 months (95% CI: 1.4, 5.2) and 6.0 months (95% CI: 3.7, 13.1) in Cohort B, respectively. Conclusions: Abemaciclib plus pembrolizumab resulted in a numerical higher rate of transaminase elevations and pneumonitis. Antitumor activity was remarkable in the KRAS-mut nonsquamous NSCLC but not noticeably higher as compared to historical data for pembrolizumab monotherapy. Clinical trial information: NCT02779751 .
Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study.
Authors: Ji Jingran , Aredo Jacqueline V , Piper-Vallillo Andrew , Huppert Laura , Rotow Julia K , Husain Hatim , Stewart Susan L , Cobb Rosemary , Wakelee Heather A. , Blakely Collin Michael , Wong Melisa L. , Gubens Matthew A. , Chen Justin , Oxnard Geoffrey R. , McCoach Caroline Elizabeth , Piotrowska Zofia , Neal Joel W. , Riess Jonathan W. 
Published: May 2020

9570 Background: Osimertinib (osi) is a 3rd generation EGFR tyrosine kinase inhibitor (TKI) approved for first line (1L) treatment of metastatic NSCLC harboring EGFR Exon 19 del and L858R (representing > 80% of EGFR activating mutations) or in NSCLC with EGFRT790M (the most common resistance mutation to 1st or 2nd generation TKI). However, it has not been well-studied in EGFR-mutant NSCLC harboring less common EGFR activating mutations such as G719X, L861Q, S768I, and exon 20 insertion (ins), among others. Methods: We conducted a multi-institution, retrospective study approved on institutional IRB protocols in a series of patients (pts.) with metastatic NSCLC treated with osi who harbored at least one atypical EGFR mutation, excluding those with concurrent L858R, Exon 19 del, or T790M. Kaplan-Meier analyses were generated with SPSS, v25 (IBM Corp., USA). Response was assessed by RECIST 1.1 in evaluable pts. Time on osi was employed as a surrogate endpoint for clinical benefit in this retrospective analysis. Results: Fifty-one NSCLC pts with uncommon EGFR mutations were identified among six US institutions. Pt characteristics: 72.5% women, median age 65 yo (44-83 yo), 82.3% ECOG PS 0-1, 43.1% never smoker, 100% lung adenocarcinoma, 58.8% Caucasian, 25.5% Asian, 3.9% Black, 2.0% Hispanic, and 9.8% Other. The most frequent mutations were L861Q (35.3%, N = 18), G719X (27.5%, N = 14), and Exon 20 ins (15.7%, N = 8). Osi was used in the 1L setting in 39.2% (N = 20). Median time on osi was 7.1 months (mo.) in the overall cohort (95% CI, 5.4 to 8.8 mo.) and 8.9 mo. (95% CI, 7.0 to 10.8 mo.) in pts receiving 1L osi. Patients harboring G719X (N = 4) and L861Q (N = 10) mutations had a median time on 1L osimertinib of 5.8 mo. and 19.3 mo., respectively. One patient’s tumor had an EGFR exon 19 ins and was on 1L osi with a partial response for 16.8 months. Two patients with Exon 20 ins were on 1L osi for 9.3 mo. and 8 mo., respectively. Conclusions: In this largest known clinically annotated dataset of patients with atypical EGFR-mutations treated with osi, activity was noted, though 1L clinical benefit on osi appears lower in this multicenter US cohort than in E19del or L858R. These results are comparable to the recently published prospective phase II trial ( Cho et al, 2019) conducted in Korea. Patients with L861Q and Exon 19 insertion appeared to benefit the most from osi in this time on treatment retrospective analysis. More detailed analysis of this cohort is planned and further prospective studies are warranted to determine clinical benefit of osi amongst diverse atypical EGFR-mutations.