bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive modeling of longitudinal circulating tumor DNA dynamics to predict clinical response to first-line immunotherapy and chemoimmunotherapy in advanced non-small cell lung cancer.
Authors: Murray Joseph Christopher , Rhymee Lamia , Marrone Kristen , Naidoo Jarushka , Levy Benjamin Philip , Ferreira Leonardo , Rosner Samuel , Lanis Mara , Hann Christine L. , Feliciano Josephine Louella , Lam Vincent K. , Ettinger David S. , Illei Peter Bela , Wang Chenguang , Brahmer Julie R. , Forde Patrick M. , Velculescu Victor E. , Scharpf Robert B. , Anagnostou Valsamo 
Published: May 2020

9525 Background: First-line immunotherapy (IO) and chemo-immunotherapy (chemo-IO) are approved for PD-L1-expressing advanced non-small cell lung cancer (NSCLC), but PD-L1 expression does not reliably predict therapeutic response. Therefore, accurate on-therapy response assessment is needed to guide clinical decision-making. Conventional radiographic imaging is the gold-standard, but may not capture the nature and timing of an immune-mediated response. We investigated whether comprehensive longitudinal circulating tumor DNA (ctDNA) dynamics could enhance prediction of clinical response. Methods: We conducted targeted error correction sequencing (TEC-Seq) of longitudinal plasma specimens and matched white blood cells (WBCs) in patients with NSCLC treated with first-line IO or chemo-IO. Plasma ctDNA variants were identified by filtering out clonal hematopoiesis (CH) and germline (GL) variants found in matched WBCs. Clinical and pathological data, including PD-L1 tumor proportion score (TPS), and imaging response by RECIST1.1 were assessed. ctDNA dynamics were modeled to predict durable clinical benefit (at 6 months), progression-free survival (PFS), and overall survival (OS). Results: A total of 143 longitudinal plasma and 24 white blood cell samples underwent TEC-Seq for 31 patients with NSCLC treated with IO (n = 17) or chemo-IO (n = 14). ctDNA variants were found in 77% (n = 24) of patients after filtering out CH and GL variants, which comprised 53% (n = 196 of 373) of all variants. Molecular response, signified by elimination of ctDNA variants, was detected in 32% (n = 10) of patients and associated with improved PFS (p = 0.0004, log rank) and OS (p = 0.017, log rank). Time to molecular response was shorter than time to best RECIST response (median 3 vs. 7.71 weeks, p = 0.048, Mann-Whitney U test). A logistic regression model incorporating molecular response, recrudescence, or emergence of new variants predicted durable clinical benefit (sensitivity 84%, specificity 76%, AUC 0.88) better than PD-L1 TPS (AUC 0.67, p = 0.046, bootstrap method). Conclusions: Comprehensive modeling of ctDNA variant dynamics predicts clinical outcome independent of PD-L1 status in patients with advanced NSCLC treated with first-line IO or chemo-IO. Verification of bona fide ctDNA variants by matched WBC sequencing is essential. Molecular response can be identified earlier than imaging response and could enable on-therapy decision-making to alter clinical outcomes.
Targeted DNA sequencing analysis to reveal genetic diversity and androgen-receptor alteration in advanced EGFR mutant lung adenocarcinoma.
Authors: Wu Wei , Okimoto Ross A. , Blakely Collin Michael , Fraser James , Bivona Trever G. 
Published: May 2020

9526 Background: Lung cancer remains the leading cause of death from cancer around the world. Several oncogenic drivers have been identified from large cancer genome projects focused mainly on profiling early-stage lung cancers. Targeted therapies have been developed for specific activated driver gene mutations and are used in advanced-stage patients. For instance, advanced EGFR mutant lung cancer is primarily treated with EGFR tyrosine receptor inhibitors (TKIs). However, resistance remains an obstacle to durable anti-tumor control. We hypothesize that concurrent genetic alterations co-exiting with EGFR driver mutations contribute to the failure of EGFR TKI therapy. Methods: To understand the complexity and diversity of genetic alterations present in EGFR mutant advanced lung cancers, we utilized 660 EGFR mutant advanced lung adenocarcinomas samples with targeted DNA sequencing from Foundation Medicine, 394 cases from MSK-IMPACT dataset, along with TCGA lung cancer data. We performed systematic co-mutation analysis, molecular simulation, functional annotation and pathway enrichment analysis. Results: We updated mutational profiling on EGFR gene with hotspots at exon 18, 19, 20 and 21. Among them, EGFR L858R, exon19 deletion, T790M and G719A are top ranking alleles among EGFR mutations. Interestingly, a subset (n = 26 cases) of EGFR T790M mutations parallel with other EGFR mutations, which could affect the TKI binding pocket as inferred by molecular simulations. Furthermore, in advanced lung cancer EGFR mutations co-occurred with known oncogenic mutations in KRAS, MET, NF-1, MAP2K1, ERBB2, and ALK/ROS-1/RET fusions. Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR mutant lung cancer were enriched in signatures of epigenetic modifiers, genome instability, WNT signaling, and RNA splicing. Compared to early stage TCGA-lung adenocarcinomas, Cell cycle, DNA repair, WNT signaling and androgen receptor-mediated signaling pathways are predominantly altered in advanced EGFR mutant lung cancers. Conclusions: We characterized the genetic landscape of advanced EGFR-mutant lung adenocarcinomas and further dissected concurrent mutated genes with EGFR driver mutations. Our findings provide a rational for polytherapy roadmap for testing in advanced EGFR-mutant lung cancer.
Residual circulating tumor DNA (ctDNA) after two months of therapy to predict progression-free and overall survival in patients treated on S1403 with afatinib +/- cetuximab.
Authors: Mack Philip C. , Redman Mary Weber , Moon James , Goldberg Sarah B. , Herbst Roy S. , Melnick Mary Ann C. , Walther Zenta , Hirsch Fred R. , Politi Katerina A. , Kelly Karen , Gandara David R. 
Published: May 2020

9532 Background: ctDNA from patient plasma has demonstrated diagnostic utility in non-small cell lung cancer (NSCLC). Longitudinal changes in mutant allele frequency (MAF) have great potential to refine clinical management on targeted therapies. Methods: S1403 was a first-line phase II study of afatinib w or w/o cetuximab in pts with EGFR-mutant NSCLC. Between March, 2015 and April, 2018, 174 pts were randomized with 168 determined to be eligible. The study closed early due to futility. Plasma specimens were prospectively collected at baseline, Cycle 3 Day 1 (C3D1; 8 weeks) and at progression, and processed for batch analysis of ctDNA by next-generation sequencing (Guardant 360). A complete case analysis approach was used. The Kaplan-Meier method was used to estimate survival distributions, a Cox model to estimate hazard ratios and confidence bounds, and the log-rank test to compare distributions. A landmark analysis was used to assess predictive value of ctDNA clearance at C3D1. Results: 104 patients (62%) had analyzable baseline plasma specimens available, with EGFR mutations detected in 83 (80%). PFS was significantly shorter for pts with EGFR ctDNA positivity at baseline (p = 0.03) (Table) compared to those with no detectable ctDNA, likely a prognostic effect. Kinetic changes in ctDNA MAFs were analyzed in 79 pts with matching baseline and C3D1 specimens. Of 62 cases with detectable ctDNA at baseline, 68% (42/62) became undetectable at C3D1 (“ctDNA clearance”); ctDNA clearance relative to residual ctDNA was associated with significantly longer PFS (p = 0.00001) and OS (0.003) (Table). To date, 29 pts had matching at-progression samples. T790M mutations were observed at progression in 6/29 (24%) cases. Other putative emergent resistance factors include: a TACC3-FGFR3 and an EML4-ALK fusion, MET exon 14 skipping, multiple MET amplifications and NF1 frameshift mutations. Conclusions: Clearance of EGFR ctDNA after 60 days of therapy was associated with a substantial and statistically significant improvement in subsequent PFS and OS. Incorporation of ctDNA kinetics into routine clinical care represents a promising platform to identify patients with inferior outcomes on TKIs and detect targetable emergent resistance mechanisms. [Table: see text]
Prediction of the molecular status in non-small cell lung cancer based on metastatic pattern: A free webtool powered by artificial intelligence.
Authors: Besse Benjamin , Dormieux Alison , Mezquita Laura , Monnet Renaud , Tazdait Melodie , Lacroix Ludovic , Rouleau Etienne , Adam Julien , Remon Masip Jordi , Bluthgen María , Facchinetti Francesco , Tzelikas Lambros , Lavaud Pernelle , Naltet Charles , Le Pechoux Cecile , Balleyguier Corinne , Planchard David , Lassau Nathalie , Cournede Paul-Henri , Caramella Caroline 
Published: May 2020

9535 Background: Molecular characterization of metastatic lung adenocarcinomas is mandatory but might be hampered by the quantity of tissue, restricted access to molecular platforms or limited economical resources. Our aim was to develop a tool supported by the hypothesis that radiological patterns of pts could help predict the rate of positivity of the most common oncogenic drivers. Methods: We defined an algorithm based on a molecularly defined cohort of 656 pts with stage IV lung adenocarcinoma. Two radiologists centrally reviewed the baseline imaging. Clinical data were retrospectively collected. There were 135 EGFR mutations, 81 ALK fusions, 47 BRAF mutations, 141 KRAS mutations, and 146 pan-negative tumors for these 4 oncogenic drivers. Univariate correlation analyses were performed to define an algorithm predicting the molecular testing positivity based on the metastatic pattern. Subsequently, an online tool was developed. This study was approved by our institutional review board. Results: Metastatic patterns correlated with the genomic drivers when compared to the pan-negative group. In the EGFR group, pleural metastases were more frequent (32% vs. 20%; p = 0.021), whereas adrenal and node metastases less frequent (6% vs.23%; p < 0.001 and 11% vs. 23% respectively; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% vs. 29%; p = 0.043 and 37% vs. 24% respectively; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (47% vs. 20%; p < 0.001 and 11% vs. 3% respectively; p = 0.04) and bone metastases less common (21% vs. 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK and BRAF groups (6%, 7% and 15% vs. 1%; p = 0,016, p = 0,009 and p < 0,001 respectively). A free online access to the algorithm is now available after registration at http//tactic-ct.fr. Physicians enter age, sex, smoking status and the sites of metastases at diagnosis (present/absent/unknown). A mutation score is calculated, reflecting the % of chance to find an oncogenic driver. On the website, contributors can also enter new cases and an artificial intelligence will refine the algorithm and expand the number of oncogenic drivers. Conclusions: Our free access tool allows establishing a hierarchy in the molecular testing based on simple clinical and radiological information. Continual learning from new cases entered in the database will increase the sensitivity of the tool. This tool might save time, tumor tissue, economical resources and accelerate access to personalized treatment.
Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC).
Authors: Liu Stephen V. , Vanderwalde Ari M. , Mamdani Hirva , Raez Luis E. , Baca Yasmine , Xiu Joanne , Korn Wolfgang Michael , Nagasaka Misako , Pai Sachin Gopalkrishna , Socinski Mark A. , Nieva Jorge J. , Kim Chul , Wozniak Antoinette J. , Ikpeazu Chukwuemeka , Lopes Gilberto , Spira Alexander I. , Judd Julia , Kim Edward S. , Borghaei Hossein 
Published: May 2020

9544 Background: KRAS is the most commonly mutated oncogene in NSCLC and the development of direct KRAS inhibitors has renewed interest in this molecular subtype. However, there are several different KRAS mts, representing unique biology and different prognostic and therapeutic impact. A more comprehensive understanding of the genomic landscape relative to each KRAS mt subset will help guide therapeutic development. Methods: Molecular profiles of 17,113 NSCLC specimens were obtained using next-generation sequencing of 592 genes (Caris Life Sciences) and classified based on presence and types of KRAS mt. Incidence of KRAS mts was noted across the cohort and by histology. Co-occurring genomic alterations, tumor mutational burden (TMB) and PD-L1 IHC (22C3, TPS score) were analyzed by KRAS mt type. Results: Across the entire cohort, 4706 (27%) of samples harbored a KRAS mt (Table). The most common was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mt was 37.2% among adenocarcinoma and only 4.4% in squamous. High TMB, defined by > 10 mts/Mb, varied across the different KRAS mt types, most common in G13X (68.3%) and least common in G12D (43.2%). PD-L1 expression also varied. G12C was the most likely to be PD-L1 positive, with 65.5% TPS > 1%, and the most likely to be PD-L1 high, with 41.3% TPS > 50%. STK11 was mutated in 8.6% of KRAS wild type NSCLC but more frequently noted in every KRAS subtype, with the highest rate in G13X (36.2%) and the lowest in G12D(14.2%). TP53 mts were more frequent in KRAS wild type NSCLC (73.6%), with the highest rate among KRAS mutants at 55.4% (G12other) and the lowest at 36.8% (Q61X). NF1 was noted to be mutated in 21.4% of KRAS G13X cases, while all other KRAS mts had a lower frequency of NF1 mts than KRAS wild type (11.5%). Conclusions: KRAS mts are relatively common in lung adenocarcinoma and KRAS G12C is the most common variant. The different KRAS mts have different co-occurring mutations and a different genomic landscape. KRAS G12C was associated with the highest rate of PD-L1 expression. The clinical relevance of these differences in the context of therapeutic intervention warrants investigation. [Table: see text]
Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Luo Jia , Bandlamudi Chaitanya , Ricciuti Biagio , Vokes Natalie , Schoenfeld Adam Jacob , Egger Jacklynn V. , Sauter Jennifer L. , Plodkowski Andrew J. , Preeshagul Isabel Ruth , Kris Mark G. , Van Allen Eliezer Mendel , Taylor Barry S. , Rizvi Hira , Donoghue Mark , Awad Mark M. , Hellmann Matthew David 
Published: May 2020

9549 Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting < 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p < 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p < 0.001). Patients with LTR were younger ( < 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p < 0.001, p < 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p < 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p < 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response.
Final analysis of KEYNOTE-189: Pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).
Authors: Rodriguez-Abreu Delvys , Powell Steven Francis , Hochmair Maximilian , Gadgeel Shirish M. , Esteban Emilio , Felip Enriqueta , Speranza Giovanna , Dómine Gomez Manuel , Cheng Susanna Y. , Bischoff Helge , Peled Nir , Reck Martin , Hui Rina , Garon Edward B. , Boyer Michael J. , Kurata Takayasu , Yang Jing , Bas Tuba , Souza Fabricio G. , Garassino Marina Chiara 
Published: May 2020

9582 Background: The phase III KEYNOTE-189 study (NCT02578680), showed significant improvements in OS and PFS with pembro + chemo vs placebo + chemo in pts with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK mutations. We report the protocol-specified final analysis of KEYNOTE-189. Methods: Pts were randomized 2:1 to receive 35 cycles of pembro 200 mg Q3W (n = 410) or placebo Q3W (n = 206) plus 4 cycles of pemetrexed (pem) and carboplatin/cisplatin followed by maintenance pem. Pts in the placebo + chemo arm could crossover to pembro upon PD. PFS and OS were primary endpoints; ORR was a secondary endpoint. PFS2 (time from randomization to objective tumor progression on next-line treatment/death), was an exploratory endpoint. Results: At data cutoff (May 20, 2019), median (range) time from randomization to data cutoff was 31.0 (26.5–38.8) mo. 17 pts in the pembro + chemo arm and 1 pt in the placebo + chemo arm were receiving initially assigned treatment; 84 pts crossed over to pembro. Median (95% CI) OS (22.0 [19.5–24.5] vs 10.6 [8.7–13.6] mo; HR 0.56 [95% CI, 0.46–0.69]) and PFS (9.0 [8.1–10.4] vs 4.9 [4.7–5.5] mo; HR 0.49 [95% CI, 0.41–0.59]) were longer with pembro + chemo vs placebo + chemo (Table). The 2-y OS rate was 45.7% vs 27.3% and the 2-y PFS rate was 22.0% vs 3.4%. ORR was 48.3% with pembro + chemo vs 19.9% with placebo + chemo. 56 pts in the pembro + chemo arm completed 35 cycles of pembro among whom ORR was 85.7% (4 CR, 44 PR, 8 SD) and median OS was not reached. 292 (72.1%) pts in the pembro + chemo arm and 135 (66.8%) pts in the placebo + chemo arm had grade 3–5 AEs. Conclusions: Pembro + chemo continued to show improved outcomes in OS, PFS, ORR and PFS2 compared with placebo + chemo, with manageable toxicity. These findings support first-line pembro + chemo in pts with previously untreated metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680 . [Table: see text]
High-dose osimertinib for CNS progression in EGFR+ non-small cell lung cancer (NSCLC): A multi-institutional experience.
Authors: Piper-Vallillo Andrew , Rotow Julia K , Aredo Jacqueline V , Shaverdashvili Khvaramza , Luo Jia , Carlisle Jennifer W , Husain Hatim , Muzikansky Alona , Heist Rebecca Suk , Rangachari Deepa , Ramalingam Suresh S. , Wakelee Heather A. , Yu Helena Alexandra , Sequist Lecia V. , Bauml Joshua , Neal Joel W. , Piotrowska Zofia 
Published: May 2020

9586 Background: High-dose osimertinib 160 mg QD (osi160) has activity in osi-naïve, EGFR+ NSCLC pts with CNS or leptomeningeal disease (LMD) per the BLOOM trial, but the role of dose-escalation for CNS progression (PD) and/or LMD that develops while on 80 mg QD (osi80) is unclear. We describe here our multi-institutional experience with osi160. Methods: 105 pts from 8 institutions with advanced EGFR+ NSCLC treated with osi160 were retrospectively reviewed. To assess the CNS efficacy of dose escalation for CNS PD, we focused on pts who escalated from osi80 to osi160 for CNS PD without the addition of chemo and/or RT during dose escalation (cohort A, 24 pts). We also examined osi escalation for CNS PD while receiving chemo and/or RT (cohort B, 34 pts) and those who started on osi160 for CNS PD as the initial osi dose without overlapping therapies (cohort C, 11 pts). Radiographic responses were clinically assessed via chart review of scan reports. Kaplan-Meier analysis was used for time-to-event endpoints. We defined median duration of CNS disease control (MedDurCNSCon) on osi160 as time from the start of osi160 to CNS PD or discontinuation of osi160. Results: Among the 105 pts, 69 (26M, 43F; median age 57) EGFR+ NSCLC pts (29 del19, 31 L858R, 9 other) received osi160 for CNS PD between 10/2013 and 1/2020. Median lines of therapy pre-osi was 1 (range 0-8). While all 69 pts had CNS PD at the start of osi160, 61 (90%) had isolated CNS/LMD PD, without systemic PD. In cohort A, osi160 monotherapy had a MedDurCNSCon of 3.8 mos (95% CI, 1.7 – 5.8). Cohort A pts with isolated LMD (11) had MedDurCNSCon 5.8 mos (95% CI, 1.7 – 9) while those with parenchymal mets only (11) had MedDurCNSCon of 2 mos (95% CI, 1 - 4.9). In cohort B, osi160 in combination with RT (22) and/or chemo (14), had a MedDurCNSCon of 5.1 mos (95% CI, 3.1 – 6.5). In cohort C, osi160 monotherapy had a MedDurCNSCon of 4.2 mos (95% CI, 1.6 – NA). Pts on osi160 had no severe or life-threatening side effects. Conclusions: In this real-world cohort of EGFR+ NSCLC pts with CNS and/or LMD PD on osi80, dose escalation to 160 provided modest benefit with median 3.8 mos added CNS disease control. Dose escalation appeared more effective in pts with LMD versus parenchymal disease (MedDurCNSCon of 5.8 vs 2 mos). Treatment intensification with osi escalation plus RT and/or chemo appeared to confer about 1 month additional CNS disease control (power for comparison limited). Osi naïve pts started at 160 for CNS PD derived similar benefit. While limited by small numbers and retrospective design, this study suggests we need improved strategies to optimally manage CNS PD arising on osi80.