bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concordance of next-generation sequencing between tissue and liquid biopsies in non-small cell lung cancer.
Authors: Basher Fahmin , Saravia Diana , Fanfan Dino , Cotta Jared Addison , Lopes Gilberto 
Published: May 2020

e21547 Background: While genetic profiling has become standard of care for patients diagnosed with non-small cell lung cancer (NSCLC), next-generation sequencing (NGS) provides a wealth of information about targetable mutations. Advances in genetic testing have led to sequencing platforms that utilize tissue itself or extracellular circulating tumor DNA in the blood, known as a “liquid biopsy.” Methods: We identified 55 patients with NSCLC who had undergone both tissue and liquid biopsy, using Foundation One and Guardant 360 at the University of Miami / Sylvester Comprehensive Cancer Center between January 2016 and December 2018, and performed retrospective analysis to determine patient characteristics as well concordance between different NGS platforms. Results: In our patient population, 34% of patients had never smoked prior to diagnosis, while 22% had more than a 30 pack-year smoking history. 64% of patients had no treatment prior to initial NGS. 40% of patients had both testing done essentially simultaneously, while 60% of patients had one test done after disease progression. Of these patients, therapy was changed as a result in 73%. Median number of days between tests was 21 days, with 56% of testing done within 90 days of the previous testing. Nine patients had an additional Foundation One tissue NGS performed. Concordance across all genes tested in both platforms was 98 ± 0.2%. Concordance with consideration of genetic alterations detected in both assays was 24.5 ± 3.0%. The median number of gene alterations determined by Foundation One testing was 4 (range 1-9), while the median for gene alterations detected by Guardant 360 was 3 (range 1-13). The median number of variants of unknown significance (VUS) was 10 (range 5-25). Conclusions: Our analysis indicates a role for both tissue-based and circulating tumor DNA-based NGS for determination of targetable mutations and thus appropriate treatment regimens. Low levels of concordance are potentially related to post-treatment changes in the tumor genetic profile as well as evolution in the testing itself.
Tumor growth rate (TGR) as an early predictor of outcomes in advanced non-small cell lung cancer treated with PD-1 axis inhibitor.
Authors: He Li-na , Zhang Xuanye , Li Haifeng , Chen Tao , Zhang Li , Hong Shaodong 
Published: May 2020

e21560 Background: Tumor growth rate (TGR) signifies percentage change in tumor size per month (%/m). We investigated the association of TGR with outcomes in patients with advanced non-small cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy. Methods: We retrospectively reviewed 172 aNSCLC patients treated with anti-PD-1/PD-L1 monotherapy in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. Computed tomography images were reviewed to calculate TGR before treatment (“TGR0”) and upon early treatment (from treatment initiation to the first evaluation; “TGR1”). X-tile software was used to determine cut-off values that maximumly differentiate overall survival (OS). Log-rank tests and Cox regression models were performed for survival analysis. Results: 73 patients with paired TGR0 and TGR1 were included in the testing cohort. The optimal cut-off values of TGR0 and TGR1 were 46.6 %/m and 10.9 %/m, respectively. Patients with higher TGR1 significantly experienced inferior OS versus those with lower TGR1 (HR 2.74, 95% CI 1.34-5.61, P = 0.006). Patients with higher TGR0 tended to have poorer OS, though not statistically significant (HR 1.79, 95% CI 0.84-3.79, P = 0.131). In multivariate analyses, TGR1 remained an independent predictor of OS (HR 2.33, 95% CI 1.12-4.83, P = 0.024). In an external validation cohort (n = 69) enrolling patients with available TGR1 but lacking TGR0 data, TGR1 was also significantly associated with OS (HR 2.73, 95% CI 1.33-5.60, P = 0.006). Conclusions: Higher TGR1 was correlated with inferior outcomes in aNSCLC patients who received anti-PD-1/PD-L1 monotherapy. Larger prospective studies are warranted to identify its added value to RECIST as an early radiological biomarker to predict long-term survival of patients undergoing immunotherapy. [Table: see text]
Evaluation of immune-related adverse events in patients treated with sequential immunotherapy and tyrosine kinase inhibitor treatment in non-small cell lung cancer.
Authors: Baroz Angel Ray , Mambetsariev Isa , Fricke Jeremy , Pharaon Rebecca , Zhao Dan , Koczywas Marianna , Massarelli Erminia , Salgia Ravi 
Published: May 2020

e21562 Background: Immune-related adverse events (irAEs) have been frequently observed with non-small cell lung cancer (NSCLC) patients treated with immunotherapy (IO). The severity of irAEs in response to IO treatment may reflect antitumor response. The effect of irAEs with sequential IO and tyrosine kinase inhibitor therapies has not been fully characterized. This study aims to evaluate the irAEs in NSCLC patients who have received sequential IO and TKI treatment. Methods: A retrospective cohort of 387 NSCLC patients previously treated with IO was identified from the City of Hope Thoracic Registry (THOR) from February 2010 to January 2020. Patients had confirmed pathologic disease and received IO and TKI, either on clinical trial or as standard of care. IO-treated patients were classified into two groups: TKI vs non-TKI treated. The non-TKI IO-treated group was used to verify that outcomes are not dependent on the immunotherapy given, but rather TKI therapy. IrAEs were collected from treatment courses and assessed based on the treating physician diagnosis. Results: A total of 63 NSCLC patients received sequential IO and TKI treatment. Histology was nonsquamous in 59 (93.7%) and squamous in 4 (6.3%). Multiple lines of therapies were accounted for in each patient. IO therapies received included nivolumab (n = 30), pembrolizumab (n = 24) and atezolizumab (n = 11). Mostly frequently used TKI therapies were erlotinib (n = 43), osimertinib (n = 25), afatinib (n = 11), crizotinib (n = 10), gefitinib (n = 5), and alectinib (n = 4). IrAEs occurred in 23 patients (36.5%). 22/23 (95.7%) patients who reported irAEs received TKI treatment prior to receiving IO treatment. The most common irAEs were pneumonitis (n = 5), diarrhea (n = 4), fatigue (n = 3) and rash/pruritus (n = 3). Other irAEs included arthralgias & myalgias (n = 2), new onset diabetes (n = 1) and renal insufficiency (n = 1). Conclusions: The severity of irAEs and sequential IO and TKI treatment in NSCLC patients is still not well-defined. Overall and progression-free survival were considered in this cohort. Preliminary data suggested that EGFR-TKI treated patients have low response to immune checkpoint inhibitors, but outcomes vary by allele variation. Further prospective analyses are needed to investigate the correlation of irAEs and survival outcomes with TKI-resistant NSCLC patients treated with IO. Also, treating physician’s diagnosis of irAEs exposed a need to clarify grade and severity of irAEs.
Can polymetastatic disease be arrested using SABR? A dosimetric analysis to inform development of a phase I trial.
Authors: Corkum Mark Thomas , Fakir Hatim , Palma David A. , Nguyen Timothy K. , Bauman Glenn 
Published: May 2020

e21567 Background: Phase II randomized trials suggest that stereotactic ablative radiotherapy (SABR) improves progression-free and overall survival in patients with oligometastatic cancer, with phase III trials currently testing SABR in up to 10 metastases. Whether SABR could provide similar benefits in polymetastatic disease ( > 10 metastases) is unknown. A critical first step is to determine the feasibility of planning SABR for a large number of metastases throughout the body while maintaining acceptable organ at risk (OAR) doses. Therefore, we sought to evaluate the dosimetric feasibility of using SABR in polymetastatic disease ( > 10 sites) while adhering to OAR constraints to be used in a phase I trial (ARREST). Methods: Five craniospinal CT simulations were utilized to retrospectively contour 24 (n = 2), 30 (n = 2) and 50 (n = 1) tumour targets not present on the initial scan. Standard PTV margins were added based on institutional immobilization practices. OAR constraints from published clinical trial protocols were used. Radiotherapy plans for the highest dose level in our planned phase I trial (30Gy in 5 fractions) were created utilizing a minimum number of isocentres. Plans were created using Raystation (RaySearch Laboratories, Stockholm, Sweden) for delivery on linear accelerators using volumetric modulated arc therapy. Results: The gross tumour volumes (GTVs) ranged from 134.8– 184.2cm3 in our five test cases. The first two cases with 24 GTVs have been planned and were deemed to be clinically acceptable. PTV volumes were 483.0cm3 and 417.4cm3, utilizing five and six isocentres for treatment respectively. Median PTV D95 was 29.7Gy and 29.0Gy, whole body V10 was 21.2% and 17.4%, and V5 was 41.8% and 44.8%. All OAR goals were met, though low-dose conformality was less than traditional SABR treatment plans (R100 of 1.04 and 0.93; R50 of 9.90 and 6.98, respectively). The remainder of the test cases will be presented. Conclusions: In our test cases, planning SABR in polymetastatic disease appears dosimetrically feasible. Our phase I clinical trial (ARREST) is under development, which will evaluate the feasibility and toxicity of delivering SABR in polymetastatic disease in a 3+3 dose escalation study. The starting dose level will be 12Gy in 2 weekly fractions, escalating the dose by adding 6Gy weekly until our target dose of 30Gy in 5 weekly fractions. Our study population will include > 10 sites of disease, all tumour types, and patients must have exhausted standard lines of systemic therapy.
A meta-analysis comparing therapeutic outcomes for anti-EGFR monotherapy to targeted therapy combinations for non-small cell lung cancer.
Authors: Kurup Sonali , Ding Qian , Amissah Felix , Assaad Kaitlin , Chandrasekhara Soniya 
Published: May 2020

e21570 Background: Small molecule inhibitors of epidermal growth factor receptor kinase (EGFR) are approved for EGFR-positive non-small cell lung cancer (NSCLC). Targeted therapies include agents that block tumor-specific molecular targets and thereby interfere with tumor growth and metastasis. This study focuses on a meta-analysis of therapeutic outcomes from phase II and III clinical trials for anti-EGFR monotherapy compared to anti-EGFR therapy in combination with targeted agents. Methods: A literature search was conducted using EMBASE, Pubmed, Scifinder Scholar, clinicaltrials.gov and the Cochrane library for the following terms: “epidermal growth factor receptor kinase”, “combination therapy”, “non-small cell lung cancer”. Eligible studies included patients of advanced stage IV NSCLC and any mutation status that met the predefined inclusion criteria. Data was extracted on trial demographics and therapeutic outcomes including progression-free survival (PFS), survival post progression (SPP), overall survival (OS) and adverse events (AE). Sub-group analysis based on patient mutation status of wild-type (wt) EGFR, mutant EGFR, wt KRAS and mutant KRAS and a correlation analysis between OS, PFS and SPP was conducted. Results: A total of 34 studies were identified that fit the inclusion criteria from 2009-2019. The pooled OS hazard ratio (HR) was 0.94 (95% Confidence Interval (CI): 0.87-1.01); the pooled PFS HR was 0.8 (95% CI: 0.74-0.87). Median OS correlated more closely with median SPP (r2 = 0.97 for monotherapy; r2 = 0.88 for combination therapy) than to median PFS (r2 = 0.90 for monotherapy; r2 = 0.82 for combination therapy), although the linear association between log-HR OS and log-HR PFS had a positive slope (β = 0.31± 0.19). A greater incidence of rash and diarrhea was observed in the combination arm compared to monotherapy. A significant improvement was observed for PFS in wt EGFR patients for combination therapy, pooled PFS HR 0.8 (95% CI: 0.67-0.95). Conclusions: A statistically significant improvement in PFS was observed for anti-EGFR combination regimens compared to anti-EGFR monotherapy. The improvement in OS was not statistically significant for anti-EGFR combination regimens compared to monotherapy.
Phase II trial of clinical activity and safety of ceritinib combined with stereotactic ablative radiotherapy (SABR) in lung adenocarcinoma patients.
Authors: Khan Saad A. , Gerber David E. , Zhu Hong , Hughes Randall S. , Mannala Samantha , Rashdan Sawsan , Dowell Jonathan , Westover Kenneth D. , Saltarski Jessica , Harrah Kasia , Priddy Laurin , Choy Hak , Timmerman Robert D. , Brekken Rolf A. , Sorrelle Noah , Iyengar Puneeth 
Published: May 2020

e21571 Background: ALK -targeting drugs and SABR are combined in patients with metastatic cancer, anecdotally yielding clinical benefit. However, the precise impact of the combination and the optimal time to introduce SABR remain unknown. Methods: This completed phase 2 study (NCT02513667) had a primary objective of doubling progression free survival (PFS) for ALK+ lung adenocarcinoma patients by consolidating all remaining disease with SABR, 8-10 weeks after ceritinib initiation. Patients who then progressed could receive repeat SABR as long as they then resumed ceritinib. Patients were divided into ALK-inhibitor naïve vs previously treated cohorts. Oligometastatic disease was NOT a requirement for study entry, CNS disease was permitted. Blood was serially analyzed for variation in 1. blood cfDNA detection of resistance mechanisms 2. flow cytometric analysis of white cell populations. Results: 14 patients were enrolled out of a planned 33; 7 female; 3 hispanic/latino; median age was 53 years (range 31-78); 5 patients had previously received crizotinib. 4 patients stopped ceritinib within 30 days due to toxicity, despite dose reductions or with-food administration. However, all patients still completed initial SABR consistent with protocol time-points. Patients predominantly had thoracic disease irradiated (11/14, 78%). Two patients had only brain metastases treated and 1 had bone only metastases treated. 4 had one fraction SBRT regimens (16-24 Gy per fraction) delivered to disease, 3 had three fraction SBRT regimens (9-11 Gy per fraction) delivered to disease, and 7 had five fraction SBRT or 15 fraction hypofractionated regimens (6 Gy per fraction or 3Gy per fraction, respectively) delivered to disease. Disease control in all irradiated areas was 100%. There was no significant grade 3 or higher toxicity associated with radiation. Broad variability in baseline and serial levels of circulating PMN-MDSC, VEGFR2, FoxP3+, CD56+CD16+ and various T-cell populations showed no clinical correlation. The trial terminated early due to increased use of alternative targeted therapies, thus the primary endpoint was not met. 8 patients had CR/PR/SD as best response. Including those who did not tolerate ceritinib, median PFS was 12 months, max of 31 months with 1 ongoing response. Conclusions: Consolidative SABR after ALK therapy is well tolerated, can be repeated and may prolong PFS compared to drug alone. Ceritinib toxicity meant higher rates of discontinuation but this did not prevent consolidative SABR in any patient. Clinical trial information: NCT02513667.
Concordance of provider treatment patterns with NCCN oncology treatment guidelines (NCCN Guidelines) for metastatic non-small cell lung cancer (mNSCLC).
Authors: Seal Brian S. , Mooradian Meghan , Yong Candice , Schroeder Amy L , Macher Dana , Bekele Biruk , Petrilla Allison 
Published: May 2020

e21574 Background: mNSCLC clinical treatment guidelines are rapidly evolving, however, their influence on prescriber use of anti-cancer treatment regimens is not known. This retrospective study evaluated whether US patients with mNSCLC received first line (1LOT), second (2LOT), or third (3LOT) line treatment regimens that were concordant with NCCN Category 1-2A recommendations. Methods: mNSCLC patients who initiated treatment between 2014-2017 were identified using medical and pharmacy claims from the 100% Medicare Fee-for-Service (FFS) Part A/B/D sample and multi-payer Inovalon MORE2 Registry. Claims-based algorithms identified mNSCLC and LOT following diagnosis; patients with other primary cancers or < 6 months follow-up were excluded. Treatment regimens were compared to active NCCN Guidelines at time of treatment to determine if regimen was concordant with Category 1-2A recommendations. Genetic mutation/biomarker status was not available. Results: 6,523 patients with mNSCLC met criteria for analysis (FFS/Medicare Advantage:78.6%; commercial:14.0%, managed Medicaid:7.4%; mean age:69.3 [SD:9.2]). For 1LOT, 81% received platinum-based doublet regimens; most common monotherapy included erlotinib, nivolumab, and pembrolizumab; 18% of 1LOT patients received maintenance therapy. For 2LOT, approximately one-third received nivolumab monotherapy, one-third received platinum-based doublets, and remainder received other regimens. Most common 3LOT included monotherapy nivolumab, pemetrexed, paclitaxel, and docetaxel. NCCN Guidelines concordance varied: 1LOT (90.5%), 2LOT (58.5%), 3LOT (71.9%). Non-concordant regimens included nivolumab as 1LOT and early adoption of platinum agent+(pemetrexed or paclitaxel) in 2LOT, and chemotherapy as 2LOT in anaplastic lymphoma kinase rearrangement-positive or epidermal growth factor receptor mutation-positive disease. Conclusions: In Medicare and non-Medicare patients with mNSCLC, 1LOT closely followed NCCN Guidelines. Most variability was observed in 2LOT where 58.5% regimens were concordant with Category 1-2A recommendations. Non-concordance may be driven by lack of effective second-line regimens and early adoption of innovative therapies.
Genomic correlates and classification of PD-L1 status in non-small cell lung cancer.
Authors: Liang Feng , Liu Sisi , Jiang Ya , Xu Xiuxiu , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Hu Xingsheng 
Published: May 2020

e21578 Background: Programmed cell death 1 (PD-L1) is the first FDA-approved predictive biomarker for non-small cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. Herein, we aim to identify potential anti-PD-L1 treatment-related biomarkers through evaluating the correlation between the PD-L1 expression level, clinical characteristics, and the mutational profile of a large Chinese NSCLC cohort. Methods: Genomic profiling of tumor biopsies from a total of 808 Chinese NSCLC patients, including 651 adenocarcinomas (ADCs) and 157 squamous cell carcinomas (SCCs), was performed using next-generation sequencing by targeting 425 cancer-relevant genes. Immunohistochemical analysis was used to evaluate PD-L1 protein expression using PD-L1 antibodies including DAKO 22C3 ( N= 695) and DAKO 28-8 ( N= 113), respectively. Results: The PD-L1 positive ( > 1%) rate was 49.2% in ADCs and 52.9% in SCCs, respectively. PD-L1 expression (22C3) was associated with the male gender( p< 0.01) and lymph node metastasis ( p= 0.048) in ADCs but not in SCC patients. PD-L1 expression (22C3) was inversely correlated with KRAS wildtype ( p< 0.001) and EGFR exon 19 deletion( p< 0.01) in ADC, while it was negatively associated with TP53 oncogenic mutations ( p= 0.049) in SCC. Copy number variation analysis revealed that MDM2 amplification ( p= 0.027), 1q gain ( p= 0.012), and 5q deletion ( p< 0.01) negatively correlated with PD-L1 expression, whereas PD-L1 and PD-L2 amplification ( p< 0.001 and p< 0.0001) were positively associated with PD-L1 expression in ADCs. In SCCs, PD-L1 expression (22C3) was negatively associated with copy number gain in EGFR ( p= 0.040), MDM2 ( p= 0.044), 14q ( p= 0.032), and 20q ( p= 0.026), along with PTPRD loss (p = 0.015) and 19p deletion (p = 0.025). However, it was positively associated with 9p amplification ( p< 0.01) and 13q deletion ( p= 0.019). Plus, KIF5B- RET ( p= 0.006) appeared to be inversely related to the PD-L1 expression levels (22C3) in ADCs alone. In addition, these predicted biomarkers were used to delineate the receiver operating characteristic (ROC) calculation to discriminate between PD-L1 low and high (22C3, 50%) with an AUC score of 0.779. Lastly, PD-L1 expression (28-8) did not show significant correlation with any detected oncogenic mutations, but negatively correlated with NKX2-1 gain ( p= 0.0379) and 9q deletion ( p= 0.0379) in ADCs. Conclusions: This study revealed the correlation between PD-L1 protein expression, clinical features, and mutational traits in NSCLC patients, and provided a classifier for PD-L1 expression prediction.
Comparison of outcomes with pembrolizumab monotherapy (P) versus combination with chemotherapy (P+C) in advanced non-small cell lung cancer (NSCLC).
Authors: Sehgal Kartik , Gill Ritu R. , Bindal Poorva , Koshy Anita Geevarghese , McDonald Danielle C , Rangachari Deepa , Costa Daniel Botelho 
Published: May 2020

e21579 Background: P and P+C are standard-of-care (SOC) treatment options for advanced NSCLC. However, they have not yet been directly compared in clinical trials. Methods: We conducted a retrospective cohort study of patients with advanced NSCLC who initiated treatment with SOC P±C 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. All radiographic scans were independently evaluated by a thoracic radiologist using iRECIST. Survival time was defined from the start of P±C. Kaplan-Meier and Cox proportional hazards model were utilized. Results: Of 103 patients with median follow up of 17.7 months, 74 (71.8%) had received P, while 29 (28.2%) had received P+C. In PD-L1 tumor proportion score (TPS) unselected population, there were no significant differences in age, sex, smoking status, driver mutation, tumor mutational burden (TMB), line of therapy, ECOG performance status (PS) or immune-related adverse events (irAE) between P and P+C groups. 71.6% in P vs 13.8% in P+C had PD-L1 TPS ≥50% (p < 0.001). There were no significant differences between the two groups in objective response rate (ORR), disease control rate (DCR), unadjusted progression-free survival (PFS) or unadjusted overall survival (OS) (Table). Multivariable adjustment for confounding factors between P+C vs P revealed no differences in OS [hazard ratio (HR) for death, 1.53, 95% CI 0.55 – 4.25] or PFS [HR for progression/death, 1.75, 95% CI 0.63 – 4.91]. Further stratification into PD-L1 TPS ≥50% and < 50% showed no significant differences between P+C vs. P in adjusted OS [HR for death, TPS < 50%- 1.54 (95% CI 0.59 – 4.03); TPS ≥50%- 0.71 (95% CI 0.11 – 4.52)] or PFS [HR for progression/death, TPS < 50%- 1.58 (95% CI 0.72 – 3.48); TPS ≥50%- 0.64 (95% CI 0.06 – 6.93)]. ECOG PS and development of irAE influenced OS in all groups, while TMB was relevant in PD-L1 ≥50% only. Conclusions: Our study shows no significant differences in outcomes with P vs P+C in advanced NSCLC in a real-world setting, albeit with limitations of single-center design, limited sample size, different line settings and lack of disease burden stratification. Ongoing phase III trials comparing front line P vs P+C will definitively address the long-term clinical benefits -if any- of combining cytotoxic chemotherapy with anti-PD-1 drugs. [Table: see text]